Compound capable of degrading epidermal growth factor receptor and application thereof

Abstract

The invention discloses a PROTAC compound capable of degrading an epidermal growth factor receptor and application of the PROTAC compound, the structural formula of the compound is shown in the formula (I), ring B represents a CRBN ligand, the ring B contains a benzene ring, a five-membered nitrogen-containing heterocyclic ring and a six-membered nitrogen-containing heterocyclic ring at the same time, and the benzene ring part in the ring B is connected with A; a represents a connecting fragment, and a main chain of A contains atoms except for 6-25 hydrogen atoms; r1 is selected from H, C1-8 alkyl, C1-8 alkenyl or a carbon chain containing a 4-8-membered heterocyclic ring on a main chain and a combination of the H, the C1-8 alkyl, the C1-8 alkenyl and the carbon chain; and R5 and R6 are independently selected from F, C1 or Br. The compound can efficiently and selectively degrade mutant EGFR and remarkably inhibit growth and proliferation of tumor cells, and is expected to be used for preparing drugs for treating EGFR-related diseases including cancers. # imgabs0 #

Description

A compound capable of degrading epidermal growth factor receptor and its use Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to a compound capable of degrading epidermal growth factor receptor and use thereof. Background Art

[0002] The epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase whose structure consists of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular kinase domain. Binding to epidermal growth factor (EGF) in the extracellular domain leads to EGFR dimerization and autophosphorylation and activation of the intracellular kinase domain. This subsequently leads to the phosphorylation and activation of a series of proteins in downstream signaling pathways, including MAPK, Akt, and JNK, thereby inducing cell proliferation.

[0003] EGFR is widely expressed in epithelial cells. Studies have found that overexpression, mutation, or gene amplification of EGFR leads to a variety of human malignancies, including esophageal cancer, glioblastoma, anal cancer, head and neck epithelial cancer, breast cancer, and lung cancer, especially non-small cell lung cancer (NSCLC). Constitutively activating mutations in the ATP-binding region of the EGFR kinase domain, such as Exon 19 deletion or L858R mutation, are considered to be driving factors for the development of non-small cell lung cancer. Lung cancer is one of the leading causes of death in cancer patients worldwide, with non-small cell lung cancer accounting for a large proportion of lung cancer. Therefore, EGFR is considered an important disease target, and a variety of targeted therapeutic drugs targeting EGFR have been developed, such as the first-generation EGFR kinase inhibitors gefitinib and erlotinib. Although the first generation of inhibitors has achieved good clinical efficacy, patients generally develop drug resistance mutations after about 9-14 months of medication, such as the T790M mutation of the gatekeeper residue in the kinase domain, which leads to loss of drug efficacy (see The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP, Yun, CH et al., Proc. Natl. Acad. Sci. USA 2008, 105, 2070-2075). Subsequently, second generation inhibitors such as Afatinib and Dacamitinib, and third generation inhibitors such as Osimertinib were developed one after another. By covalently binding to C797, the binding ability of the inhibitor to the kinase domain was improved, which can target the L858R / T790M double mutation. However, the second and third generation covalent inhibitors can also induce the occurrence of the drug resistance mutation C797S. Currently, the fourth generation inhibitors that bind to the allosteric regulatory pocket have been developed, such as EAI045, to deal with the L858R / T790M / C797S triple mutation. The continued emergence of drug-resistant mutations is a persistent problem faced by EGFR kinase inhibitor drugs.

[0004] Proteolysis targeting chimeras (PROTACs) are a class of bifunctional molecules typically composed of a target protein-binding fragment, an E3 enzyme-binding fragment, and an intermediate linker fragment. One end of the PROTAC molecule binds the target protein, while the other end binds the E3 enzyme, bringing the two together to form a stable target protein-PROTAC-E3 enzyme ternary complex. The spatial proximity of the E3 enzyme to the target protein triggers ubiquitination and degradation by the proteasome.

[0005] Currently, PROTAC has become an emerging trend in drug research and development. Unlike protein inhibitors or agonists, protein degraders are similar to catalysts and do not need to continuously occupy the functional pockets of proteins. Their mode of action has changed from "occupancy-driven" to "event-driven". PROTAC molecules targeting EGFR can not only inhibit the activity of the EGFR kinase domain by degrading the EGFR protein as a whole, but also reduce the function of other non-kinase regions, thereby regulating a variety of EGFR-driven diseases, especially the treatment of EGFR-driven malignancies. In addition, the protein degradation mechanism also has the potential to overcome persistent drug-resistant mutations caused by inhibitors.

[0006] CRBN is a type of E3 enzyme that can ubiquitinate a variety of proteins and is also the target of anti-tumor drugs such as thalidomide.

[0007] Chinese patent CN110372669A discloses a compound based on CRBN ligand-induced EGFR degradation However, its antitumor activity is not high enough.

[0008] Summary of the Invention

[0009] The technical problem to be solved by the present invention is to address the shortcomings and deficiencies of the existing technology and provide a compound that can efficiently and selectively degrade mutant EGFR and significantly inhibit the growth and proliferation of tumor cells, which is expected to be used to prepare compounds for the treatment of EGFR-related diseases including cancer.

[0010] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0011] A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0012] Wherein: Ring B represents a CRBN ligand, and Ring B contains a benzene ring, a five-membered nitrogen-containing heterocycle, and a six-membered nitrogen-containing heterocycle, and the benzene ring portion of Ring B is connected to A;

[0013] A represents a connecting fragment, and the main chain of A contains 6-25 atoms other than hydrogen atoms;

[0014] R1 is selected from H, C1-8 alkyl, C1-8 alkenyl, or a carbon chain containing a 4-8 membered heterocycle on the main chain, and combinations thereof;

[0015] R5, R6 are independently selected from F, Cl or Br.

[0016] In the present invention, "the benzene ring portion of ring B is connected to A" means that the benzene ring in ring B is directly connected to A, or that a substituent on the benzene ring in ring B is connected to A. In the present invention, the main chain of A may include a carbon chain portion, a non-carbon chain portion such as a portion containing a heteroatom, a carbon ring portion, or a heterocyclic portion. The carbon chain portion may be a straight chain portion without a side chain or a carbon chain portion with a side chain. The main chain of A only needs to contain atoms other than 6-25 hydrogen atoms, and such atoms may be carbon atoms or other atoms. The specific structure of A is not particularly limited.

[0017] The linker fragments of the prior art PROTAC molecules targeting EGFR are usually set at the -OR1 position, but the activity of these molecules in degrading EGFR is not sufficient. The present invention can significantly improve the activity of the PROTAC molecule by placing a specific linker fragment A at a specific position in the structure of formula (I).

[0018] In some embodiments, the ring B is selected from the following structures:

[0019] Wherein: R2 and R3 are each independently selected from halogen, cyano, C1-8 alkyl and C1-8 alkoxy;

[0020] m is an integer of 0-3; n is an integer of 0-2; l is an integer of 0-3.

[0021] In some embodiments, the ring B is R2 is halogen, and m is 0 or 1.

[0022] In some embodiments, R2 and R3 are both halogen.

[0023] In some embodiments, R2 and R3 are both F.

[0024] In some embodiments, m, n, and l are all 1.

[0025] In some embodiments, the A is linear.

[0026] In some embodiments, the linear A contains 1-8 heteroatoms, and the heteroatoms are selected from O or N.

[0027] In some embodiments, the A comprises 1-2 4-8 membered cycloalkylene groups or 1-2 4-8 membered heterocycloalkylene groups on the main chain.

[0028] In some embodiments, the 4-8 membered heterocycloalkylene group contains 1-2 heteroatoms, and the heteroatom is N.

[0029] In some embodiments, the A comprises 1-2 six-membered heterocycloalkylene groups in the main chain, and the six-membered heterocycloalkylene group contains 1-2 N atoms.

[0030] In some embodiments, the A includes 1-2 4-8 membered heterocycloalkylene groups on the main chain, and the A further includes a carbonyl group on the main chain, and the carbonyl group is connected to a heteroatom in the 4-8 membered heterocycloalkylene group.

[0031] In some embodiments, the 4-8 membered heterocyclic ring in R1 contains 1-2 heteroatoms, and the heteroatoms are selected from O, S or N.

[0032] In some embodiments, the A is selected from the following structures: -O(CH2) x -O-, wherein x is an integer of 4-12, y is an integer of 6-12, z is an integer of 2-5, p is an integer of 1-5, and q is an integer of 2-4.

[0033] In some embodiments, A is selected from the following structures: wherein y is an integer of 7-10, z is independently an integer of 2-5, p is an integer of 1-5, and q is independently an integer of 2-4. In some embodiments, R1 is selected from a C1-8 straight or branched alkyl group or Wherein R7 is a C1-6 alkylene group.

[0034] In some embodiments, the R1 is selected from methyl or Wherein R7 is a C2-4 alkylene group.

[0035] In some embodiments, the R1 is selected from methyl or Wherein R7 is -CH2CH2CH2.

[0036] In some embodiments, R5 is F and R6 is Cl.

[0037] In some embodiments, the compound is selected from the compounds shown in the following structures:

[0038] The present invention further relates to the use of a compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof as a proteolytic targeting chimera PROTAC for epidermal growth factor receptor (EGFR). The present invention further relates to the use of a compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof for preparing a drug for treating tumors.

[0039] In some embodiments, the tumor is selected from one or more combinations of esophageal cancer, gastric cancer, glioblastoma, anal cancer, head and neck epithelial cancer, head and neck squamous cell carcinoma, breast cancer, lung cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, brain metastasis, solid tumor, oropharyngeal cancer, bronchial tumor and skin cancer. Preferably, the tumor is lung cancer. More preferably, the lung cancer is non-small cell lung cancer.

[0040] The present invention further relates to a method for treating a disease responsive to degradation of EGFR mutant protein, which comprises administering an effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof to an animal or human in need of treatment.

[0041] Furthermore, the disease responsive to degradation of EGFR mutant protein is selected from one or more combinations of esophageal cancer, gastric cancer, glioblastoma, anal cancer, head and neck epithelial cancer, head and neck squamous cell carcinoma, breast cancer, lung cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, brain metastasis, solid tumor, oropharyngeal cancer, bronchial tumor and skin cancer. Further, the disease responsive to degradation of EGFR mutant protein is lung cancer; preferably non-small cell lung cancer.

[0042] The present invention also provides several synthetic routes for the compound having the structure shown in the above formula (I).

[0043] The first synthetic route is as follows, involving the synthesis of compounds 1-3, 5, 7-8:

[0044] The definitions of n, R, and X are as follows:

[0045] The second synthetic route is as follows, involving the synthesis of compound 4:

[0046] The third synthetic route is as follows, involving the synthesis of compound 6:

[0047] The fourth synthetic route is as follows, which involves the synthesis of compound 9:

[0048] The fifth synthetic route is as follows, which involves the synthesis of compounds 10-14:

[0049] The definitions of m, n, and R are as follows:

[0050] The sixth synthetic route is as follows, involving compounds 15, 27, 31, 43, and 50:

[0051] Wherein, n, R1, and R2 are defined as follows:

[0052] The seventh compound route is as follows, involving compounds 17, 29, 33, and 45;

[0053] The definitions of R1 and R2 are as follows:

[0054] The eighth compound route is as follows, involving compound 36;

[0055] The ninth compound route is as follows, involving compound 46;

[0056] The tenth compound route is as follows, involving compound 34;

[0057] The eleventh compound route is as follows, involving compounds 47-49;

[0058] Due to the implementation of the above technical solution, the present invention has the following advantages compared with the prior art:

[0059] The present invention sets the connecting fragment A in the middle of PROTAC at a specific substitution position of the molecular fragment that binds to the target protein. At the same time, through design, development and verification, it is found that the PROTAC molecule with the connecting fragment A in the middle of a specific position and specific structure can degrade the EGFR protein as a whole, and the degradation activity is high. At the same time, it can inhibit the activity of the EGFR kinase region and reduce the function of other non-kinase regions, which can be used to treat EGFR-driven malignant tumors. This protein degradation mechanism also has the potential to overcome the persistent drug-resistant mutations brought by inhibitors. At the same time, the PROTAC molecule of the present invention has high inhibitory activity on tumor cells and can selectively degrade Exon 19 deletion and L858R mutant EGFR. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 is the protein immunoblotting results of the compounds of the present invention and the control compounds; Figure 2 is the protein immunoblotting results of some compounds of the present invention; Figure 3 is the protein immunoblotting results of some compounds of the present invention; Figure 4 is the results of EGFR protein immunoblotting experiments on some compounds of the present invention in various cells; Figure 5 is the results of cell viability experiments on some compounds of the present invention and the control compounds; Figure 6 is the results of cell clone formation experiments on compound 14 of the present invention; Figure 7 is the protein immunoblotting results of compound 3 of the present invention. DETAILED DESCRIPTION

[0061] Definition of terms

[0062] In the compounds described herein, when any variable (e.g., R1, R2, etc.) occurs more than once in any component, its definition at each occurrence is independent of the definition at every other occurrence. Similarly, combinations of substituents and variables are permitted so long as such combinations result in a stable compound. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide chemically stable compounds that can be readily synthesized from readily available raw materials using techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it will be appreciated that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable.

[0063] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0064] The term "salt" refers to a pharmaceutically acceptable salt formed between the compound of the present invention and an acid, wherein the acid can be an organic acid or an inorganic acid, and can be specifically selected from phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, or the like.

[0065] The term "halogen" refers to fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine, and bromine.

[0066] In addition to standard methods known in the literature or exemplified in the experimental procedures, the following synthetic schemes can be used to prepare the compounds of the present invention.

[0067] The following synthetic schemes can provide a better understanding of the compounds and synthetic methods described in the present invention. The synthetic schemes described herein describe methods that can be used to prepare the compounds described in the present invention. The described synthetic schemes are merely illustrative schemes for illustrative purposes and do not constitute a limitation on the scope of the present invention.

[0068] The present invention is further described below with reference to examples, but the examples are not intended to limit the scope of protection of the present invention.

[0069] The technical features of the embodiments described below can be combined arbitrarily. To make the description concise, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0070] The following examples merely illustrate several embodiments of the present invention. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

[0071] The present invention will be further described below with reference to specific embodiments:

[0072] Example 1: Synthesis of Compound 1

[0073] a. Combine 2-(2,6-dioxypyridin-3-yl)-5-hydroxyisoindole-1,3-dione (1 g, 3.6 mmol), 1,8-dibromopentane (1.5 g, 5.5 mmol), and 0.8 g of NaCO in DMF (10 mL). Heat the mixture at 75°C for 5 hours. Then, add 20 mL of water, extract with DCM (20 mL x 3), and wash with brine (10 mL). Purify by chromatography to yield 650 mg of a solid.

[0074] Liquid chromatography mass spectrometry (LC_MS): (ES+): m / z 423.12 [M+H] +.t R =3.211min. Molecular formula: C 21 H 25BrN2O5; molecular weight: 423.26.

[0075] b. 5-[(5-bromopentyl)oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (0.2 g, 0.43 mmol), O-desmethyl gefitinib (0.19 g, 0.43 mmol), and Na2CO3 (0.09 g, 0.86 mmol) were dissolved in DMF (3 mL) and heated at 75°C for 2 hours. The reaction mixture was poured into 30 mL of water, extracted with DCM (20 mL x 3), and washed with water (10 mL). Purification by chromatography yielded 52 mg of a solid.

[0076] Liquid chromatography mass spectrometry (LC_MS): (ES+): m / z 775.20 [M+H]+, t R =2.715min. Molecular formula: C 39 H 40 ClFN6O8; molecular weight: 775.23.

[0077] 1 H NMR(400MHz, DMSO-d6)9.58(s,1H),8.49(s,1H),8.14(dd,J=6.9,2.6Hz,1H),7.87–7.76 (m,2H),7.50–7.41(m,1H),7.35(dd,J=8.3,2.3Hz,1H),7.21(s,1H),5.12(dd,J=12.9,5. 3 Hz, 1H), 4.20 (dt, J = 11.9, 6.2 Hz, 4H), 3.56 (s, 2H), 2.62–2.53 (m, 1H), 2.38 (s, 2H), 2.09–1.97 (m, 1H), 1.90 (q, J = 7.1 Hz, 3H), 1.67 (q, J = 7.1, 6.3 Hz, 1H), 1.24 (d, J = 8.6 Hz, 1H). The total number of hydrogen atoms calculated from the H NMR data was 40.

[0078] Example 2: Synthesis of Compound 2

[0079] a. Mix 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole dione (1g, 3.6mmol), 1,8-dibromooctane (1.5g, 5.5mmol), and 0.8g Na2CO3 in DMF (10mL) and heat the reaction at 75°C for 5 hours. The reaction mixture was poured into 100ml of water, then extracted with DCM (20ml x3) and washed with water (10ml). Purified by chromatography to obtain 550mg of solid. Liquid phase mass spectrum (LC_MS): (ES+): m / z 465.12[M+H]+, t R =3.111min. Molecular formula: C 21 H 25 BrN2O5; molecular weight: 465.34.

[0080] b. 5-[(8-bromooctyl)oxy]-2-[2,6-dioxopiperidin-3-yl]isoindole-1,3-dione (0.2 g, 0.43 mmol), O-desmethyl gefitinib (0.19 g, 0.43 mmol), and Na2CO3 (0.09 g, 0.86 mmol) were dissolved in DMF (3 mL) and heated at 75°C for 2 hours. The reaction mixture was poured into 30 mL of water, extracted with DCM (20 mL x 3), and washed with water (10 mL). Purification by chromatography yielded 40 mg of a solid.

[0081] Liquid chromatography mass spectrometry (LC_MS): (ES+): m / z 817.23 [M+H] +.t R =1.723minMolecular formula: C 42 H 46 ClFN6O8; molecular weight: 817.31. 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.57(s,1H),8.48(s,1H),8.12(dd,J=6.8,2.7Hz,1 H),7.82(s,2H),7.80–7.77(m,1H),7.46–7.39(m,2H),7.33(dd,J=8.3,2.3Hz,1H),7.18(s ,1H),5.11(dd,J=12.8,5.4Hz,1H),4.27–4.05(m,8H),3.59(t,J=4.7Hz,6H),2.63–2.58(m,2H),2.08–1.96(m,4H),1.81–1.74(m,4H),1.45(dd,J=12.1,6.0Hz,9H),1.22(s,2H). The total number of hydrogen atoms calculated from the H NMR data was 46.

[0082] Example 3: Synthesis of Compound 3

[0083] a. Mix 5-hydroxythalidomide (1 g, 3.6 mmol), 1,8-dibromooctane (1.5 g, 5.5 mmol), and Na2CO3 (0.8 g) in DMF (10 mL) and heat with stirring to 75°C for 5 hours. The reaction mixture was then poured into 100 ml of water, extracted with 20 ml of DCM*3, and washed with 10 ml of water. Purification by chromatography gave 350 mg of a solid. Liquid chromatography-mass spectrometry (LC-MS): (ES+): m / z 507.21 [M+H]+, t R =3.511 minutes. Molecular formula: C24H 31 BrN2O5; molecular weight: 507.43.

[0084] b. The solid obtained in step a (0.2 g, 0.43 mmol) and 4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazacyclohexane-4-yl)propyl]oxy}quinazolin-7-ol (Gefitinib-PROTAC-1-3) (0.19 g, 0.43 mmol), and Na2CO3 (0.09 g, 0.86 mmol) were heated to 75 ° C in DMF (3 ml) for 2 hours. The reaction mixture was poured into 30 ml of water, then extracted with 20 ml × 3 DCM and washed with 10 ml of water. Purification by chromatography gave 23 mg of a solid product. Liquid phase mass spectrum (ES+): m / z 859.30 [M+H]+, t R =3.204min. Molecular formula: C 45 H 52 ClFN6O8; molecular weight: 859.39.

[0085] 1 H NMR (400 MHz, DMSO-d6): δ 11.13 (s, 1H), 9.59 (s, 1H), 8.50 (s, 1H), 8.15 (dd, J = 6.9, 2.6 Hz, 1H), 7.90–7.76 (m, 3H), 7.50–7.39 (m, 2H), 7.33 (dd, J = 8.4, 2.3 Hz, 1H), 7.19 (s, 1H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.27–4.06 (m, 6H), 3.63 (s, 4H). The total number of hydrogen atoms calculated from the H NMR data was 52.

[0086] Example 4: Synthesis of Compound 4

[0087] a. 2-(2,6-dioxohexahydropyridine-3-yl)-4-(piperazine-1-yl)isoindole-1,3-dione hydrochloride (1 g, 2.6 mmol), 1,8-dibromooctane (1.8 g, 6.6 mmol), and 1.3 g of DIPEA were heated in DMSO at 135°C for 2 hours. The reaction mixture was poured into 100 ml of water, then extracted with DCM (20 ml * 3 times) and washed with 10 ml of water. Purification by chromatography gave 240 mg of a solid. Liquid phase mass spectrum (LC-MS): (ES+): m / z 380.31 [M+H]+, t R =2.871min. Molecular formula: C 17 H 19 ClN4O4; molecular weight: 378.81.

[0088] b. Mix the solid obtained in step a (0.2 g, 0.37 mmol), Gefitinib-PROTAC-1-3 (0.18 g, 0.42 mmol), and Na2CO3 (0.06 g, 0.57 mmol) in DMF (3 mL) and heat to 75°C for 2 hours. The reaction mixture was poured into 30 ml of water, then extracted with DCM three times, 20 ml each time, and washed with 10 ml of water. Purification by chromatography gave 29 mg of solid. Liquid chromatography mass spectrometry (LC-MS): (ES+): m / z 885.40 [M+H]+, t R =2.704min. Molecular formula: C 46 H 54 ClFN8O7; molecular weight: 885.4354.

[0089] 1 H NMR (400MHz, DMSO-d6): δ11.11(s,1H),9.61(s,1H),8.50(s,1H),8.14(dd,J=6.9,2.6Hz,1H),7.88–7. 79(m,2H),7.67(d,J=8.4Hz,1H),7.45(t,J=9.1Hz,1H),7.34(s,1H),7.24(d,J=8.5Hz,1H),7.19(s,1H ),5.08(dd,J=12.9,5.3Hz,1H),4.17(dt,J=20.3,6.3Hz,4H),3.60(s,4H),2.65–2.53(m,4H),2.47–2. 21 (m, 8H), 2.00 (d, J = 8.3Hz, 4H), 1.80 (t, J = 7.2Hz, 2H), 1.48 (d, J = 8.4Hz, 4H), 1.36 (d, J = 27.7Hz, 8H).

[0090] From the H NMR data, there are 54 hydrogen atoms in total.

[0091] Example 5: Synthesis of Compound 5

[0092] a. Mix 2-(2,6-dioxohexylpyridin-3-yl)-5-(piperazine-1-yl)isoindole-1,3-dione hydrochloride (1g, 2.6mmol), 1,8-dibromooctane (1.8g, 6.6mmol), 1.3g of N,N-diisopropylethylamine DIPEA, dissolve in dimethyl sulfoxide DMSO (10mL), and heat to react at 135°C for 2 hours. The reaction mixture was poured into 100ml of water, then extracted with 20ml*3DCM, and then washed with 10ml of water. Purified by chromatography to obtain 200mg of solid. Liquid phase mass spectrum (LC_MS): (ES+): m / z 380.31[M+H]+, t R =2.871min. Molecular formula: C 17 H 19 ClN4O4; molecular weight: 378.81.

[0093] b. The solid obtained in step a (0.2 g, 0.37 mmol) and Gefitinib-PROTAC-1-3 (0.18 g, 0.42 mmol) were dissolved in DMF (3 mL), and Na2CO3 (0.06 g, 0.57 mmol) was added and reacted at 75 ° C for 2 hours. The reaction mixture was poured into 30 mL of water, then extracted with 20 mL*3DCM, washed with 10 mL of water, and purified by chromatography to obtain 35 mg of solid product. Liquid phase mass spectrometry (LC_MS): (ES+): m / z 885.40 [M+H]+, t R =2.704min. Molecular formula: C 46 H 54 ClFN8O7; molecular weight: 885.4354.

[0094] 1H NMR (400MHz, DMSO-d6): δ11.11 (s, 1H), 9.61 (s, 1H), 8.50 (s, 1H), 8.14 (dd, J=6.9, 2.6Hz, 1H), 7.88–7. 79 (m, 2H), 7.67 (d, J=8.4Hz, 1H), 7.45 (t, J=9.1Hz, 1H), 7.34 (s, 1H), 7.24 (d, J=8.5Hz, 1H), 7.19 (s, 1H ), 5.08 (dd, J=12.9, 5.3Hz, 1H), 4.17 (dt, J=20.3, 6.3Hz, 4H), 3.60 (s, 4H), 2.65–2.53 (m, 4H), 2.47–2. 21 (m, 8H), 2.00 (d, J=8.3Hz, 4H), 1.80 (t, J=7.2Hz, 2H), 1.48 (d, J=8.4Hz, 4H), 1.36 (d, J=27.7Hz, 8H).

[0095] According to HNMR data, the total number of hydrogen atoms is 54.

[0096] Example 6: Synthesis of Compound 6

[0097] a. A mixture of 1 (0.1 g, 0.29 mmol), 2 (0.07 g, 0.32 mmol), DIPEA (0.07 g, 0.6 mmol), and HATU (0.2 g, 0.32 mmol) was stirred in DMF (10 ml) at room temperature for 2 hours. TLC indicated the reaction was complete. The reaction mixture was poured into water (100 ml) and extracted with DCM (20 ml x 3). The organic phase was collected, washed with water (30 ml) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a concentrate. Purification by preparative TLC (5% methanol / dichloromethane as eluent) gave 5-[4-(8-bromo-1-oxooctyl)piperazin-1-yl]-2-(2,6-dioxooctyl)piperidin-3-yl)isoindole-1,3-dione (68 mg, 43%) as a yellow solid. Liquid chromatography mass spectrometry (LC_MS): (ES+) m / z 547.62 [M+H]+. Molecular formula: C 25 H 31 BrN4O5; molecular weight: 547.45.

[0098] b. Compound 5-3 (68 mg, 0.2 mmol), compound 5-4 (65 mg, 0.3 mmol) and Na2CO3 (0.06 g, 0.57 mmol) were dissolved in DMF (3 ml) and stirred at 105°C for 2 hours. TLC showed that the reaction was complete. The reaction mixture was poured into water (30 ml) and extracted with dichloromethane (20 ml x 3). The organic phase was collected and washed with water (20 ml) and saturated brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a concentrate. Compound 5 (45 mg, 25%) was obtained by preparative TLC purification (with 10% methanol / dichloromethane as eluent) as a yellow solid. Liquid phase mass spectrometry (LC_MS): (ES+) m / z 899.53 [M+H]+. Molecular formula: C 46 H 52 ClFN8O8; molecular weight: 899.42.

[0099] 1 H NMR (400MHz, DMSO-d6): δ11.11(s,1H), 9.61(s,1H), 8.50(s,1H), 8.14(dd, J=6.9, 2.6Hz, 1H), 7.88–7. 79 (m, 2H), 7.67 (d, J=8.4Hz, 1H), 7.45 (t, J=9.2Hz, 1H), 7.34 (s, 1H), 7.24 (d, J=8.6Hz, 1H), 7.19 (s, 1H ), 5.08 (dd, J=12.9, 5.3Hz, 1H), 4.17 (dt, J=20.3, 6.3Hz, 4H), 3.60 (s, 4H), 2.65–2.53 (m, 4H), 2.47–2. 21 (m, 8H), 2.00 (d, J=8.3Hz, 4H), 1.80 (t, J=7.2Hz, 2H), 1.48 (d, J=8.4Hz, 4H), 1.36 (d, J=27.7Hz, 8H).

[0100] Example 7: Synthesis of Compound 7

[0101] a. 2-(2,6-dioxohexahydropyridine-3-yl)-5-(piperazine-1-yl)isoindole-1,3-dione hydrochloride (0.5 g, 1.3 mmol), 1,10-dibromooctane (0.9 g, 3.3 mmol), and 0.65 g of diisopropylethylamine (DIPEA) were heated to 135° C. in DMSO (10 mL) and reacted for 2 hours. The reaction mixture was poured into 100 ml of water and extracted with 20 ml*3 of DCM and washed with 10 ml of water. Purification by chromatography gave 100 mg of solid. Liquid phase mass spectrometry (LC_MS): (ES+): m / z 380.31 [M+H]+, t R =2.871min. Molecular formula: C 17 H 19 ClN4O4; molecular weight: 378.81.

[0102] b. Mix the solid obtained in step a (0.1 g, 0.37 mmol) and Gefitinib-PROTAC-1-3 (0.18 g, 0.42 mmol) and Na2CO3 (0.06 g, 0.57 mmol) in DMF (3 mL) and heat the reaction at 105 ° C for 2 hours. The reaction mixture was poured into 30 mL of water, then extracted three times with DCM, 20 mL each time, and washed with 10 mL of water. Purified by chromatography to obtain 25 mg of solid. Liquid phase mass spectrometry (LC_MS): (ES+): m / z 913.42 [M+H]+, t R =2.651min. Molecular formula: C 48 H 58 ClFN8O7; molecular weight: 913.42.

[0103] 1 H NMR (400MHz, DMSO-d6): δ11.11(s,1H),9.61(s,1H),8.50(s,1H),8.14(dd,J=6.9,2.6Hz,1H),7.88–7. 79(m,2H),7.67(d,J=8.4Hz,1H),7.45(t,J=9.1Hz,1H),7.34(s,1H),7.24(d,J=8.5Hz,1H),7.19(s,1H ), 5.08 (dd, J = 12.9, 5.3 Hz, 1H), 4.17 (dt, J = 20.3, 6.3 Hz, 4H), 3.60 (s, 4H), 2.65–2.53 (m, 4H), 2.47–2.21 (m, 8H), 2.00 (d, J = 8.3 Hz, 4H), 1.80 (t, J = 7.2 Hz, 2H), 1.48 (d, J = 8.4 Hz, 4H), 1.36 (d, J = 27.7 Hz, 8H). According to H NMR data, the total number of hydrogen atoms was 58.

[0104] Example 8: Synthesis of Compound 8

[0105] a. A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione hydrochloride (200 mg, 0.53 mmol), 1,11-dibromoundecane (333 mg, 1.06 mmol), and DIPEA (273 mg, 2.12 mmol) was stirred in N,N-dimethylformamide (8 mL) at 85°C for 3 hours. Liquid chromatography-mass spectrometry (LCMS) indicated the reaction was complete. The reaction mixture was partitioned into water (40 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with water (40 mL x 2) and saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. Purification by silica gel column chromatography (2.5% methanol / dichloromethane as eluent) gave 5-(4-(11-bromondecyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (113 mg, 37%) as a light yellow solid. Liquid chromatography-mass spectrometry (LC-MS): (ES+) m / z 577.05 [M+H]+. Molecular formula: C 28 H 39 BrN4O4; molecular weight: 574.54.

[0106] b. A mixture of 4-((3-chloro-4-fluorophenyl)amino)-6-(3-morpholinopropoxy)quinazolin-7-ol (85 mg, 0.2 mmol), 5-(4-(11-bromondecyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (113 mg, 0.2 mmol), and potassium carbonate (54.3 mg, 0.4 mmol) was stirred in acetonitrile (6 ml) at 75°C for 24 hours. Liquid chromatography-mass spectrometry (LCMS) indicated the reaction was complete. The reaction mixture was poured into water (40 ml) and extracted with 10% methanol / dichloromethane (10 ml x 3). The organic phase was collected, washed with water (30 ml x 2) and saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. Purification by preparative high-performance liquid chromatography gave 5-(4-(11-((4-((3-chloro-4-fluorophenyl)amino)-6-(3-morpholinopropoxy)quinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (41.8 mg, 23%) as a yellow solid. Liquid chromatography-mass spectrometry (LC-MS): (ES+) m / z 927.35 [M+H].

[0107] Molecular formula: C49 H 60 ClFN8O7; molecular weight: 927.50.

[0108] 1 H NMR (400MHz, DMSO-d6): δ11.10 (s, 1H), 10.14-9.79 (m, 1H), 8.73 (s, 1H), 8.06-8.00 (m, 2H), 7.78-7.71 (m, 2H), 7.5 5-7.49 (m, 2H), 7.37-7.32 (m, 2H), 5.12-5.07 (m, 1H), 4.26 (t, J=5.8Hz, 2H), 4.19 (t, J=6.8Hz, 2H), 4.05-3.98 (m, 2H ), 3.73-3.63 (m, 8H), 3.61-3.53 (m, 8H), 3.34-3.26 (m, 4H), 3.17-3.08 (m, 6H), 2.94-2.85 (m, 1H), 2.62-2.55 (m, 4H), 2.30-2.24 (m, 2H), 2.06-2.00 (m, 1H), 1.86-1.79 (m, 2H), 1.69-1.64 (m, 2H), 1.50-1.42 (m, 2H), 1.38-1.34 (m, 2H). The total number of hydrogen atoms calculated by H NMR data: 60.

[0109] Example 9: Synthesis of Compound 9

[0110] a. Dissolve 4-bromobutyric acid (1 g, 6 mmol) and N,N-dimethylformamide (4.4 mg, 0.6 mmol) in dichloromethane (8 ml) and stir the reaction mixture at room temperature. Slowly add oxalyl chloride (1.14 g, 9 mmol) dropwise and continue stirring at room temperature for 2 hours. The reaction mixture is directly concentrated under reduced pressure to obtain 4-bromobutyryl chloride (1.34 g, crude product), which is used in the next reaction without further purification.

[0111] b. A mixture of 4-bromobutyryl chloride (1.34 g, 7.2 mmol), tert-butylpiperazine-1-carboxylate (1.12 g, 6 mmol), and triethylamine (1.82 g, 18 mmol) was stirred in dichloromethane (10 ml) at room temperature overnight. TLC indicated the reaction was complete. The reaction mixture was partitioned into dichloromethane (20 ml) and water (20 ml). The organic phase was collected, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (20%-50% ethyl acetate / n-hexane as eluent) afforded tert-butyl-4-(4-bromobutyryl)piperazine-1-carboxylate (540 mg, 27% over two steps) as a colorless oil. Molecular formula: C13 H 23 BrN2O3; molecular weight: 335.24. 1 H NMR (400 MHz, CDCl3): δ 4.36 (t, J = 7.0 Hz, 1H), 3.70-3.59 (m, 4H), 3.46-3.40 (m, 5H), 2.54-2.48 (m, 2H), 2.31-2.23 (m, 1H), 2.17-2.11 (m, 1H), 1.47 (s, 9H). The total number of hydrogen atoms calculated by H NMR data: 23.

[0112] c. A mixture of tert-butyl 4-(4-bromobutyryl)piperazine-1-carboxylate (265 mg, 0.79 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione hydrochloride (300 mg, 0.79 mmol), N-ethyl-N-isopropylpropan-2-amine (307 mg, 2.38 mmol), and potassium iodide (132 mg, 0.79 mmol) was stirred at 85°C for 15 hours in N,N-dimethylformamide (10 ml). TLC indicated the reaction was complete. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (15 ml x 3). The organic phase was collected, washed with water (50 ml x 2) and saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (4% methanol / dichloromethane as eluent) gave tert-butyl 4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)butyryl)piperazine-1-carboxylate (166 mg, 35%) as a yellow solid. Liquid chromatography-mass spectrometry (LC-MS): (ES+) m / z 597.25 [M+H]+. Molecular formula: C 30 H 40 N6O7; molecular weight: 596.67.

[0113] d. A mixture of tert-butyl 4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)butyryl)piperazine-1-carboxylate (166 g, 0.28 mmol) was stirred at room temperature for 3 hours in a methanol (2 ml)-HCl / dioxane solution (4 M, 2 ml). TLC indicated the reaction was complete. The reaction mixture was concentrated to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-oxo-4-(piperazin-1-yl)butyl)piperazin-1-yl)isoindole-1,3-dione hydrochloride (147 mg, 99%) as a yellow solid. Liquid chromatography-mass spectrometry (LC-MS): (ES+) m / z 497.6 [M+H]+. Molecular formula: C 25 H 33 ClN6O5; molecular weight: 533.02.

[0114] e. In acetonitrile (100 ml), a mixture of 4-((3-chloro-4-fluorophenyl)amino)-6-(3-morpholinopropoxy)quinazolin-7-ol (1 g, 2.3 mmol), 3-bromopropanol (803 mg, 5.78 mmol) and potassium carbonate (511 mg, 3.08 mmol) was stirred at 95° C. for 24 hours. TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (using 2.5%-10% methanol / dichloromethane as eluent) gave 3-((4-((3-chloro-4-fluorophenyl)amino)-6-(3-morpholinopropoxy)quinazolin-7-yl)oxy)propanol (750 mg, 66%) as a white solid. Liquid phase mass spectrum (LC_MS): (ES+) m / z 490.90 [M+H]+. Molecular formula: C 24 H 28 ClFN4O4; molecular weight: 490.95.

[0115] f. A mixture of 3-((4-((3-chloro-4-fluorophenyl)amino)-6-(3-morpholinopropoxy)quinazolin-7-yl)oxy)propanol (300 mg, 0.61 mmol), triethylamine (124 mg, 1.23 mmol), 4-dimethylaminopyridine (7.5 mg, 0.061 mmol), and p-toluenesulfonyl chloride (117 mg, 0.61 mmol) in dichloromethane (20 ml) was stirred at room temperature for 3 hours. TLC indicated the reaction was complete. The reaction mixture was poured into water (30 ml) and extracted with 10% methanol / dichloromethane (15 ml x 3). The organic phase was collected, washed with water (30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. Purification by silica gel column chromatography (5% methanol / dichloromethane as eluent) gave 3-((4-((3-chloro-4-fluorophenyl)amino)-6-(3-morpholinopropoxy)quinazolin-7-yl)oxy)propyl p-toluenesulfonate (340 mg, 86%) as a white solid. Liquid chromatography mass spectrum (LC-MS): (ES+) m / z 646.40 [M+H]+. Molecular formula: C 31 H 34 ClFN4O6S; molecular weight: 645.14.

[0116] g. A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-oxo-4-(piperazin-1-yl)butyl)piperazin-1-yl)isoindole-1,3-dione hydrochloride (83 mg, 0.156 mmol), 3-({4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazepan-4-yl)propyl]oxy}quinazolin-7-yl}oxy)propyl 4-methylbenzenesulfonate (101 mg, 0.156 mmol), and potassium carbonate (65 mg, 0.47 mmol) was stirred at 75°C for 24 hours. Liquid chromatography mass spectrometry (LCMS) indicated the reaction was complete. The reaction mixture was partitioned between water (30 ml) and ethyl acetate (15 ml x 3). The organic phase was collected and washed with water (30 ml x 2) and saturated brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. Purification by preparative thin layer chromatography (with 10% methanol / dichloromethane as eluent) gave 5-(4-(4-(4-(3-((4-((3-chloro-4-fluorophenyl)amino)-6-(3-morpholinopropoxy)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-4-oxobutyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (18.7 mg, 12%) as a yellow solid. Liquid phase mass spectrum (LC_MS): (ES+) m / z 969.30 [M+H]+. Molecular formula: C49 H 58 ClFN 10 O8; molecular weight: 969.50.

[0117] 1H NMR (400MHz, DMSO-d6): δ11.10 (s, 1H), 9.65 (brs, 1H), 8.49 (s, 1H), 8.17-8.14 (m, 1H), 7.88 (brs, 1H), 7.85-7.81 (m, 1H), 7.69 (d, J=8.8Hz, 1H), 7.45 (t, J=9.2Hz, 1H), 7.36 (brs, 1H), 7.27 (d, J=8. 8 Hz, 1H), 7.21 (s, 1H), 5.10-5.06 (m, 1H), 4.27-4.10 (m, 4H), 3.66-3.56 (m, 6H), 3.53-3.42 (m, 10H), 2.93-2.84 (m, 1H), 2.67-2.51 (m, 16H), 2.40-2.33 (m, 4H), 2.03-1.99 (m, 4H), 1.80-1.68 (m, 1H). The total number of hydrogen atoms calculated by H NMR data: 58.

[0118] Example 10 Synthesis of Compound 10

[0119] a. tert-Butyl 4-(4-chlorobutyl)piperazine-1-carboxylate (158 mg, 0.57 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (217 mg, 0.57 mmol) were dissolved in DMF (3 ml). Diisopropylethylamine (369 mg, 2.86 mmol) and potassium iodide (105 mg, 0.63 mmol) were added. The reaction mixture was heated to 85°C and stirred for 16 hours. Liquid chromatography mass spectrometry (LCMS) indicated that the reaction was complete. The reaction mixture was concentrated and extracted with water (50 ml) and dichloromethane (50 ml x 3). The organic layer was collected and washed with saturated brine (60 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was then purified by flash gel chromatography (dichloromethane:methanol = 30:1 v / v) to give tert-butyl 4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl}-butyl)piperazine-1-carboxylate (180 mg, 42% yield) as a yellow oil. Liquid chromatography-mass spectrometry (LC-MS): (ES+): m / z 569.95 [M+H]+, t R =0.985min. Molecular formula: C29H40N6O6, molecular weight: 568.68.

[0120] b. tert-Butyl 4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl}-butyl)piperazine-1-carboxylate (180 mg, 0.31 mmol) was dissolved in methanol (1.5 ml) and HCl / dioxane (2 ml) was added. The reaction mixture was stirred at room temperature for 4 hours. Liquid chromatography-mass spectrometry (LCMS) indicated that the reaction was complete. The reaction mixture was cooled to dry ice temperature and filtered. The filter cake was collected and concentrated under reduced pressure to obtain a filtrate. The crude product was washed thoroughly with dichloromethane / methanol (10:1, volume ratio) and filtered to obtain 2-(2,6-dioxopiperidin-3-yl)-5-{4-[4-(piperazin-1-yl)butyl]piperazin-1-yl}isoindoline-1,3-dione hydrochloride (110 mg, 74% yield) as a yellow powder. Liquid chromatography-mass spectrometry (LC-MS): (ES+): m / z 469.80 [M+H]+, t R =0.661min. Molecular formula: C24H32N6O4, molecular weight: 468.56.

[0121] c. 4-((3-chloro-4-fluorophenyl)amino)-6-(3-morpholinopropoxy)quinazolin-7-ol (400 mg, 0.93 mmol) and 1-bromo-3-chloropropane (291 mg, 1.85 mmol) were dissolved in DMF (3.2 ml). K2CO3 (138 mg, 2.78 mmol) was added, and the reaction mixture was heated to 50°C and stirred for 16 hours. Liquid chromatography-mass spectrometry (LCMS) showed that the reaction was complete. The reaction mixture was filtered through celite and concentrated under reduced pressure to obtain a crude product, which was then purified by flash gel chromatography (dichloromethane / methanol = 15:1 v / v) to obtain N-(3-chloro-4-fluorophenyl)-7-(3-chloropropoxy)-6-(3-morpholinopropanoxy)quinazolin-4-amine (286 mg, 60% yield) as a yellow powder. Liquid chromatography-mass spectrometry (LC-MS): (ES+): m / z 510.85 [M+H]+, t R =1.782min. Molecular formula: C24H27Cl2FN4O3, molecular weight: 509.40.

[0122] d. N-(3-chloro-4-fluorophenyl)-7-(3-chloropropoxy)-6-(3-morpholinopropoxy)quinazolin-4-amine (100 mg, 0.20 mmol) was dissolved in acetonitrile (2.0 ml), and 2-(2,6-dioxopiperidin-3-yl)-5-{4-[4-(piperazin-1-yl)butyl]piperazin-1-yl}isoindoline-1,3-dione hydrochloride (130 mg, 0.24 mmol) and NaHCO3 (99 mg, 1.18 mmol) were added. The reaction mixture was heated to 75°C and stirred for 24 hours. Liquid chromatography-mass spectrometry (LCMS) showed that the reaction was complete. The reaction mixture was filtered through celite and concentrated under reduced pressure to obtain a crude product, which was then purified by thin-layer chromatography (dichloromethane:methanol = 5:1 v / v) to obtain compound 10 (10.7 mg, 6% yield) as a yellow powder.

[0123] 1 H NMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 10.37 (s, 1H), 8.71 (s, 1H), 8.06 (dd, J=6.8, 2.5Hz, 1H), 8.00 (s, 1 H), 7.78 (d, J=8.5Hz, 1H), 7.76-7.70 (m, 1H), 7.57-7.46 (m, 2H), 7.37 (dd, J=8.7, 2.1Hz, 1H), 7.34 (s, 1H) , 5.10 (dd, J = 12.9, 5.4 Hz, 1H), 4.27 (t, J = 5.9 Hz, 4H), 4.00 (s, 4H), 3.55 (s, 15H), 3.21-3.07 (m, 7H), 2.94-2.83 (m, 4H), 2.69-2.54 (m, 3H), 2.35-2.21 (m, 3H), 2.12 (s, 2H), 2.07-1.92 (m, 2H), 1.77-1.59 (m, 4H). Liquid chromatography-mass spectrometry (LC-MS): (ES+): m / z 955.35 [M+H]+, t R =1.665min. Molecular formula: C 49 H 60 ClFN 10 O7, molecular weight: 955.53. According to HNMR data, the total number of hydrogen atoms is 60.

[0124] Example 11 Synthesis of Compound 11

[0125] a. Dissolve tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (500 mg, 2.016 mmol) and diisopropylethylamine (1.04 g, 8.063 mmol) in DMSO (10 ml). Add 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione hydrochloride (764 mg, 2.016 mmol) and heat to 95°C for 16 hours. Liquid chromatography-mass spectrometry (LCMS) indicates the reaction is complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by flash gel chromatography (methanol:dichloromethane = 1:25 v / v) to obtain 4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperazine-1-carboxylate (325 mg, yield 29%). Liquid chromatography-mass spectrometry (LC-MS): (ES+): m / z 555.65 [M+H]+, t R =1.552min. Molecular formula: C28H38N6O6, molecular weight: 554.63.

[0126] b. 4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperazine-1-carboxylate (325 mg, 0.587 mmol) was gradually added to an ice-cooled dioxane / hydrogen chloride solution (20 ml, 2 M). The resulting mixture was stirred at 0-10°C for 30 minutes, then returned to room temperature and stirred for 1 hour. Liquid chromatography-mass spectrometry (LCMS) showed that the reaction was complete. The resulting mixture was concentrated under reduced pressure to obtain 2-(2,6-dioxopiperidin-3-yl)-5-10024-[2-(piperazin-1-yl)ethyl]piperazin-1-ylisoindole-1,3-dione hydrochloride (293 mg, 95% yield) without further purification. Liquid chromatography-mass spectrometry (LC-MS): (ES+): m / z 455.55 [M+H]+, t R =0.759min. Molecular formula: C23H32Cl2N6O4, molecular weight: 527.44.

[0127] c. 4-((3-chloro-4-fluorophenyl)amino)-6-(3-morpholinopropoxy)quinazolin-7-ol (300 mg, 0.69 mmol) and 1-bromo-2-chloroethane (198 mg, 1.39 mmol) were dissolved in acetonitrile (2.5 ml), K2CO3 (288 mg, 2.08 mmol) was added, and the reaction mixture was heated to 50°C and stirred for 16 hours. Liquid phase mass spectrometry (LCMS) showed that the reaction was complete. The reaction mixture was filtered through celite and concentrated under reduced pressure to give a crude product, which was purified by flash gel chromatography (dichloromethane:methanol=15:1 v / v) to give N-(3-chloro-4-fluorophenyl)-7-(2-chloroethoxy)-6-(3-morpholinopropoxy)quinazolin-4-amine (220 mg, 64% yield). Liquid chromatography mass spectrometry (LC_MS): (ES+): m / z 495.55 [M+H]+, t R =1.466min. Molecular formula: C23H25Cl2FN4O3, molecular weight: 495.38.

[0128] d. N-(3-chloro-4-fluorophenyl)-7-(2-chloroethoxy)-6-(3-morpholinopropoxy)quinazolin-4-amine (100 mg 0.20mmol) was dissolved in acetone (2.5ml), 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(piperazin-1-yl)ethyl)piperazin-1-ylisoindoline-1,3-dione hydrochloride (128mg, 0.24mmol) and K2CO3 (167mg, 1.21mmol) were added, and the resulting mixture was heated to 75°C and stirred for 24 hours. Liquid phase mass spectrometry (LCMS) results showed that the reaction was complete. The resulting mixture was filtered through celite and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin layer chromatography (dichloromethane:methanol=2:1v / v). The crude product was purified by preparative thin layer chromatography to obtain compound 11 (11.6mg, 6%).

[0129] 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.37(s,1H),8.72(s,1H),8.07(dd,J=6.8,2.6Hz,1H),8. 02(s,1H),7.79–7.73(m,2H),7.53(t,J=9.1Hz,1H),7.48(d,J=1.6Hz,1H),7.42(s,1H),7.36(dd, J=8.6,2.0Hz,1H),5.10(dd,J=12.9,5.4Hz,1H),4.57(s,2H),4.28(t,J=5.8Hz,2H),3.73(s,10H),3.37–3.16(m,17H),2.95–2.82(m,4H),2.68–2.55(m,2H),2.38–2.11(m,3H),2.09–1.82(m,2H). Liquid chromatography-mass spectrometry (LC-MS): (ES+): m / z 913.25[M+H]+, t R =2.479min. Molecular formula: C 46 H 54 ClFN 10 O7, molecular weight: 913.45, total hydrogen number 54 according to HNMR data.

[0130] Example 12 Synthesis of Compound 12

[0131] a. 4-((3-chloro-4-fluorophenyl) amino)-6-(3-morpholine propoxy) quinazoline-7-ol (400mg, 0.93mmol), 1-bromo-3-chloropropane (291mg, 1.85mmol) were dissolved in a solution of DMF (3.2ml), and K2CO3 (138mg, 2.78mmol) was added. The reaction mixture was heated to 50°C and stirred for 16 hours. Liquid phase mass spectrometry (LCMS) showed that the reaction was complete. The resulting mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give a crude product. The crude product was purified by flash gel chromatography (dichloromethane / methanol=15:1v / v) to give N-(3-chloro-4-fluorophenyl)-7-(3-chloropropoxy)-6-(3-morpholine propoxy) quinazoline-4-amine (286mg, 60%) as a yellow powder. Liquid chromatography mass spectrometry (LC_MS): (ES+): m / z 510.85 [M+H]+, t R =1.782min. Molecular formula: C 24 H 27 Cl2FN4O3, molecular weight: 509.40.

[0132] b. 3-chloro-4-fluorophenyl)-7-(3-chloropropoxy)-6-(3-morpholinopropoxy)quinazolin-4-amine (140 mg, 0.28 mmol) was dissolved in acetonitrile (1.4 ml) and 2-(2,6-diketopiperazin-3-yl)-5-(4-(2-(piperazin-1-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione hydrochloride (174 mg, 0.33 mmol) and K2CO3 (227 mg, 1.65 mmol) were added. The resulting mixture was heated to 75°C and stirred for 16 hours. Liquid chromatography-mass spectrometry showed that the reaction was complete. The resulting mixture was filtered through celite and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (dichloromethane / methanol = 2:1 volume ratio) to obtain a crude product. The crude product was purified by preparative chromatography to obtain compound 12 (79.1 mg, 31%) as a yellow powder.

[0133] 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.83(s,1H),8.82(s,1H),8.09(s,1H),8.03(dd,J=2.4,2.4Hz,1H), 7.78(d,J=8.4Hz,1H),7.75-7.71(m,1H),7.55(t,J=18Hz,1H),7.49(d,J=2.0Hz,1H),7.43(s,1H),7.37(dd, J = 2.0, 2.0 Hz, 1H), 5.10 (dd, J = 5.6, 5.6 Hz, 1H), 4.32-4.27 (m, 4H), 4.00 (s, 3H), 3.77 (s, 7H), 3.54 (s, 5H), 3.42 (s, 4H), 3.29 (s, 2H), 3.14 (s, 7H), 2.94-2.82 (m, 4H), 2.68-2.55 (m, 2H), 2.28 (s, 5H), 2.05-2.02 (m, 1H). Liquid chromatography-mass spectrometry (ES+): m / z 927.40 [M+H]+. t R =1.746min. Molecular formula: C 47 H 56 ClFN 10 O7, molecular weight: 927.48. The total number of H atoms obtained from H NMR data is 56.

[0134] Example 13 Synthesis of Compound 13

[0135] a. Dissolve tert-butyl 4-(3-chloropropyl)piperazine-1-carboxylate (150 mg, 0.57 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (217 mg, 0.57 mmol) in DMF (3 ml), and add diisopropylethylamine (369 mg, 2.86 mmol) and potassium iodide (105 mg, 0.63 mmol). The reaction mixture was heated to 95°C and stirred for 24 hours. Liquid chromatography-mass spectrometry (LCMS) results indicated that the reaction was complete. The reaction mixture was concentrated and extracted with water (50 ml) and dichloromethane (50 ml x 3). The organic layer was collected, washed with saturated brine (60 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an unpurified crude product, which was purified by flash gel chromatography (dichloromethane:methanol = 30:1 v / v) to give tert-butyl 4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)piperazine 1-carboxylate (180 mg, 42%) as a yellow oil. Liquid chromatography-mass spectrometry (LC-MS): (ES+): m / z 569.95 [M+H]+, t R =0.985min. Molecular formula: C29H40N6O6, molecular weight: 568.68.

[0136] b. Tert-butyl 4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)piperazine 1-carboxylate (180 mg, 0.32 mmol) was dissolved in methanol (1.5 ml) and HCl / dioxane (2 ml) was added. The reaction mixture was stirred at room temperature for 4 hours. Liquid chromatography-mass spectrometry (LCMS) indicated that the reaction was complete. The reaction mixture was cooled under dry ice and filtered to collect the filter cake. The filtrate was then concentrated under reduced pressure. The crude product was washed with an appropriate amount of dichloromethane / methanol (10:1 volume ratio) and filtered to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(piperazin-1-yl)propyl)piperazin-1-ylisoindoline-1,3-dione hydrochloride (110 mg, 74%) as a yellow powder. Liquid chromatography mass spectrum (LC_MS): (ES+): m / z 469.80 [M+H]+, t R =0.661min. Molecular formula: C24H32N6O4, molecular weight: 468.56.

[0137] c. N-(3-chloro-4-fluorophenyl)-7-(2-chloroethoxy)-6-(3-morpholinopropoxy)quinazolin-4-amine (100 mg, 0.20 mmol) was dissolved in different (3 ml), 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(piperazin-1-yl)propyl)piperazin-1-yl)isoindoline-1,3-dione (110 mg, 0.24 mmol), K2CO3 (167 mg, 1.21 mmol) were added, and the resulting mixture was heated to 75 ° C. and stirred for 24 hours. LCMS showed that the reaction was complete. The resulting mixture was filtered through celite and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (dichloromethane: methanol = 2: 1 volume ratio) to obtain a crude product. The crude product was purified by preparative TLC to give 5-(4-(3-(4-(2-((4-((3-chloro-4-fluorophenyl)amino)-6-(3-morpholinopropoxy)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (39 mg, 15%) as a yellow powder.

[0138] 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.67(s,1H),8.78(s,1H),8.05(s,1H),8.03(dd,J=2.4,2.4Hz,1H) ,7.78(d,J=8.4Hz,1H),7.75-7.71(m,1H),7.54(t,J=18Hz,1H),7.50(d,J=2.0Hz,1H),7.43(s,1H),7.37( d,J=2.0Hz,1H),5.10(dd,J=5.6,5.6Hz,1H),4.44(s,2H),4.27(t,J=11.6Hz,2H),4.00(s,8H),3.32(t,J= 15.6,10H),3.18(t,J=14,9H),2.86-2.94(m,5H),2.55-2.62(m,2H),2.25-2.29(m,2H),2.02-2.07(m,3H). LC_MS:(ES+):m / z 927.30[M+H]+,t R =1.981min. Molecular formula: C 47 H 56 ClFN 10 O7, relative molecular mass: 927.48. According to HNMR data, there are 56 hydrogen atoms in total.

[0139] Example 14 Synthesis of Compound 14

[0140] a. 4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline (200 mg, 0.70 mmol) and 3-chloro-4-fluoroaniline (202 mg, 1.39 mmol) were dissolved in DMF (2 ml). The reaction mixture was stirred at 50 ° C for 3 hours. Liquid phase mass spectrometry showed that the reaction was complete. The reaction mixture was cooled to room temperature, filtered, washed with methyl tert-butyl ether and concentrated under reduced pressure to obtain a crude product. After slurrying and purification with 1.5 ml of ethanol, N-(3-chloro-4-fluorophenyl)-7-(3-chloropropoxy)-6-methoxyquinazoline-4-amine (202 mg, yield 73%) was obtained as an off-white solid powder. Liquid phase mass spectrometry (LC_MS): (ES+) m / z 397.85 [M+H] +, t R =2.370min. Molecular formula: C 18 H 16 Cl2FN3O2, molecular weight: 396.24.

[0141] b. N-(3-chloro-4-fluorophenyl)-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (100 mg, 0.25 mmol) was dissolved in acetonitrile (2.5 mL), and 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(piperazin-1-yl)propyl)piperazin-1-ylisoindoline-1,3-dione hydrochloride (160 mg, 0.30 mmol) and K2CO3 (210 mg, 1.52 mmol) were added. The mixture was heated to 75 ° C and stirred for 24 hours. The liquid phase Mass spectrometry (LCMS) results showed that the reaction was complete. The resulting mixture was filtered through celite and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 5:1 v / v) to obtain 5-(4-(2-(4-(3-(4-((3-chloro-4-fluorophenyl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (26 mg, 12%).

[0142] 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),9.58(s,1H),8.50(s,1H),8.14(dd,J=6.8,2.5Hz,1 H),7.86–7.77(m,2H),7.67(d,J=8.5Hz,1H),7.45(t,J=9.1Hz,1H),7.37–7.30(m,1H),7. 28–7.22 (m, 1H), 7.19 (s, 1H), 5.13–5.02 (dd, J=5.2, 5.6 Hz, 1H), 4.18 (t, J=12.4 Hz, 2H), 3.97 (s, 3H), 3.58-3.41 (m, 10H), 2.93–2.83 (m, 1H), 2.73–2.53 (m, 9H), 2.15-1.85 (m, 4H). Liquid chromatography-mass spectrometry (LC-MS): (ES+): m / z 814.30 [M]+, t R =1.987min. Molecular formula: C41H45ClFN9O6, molecular weight: 814.30. According to HNMR data, the total number of hydrogen atoms is 45.

[0143] Example 15 Synthesis of Compound 15

[0144] a. To a solution of 2-(2,6-dioxohexahydropyridin-3-yl)-6-fluoro-5-(piperazin-1-yl)isoindole-1,3-dione hydrochloride (220 mg, 0.553 mmol) and 2-methylpropan-2-yl 4-(2-bromoethyl)hexahydropyridine-1-carboxylate (177 mg, 0.608 mmol) in DMF (2.2 mL) was added DIPEA (357 mg, 2.765 mmol), and the resulting mixture was heated to 85° C. and stirred for 16 hours. LCMS showed the reaction was complete. The resulting mixture was concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (chloroform:methanol=13:1 v / v) to give 2-methylpropan-2-yl 4-(2-{4-[2-(2,6-dioxohexahydropyridin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}ethyl)piperidine-1-carboxylate (160 mg, 50%) as a yellow solid. LC-MS: (ESI): + ):m / z 571.90[M+H] + .t R =2.063min.Molecular formula: C 29 H 38 FN5O6, molecular weight: 571.65

[0145] b. To a solution of 2-methylpropan-2-yl 4-(2-{4-[2-(2,6-dioxopyridin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}ethyl)piperidine-1-carboxylate (160 mg, 0.280 mmol) in DCM (0.5 mL) was added HCl / dioxane (4 mL) at 0° C. and stirred for 15 minutes. The resulting mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The resulting mixture was filtered for solids and concentrated under reduced pressure to give 2-(2,6-dioxopyridin-3-yl)-6-fluoro-5-{4-[2-(piperidin-4-yl)ethyl]piperazin-1-yl}isoindole-1,3-dione hydrochloride (144 mg, 91%) as a yellow solid. LC_MS:(ES+):m / z 472.40[M+H] + .t R =0.707min. Molecular formula: C24H30FN5O4, molecular weight: 471.53

[0146] c. To a DMF (3 mL) solution containing 4-[(3-chloro-4-fluorophenyl)amino]-7-[(3-chloropropyl)oxy]-6-methoxyquinazoline (87 mg, 0.220 mmol), 2-(2,6-dioxohexahydropyridine-3-yl)-6-fluoro-5-{4-[2-(hexahydropyridine-4-yl)ethyl]piperazine-1-yl}isoindole-1,3-dione hydrochloride (144 mg, 0.264 mmol), K3PO4 (279 mg, 1.318 mmol) were added and the resulting mixture was heated to 55°C and stirred for 16 hours. LCMS showed that the reaction was complete. The resulting mixture was filtered through celite and concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (chloroform: methanol: triethylamine = 10: 1: 0.01 v / v) to give a crude product. The crude product was purified by preparative chromatography to give 5-[4-(2-{1-[3-({4-[(3-chloro-4-fluorophenyl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]hexahydropyridin-4-yl}ethyl)piperazin-1-yl]-2-(2,6-dioxohexahydridine-3-yl)-6-fluoroisoindole-1,3-dione (15 mg, 8%).

[0147] 1H NMR(400MHz, DMSO)δ11.14(s,1H),10.86–10.62,10.39–10.09,10.84–9.46(m,1H),8.81(d,J=2.2Hz,1H),8.12–8.01(m,2H), 7.85(d,J=11.1Hz,1H),7.80–7.72(m,1H),7.64(d,J=7.3Hz,1H),7.56(t,J=9.1Hz,1H),7.42(d,J=6.8Hz,1H).5.13(dd,J=12. 9,5.4Hz,1H),4.32(t,J=5.9Hz,2H),4.02(s,3H),3.86–3.81(m,2H),3.70–3.60(m,5H),3.32–3.23(m,7H),3.03–2.88(m,3H) ,2.73–2.55(m,2H),2.38–2.23(m,2H),2.14–2.03(m,1H),2.01–1.88(m,2H),1.76–1.58(m,3H),1.53–1.36(m,2H).LC_MS:(ES + ):m / z831.25[M+H] + .t R =1.706min.Molecular formula: C 42 H 45 ClF2N8O6, molecular weight: 831.31. 1 Total hydrogen number obtained from H NMR data: 45

[0148] Example 16 Synthesis of Compound 17

[0149] a. To a solution of (1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidin-4-yl)acetic acid (200 mg, 0.823 mmol) and 2-(2,6-dioxopyridin-3-yl)-6-fluoro-5-(piperazin-1-yl)isoindole-1,3-dione (356 mg, 0.988 mmol) in DMF (4 mL) was added HATU (626 mg, 1.646 mmol) and DIPEA (319 mg, 2.469 mmol). The resulting reaction was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction mixture was extracted with water (30 mL) and ethyl acetate (30 mL x 3). The organic layer was collected, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (petroleum ether: ethyl acetate = 1:2 v / v) to give a yellow solid 2-methylpropane-2-yl 4-(2-{4-[2-(2,6-dioxohexahydropyridine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-yl}-2-oxoethyl)hexahydropyridine-1-carboxylate (486 mg, 98%). LC_MS: (ES + ):m / z 586.10[M+H] + .t R =2.767min. Molecular formula: C 29 H 36 FN5O7, molecular weight: 585.63

[0150] b. To a solution of 2-methylpropane-2-yl 4-(2-{4-[2-(2,6-dioxopyridin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-2-oxoethyl)piperidine-1-carboxylate (486 mg, 0.831 mmol) in DCM (1.5 mL) was added ice-cooled HCl / Dioxane (8 mL) and stirred for 15 minutes. The resulting reaction was then brought to room temperature and stirred for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was cooled with dry ice until a solid precipitated. After filtration, the filter cake was concentrated under reduced pressure to obtain a yellow solid 2-(2,6-dioxohexahydropyridin-3-yl)-6-fluoro-5-{4-[2-(hexahydropyridin-4-yl)acetyl]piperazin-1-yl}isoindole-1,3-dione hydrochloride (388 mg, 96%). LC_MS: (ES + ):m / z 486.40[M+H] + .t R =1.621min.Molecular formula: C 24 H 28 FN5O5, molecular weight: 485.52

[0151] c. To a solution of 4-[(3-chloro-4-fluorophenyl)amino]-7-[(3-chloropropyl)oxy]-6-methoxyquinazoline (100 mg, 0.253 mmol) in acetone (3 mL) was added NaI (57 mg, 0.380 mmol), and the resulting mixture was heated to 50°C and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was then dissolved in DMF (2.5 mL), and 2-(2,6-dioxohexahydropyridin-3-yl)-6-fluoro-5-{4-[2-(hexahydropyridin-4-yl)acetyl]piperazin-1-yl}isoindole-1,3-dione hydrochloride (170 mg, 0.304 mmol) and K3PO4 (322 mg, 1.518 mmol) were added. The resulting mixture was heated to 55°C and stirred for 16 hours. LCMS indicated the reaction was complete. The resulting mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give a crude product. The crude product was purified by thin layer chromatography (dichloromethane: methanol: triethylamine = 10: 1: 0.01, v / v) to give a crude product. The crude product was purified by preparative thin layer chromatography to give 5- [4- (2- {1- [3- ( {4- [ (3- chloro-4-fluorophenyl) amino] -6- methoxyquinazolin-7-yl} oxy) propyl] hexahydropyridine -4- yl} acetyl) piperazine -1- base] -2- (2,6- dioxo hexahydropyridine -3- base) -6- fluoroisoindole -1,3- dione (41 mg, 19%). 1 H NMR (400MHz, DMSO) δ11.12(s,1H),10.70(s,1H),9.20(s,1H),8.80(s,1H),8.07–7.99(m,2H),7.79(d,J=11.3Hz,1H),7.75 -7.69(m,1H),7.55(t,J=9.0Hz,1H),7.49(d,J=7.4Hz,1H),7.35(s,1H),5.12(dd,J=12.8,5.4Hz,1H),4.29(t,J=5.5Hz,2H) ,4.00(s,3H),3.66(s,4H),3.58(d,J=11.2Hz,2H),3.30–3.20(m,6H),3.07–2.96(m,2H),2.94–2.82(m,1H),2.64-2.52(m, 2H),2.38(d,J=6.2Hz,2H),2.30–2.23(m,2H),2.11-2.01(m,2H),1.97(d,J=13.9Hz,2H),1.43(q,J=11.5Hz,2H).LC_MS:(ES + ):m / z845.15[M+H] + .tR =1.964min.Molecular formula: C 42 H 43 ClF2N8O7, molecular weight: 845.30; total hydrogen atoms: 44, calculated from H NMR data.

[0152] Example 17 Synthesis of Compound 27

[0153] a. To a solution of 2-(2,6-dioxohexahydropyridin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione hydrochloride (220 mg, 0.579 mmol) and 2-methylpropan-2-yl 4-(2-bromoethyl)hexahydropyridine-1-carboxylate (186 mg, 0.637 mmol) in DMF (2.2 mL) was added DIPEA (373 mg, 2.895 mmol) and KI (106 mg, 0.637 mmol). The resulting mixture was heated to 85° C. and stirred for 16 hours. LCMS showed that the reaction was complete. The resulting mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography (dichloromethane:methanol=13:1, v / v) to give 2-methylpropan-2-yl 4-(2-{4-[2-(2,6-dioxohexahydropyridin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}ethyl)piperidine-1-carboxylate (159 mg, 50%) as a yellow solid. LC_MS: (ES + ):m / z 554.50[M+H] + .t R =2.084min.Molecular formula: C 29 H 39 N5O6, molecular weight: 553.66

[0154] b. To a DCM (1 mL) solution containing 2-methylpropane-2-yl 4-(2-{4-[2-(2,6-dioxohexahydropyridine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-yl}ethyl)hexahydropyridine-1-carboxylate (159 mg, 0.288 mmol) was added HCl / Dioxane (4 mL) and stirred at 0°C for 15 minutes. The resulting mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The resulting mixture was filtered and concentrated under reduced pressure to give a yellow solid 2-(2,6-dioxohexahydropyridine-3-yl)-5-{4-[2-(hexahydropyridine-4-yl)ethyl]piperazine-1-yl}isoindole-1,3-dione hydrochloride (128 mg, 98%). LC_MS: (ES + ):m / z 454.35[M+H] +.t R =0.692min.Molecular formula: C 24 H 31 N5O4, molecular weight: 453.54

[0155] c. To a solution of 4-[(3-chloro-4-fluorophenyl)amino]-7-[(3-chloropropyl)oxy]-6-methoxyquinazoline (80 mg, 0.202 mmol) in acetone (2.4 mL) was added NaI (45 mg, 0.303 mmol), and the resulting mixture was heated to 56 ° C and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was then dissolved in DMF (3 mL), 2-(2,6-dioxohexahydropyridine-3-yl)-5-{4-[2-(hexahydropyridine-4-yl)ethyl]piperazine-1-yl}isoindole-1,3-dione hydrochloride (128 mg, 0.243 mmol), K3PO4 (257 mg, 1.212 mmol) were added, and the resulting mixture was heated to 55 ° C and stirred for 16 hours. LCMS showed that the reaction was complete. The resulting mixture was filtered through celite and concentrated under reduced pressure to give a crude product. The crude product was purified by thin layer chromatography (dichloromethane:methanol:triethylamine=10:1:0.01v / v) to give a crude product. The crude product was purified by preparative TLC to give 5-[4-(2-{1-[3-({4-[(3-chloro-4-fluorophenyl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]hexahydropyridine-4-yl}ethyl)piperazine-1-yl]-2-(2,6-dioxohexahydropyridine-3-yl)isoindole-1,3-dione (79 mg, 48%).

[0156] 1H NMR (400MHz, DMSO) δ11.12(s,1H),10.89–10.63,10.42–10.13,9.80–9.46(m,1H),8.81(d,J=2.2Hz,1H),8.07(dd,J=7.0, 2.4Hz,2H),7.80(d,J=8.5Hz,1H),7.78–7.72(m,1H),7.60–7.51(m,2H),7.40(dd,J=12.1,3.0Hz,2H),5.13(dd,J=12.9,5. 4Hz,1H),4.32(t,J=5.9Hz,2H),4.26(s,2H),4.02(s,3H),3.63(d,J=11.1Hz,5H),3.34–3.19(m,7H),3.05–2.86(m,3H),2. 72–2.55(m,2H),2.39–2.32(m,2H),2.13–2.02(m,1H),2.01–1.88(m,2H),1.83–1.56(m,3H),1.54–1.36(m,2H).LC_MS:(ES + ):m / z 813.35[M+H] + .t R =1.684min.Molecular formula: C 42 H 46 ClFN8O6, molecular weight: 813.32. Total hydrogen atoms calculated from H NMR data: 46

[0157] Example 18 Synthesis of Compound 29

[0158] The synthesis route is shown in the figure above, and the synthesis method is similar to that of compound 17.

[0159] a. The product 2-methylpropyl-2-yl 4-(2-{4-[2-(2,6-dioxopyridin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoxazin-5-yl]piperazin-1-yl}-2-oxoethyl)piperidine-1-carboxylate (180 mg 77%) was obtained as a yellow solid.

[0160] LC_MS:(ES + ):m / z 568.25[M+H] + .t R =2.642min.

[0161] Molecular formula: C 29 H 37 N5O7, molecular weight: 567.64

[0162] b. The product 2-(2,6-dioxohexahydropyridin-3-yl)-5-{4-[2-(ohexahydropyridin-4-yl)acetyl]piperazin-1-yl}isoxazine-1,3-dione hydrochloride (143 mg 96%) was obtained as a yellow solid.

[0163] LC_MS:(ES + ):m / z 468.50[M+H] + .t R =1.261min.

[0164] Molecular formula: C 24 H 29 N5O5, molecular weight: 467.53

[0165] c. The final product 5-[4-(2-{1-[3-({4-[(3-chloro-4-fluorophenyl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-yl}acetyl)piperazin-1-yl]-2-(2,6-dioxopyridin-3-yl)isoindole-1,3-dione (41 mg 19%) was obtained.

[0166] 1 H NMR (400MHz, DMSO) δ11.09(s,1H),10.59(s,1H),9.11(s,1H),8.78(s,1H),8.04(dd,J=6.8,2.5Hz,1H),8.00(s,1H),7.77-7.68(m ,2H),7.54(t,J=9.1Hz,1H),7.37(d,J=2.0Hz,1H),7.31(s,1H),7.26(dd,J=8.6,2.2Hz,1H),5.08(dd,J=12.9,5.3Hz,1H),4.28(t, J=5.6Hz,2H),3.99(s,3H),3.64(s,4H),3.60-3.51(m,4H),3.50-3.45(s,2H),3.28–3.19(m,2H),3.01(q,J=10.5Hz,2H),2.94-2.8 3(m,5.5Hz,1H),2.64–2.53(m,2H),2.38(d,J=6.3Hz,2H),2.30–2.21(m,2H),2.08–1.91(m,4H),1.42(q,J=11.4Hz,2H).LC_MS:(ES + ):m / z 827.20[M+H] + .t R =1.954min.Molecular formula: C 42 H 44ClFN8O7, molecular weight: 827.31. Total hydrogen atoms: 45, calculated from H NMR data.

[0167] Example 19 Synthesis of Compound 31

[0168] The synthetic route is shown in the figure above, and the operation method is similar to that of compound 27.

[0169] a. The product was 2-methylpropane-2-yl 4-(2-{4-[2-(2,6-dioxopyridin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}ethyl)piperidine-1-carboxylate (124 mg 38%), a yellow solid. LC_MS: (ES + ):m / z 571.90[M+H] + .t R =2.115min.Molecular formula: C 29 H 38 FN5O6, molecular weight: 571.65

[0170] b. The product was 2-(2,6-dioxypyridin-3-yl)-6-fluoro-5-{4-[2-(pyridin-4-yl)ethyl]piperazin-1-yl}isoindole-1,3-dione (105 mg 95%), which was a yellow solid. LC_MS: (ES + ):m / z 472.45[M+H] + .t R =0.695,0.925min.Molecular formula: C 24 H 30 FN5O4, molecular weight: 471.53.

[0171] c. The final product was 6-[4-(2-{1-[3-({4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazepan-4-yl)propyl]oxy}quinazolin-7-yl}oxy)propyl]piperidin-4-yl}ethyl)piperazin-1-yl]-2-(2,6-dioxoylidenepiperidin-3-yl)-5-fluoroisoindole-1,3-dione (20 mg 13%), a yellow solid.

[0172] 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),10.44–9.83(m,1H),8.72(s,1H),8.06(dd,J=6.8,2.6Hz,1H),8.02(s,1H),7.83(d,J=11.2Hz,1H),7 .78–7.71(m,1H),7.61(d,J=7.3Hz,1H),7.52(t,J=9.1Hz,1H),7.38(s,1H),5.13(dd,J=12.8,5.4Hz,1H),4.28(t,J=6.1Hz,4H),4.09–4.0 0(m,3H),3.97–3.90(m,2H),3.87–3.78(m,5H),3.75–3.68(m,4H),3. 63–3.57(m,4H),3.53–3.47(m,2H),3.28–3.21(m,6H),3.02–2.82(m, 3H),2.70–2.53(m,2H),2.33–2.21(m,4H),2.10–2.00(m,1H),1.93(d,J=13.5Hz,1H),1.72–1.54(m,3H),1.44(t,J=12.3Hz,1H).LC_MS:(ES + ):m / z 944.40[M+H] + .t R =1.136,1.614min.

[0173] Molecular formula: C 48 H 56 ClF2N9O7, molecular weight: 944.47. Total hydrogen atoms calculated from H NMR data: 56

[0174] Example 20 Synthesis of Compound 33

[0175] The synthetic route is shown in the figure above, and the synthetic operation method is similar to that of compound 17.

[0176] a. The product tert-butyl 4-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl]piperazin-1-yl}-2-oxoethyl)piperidine-1-carboxylate (486 mg 98%) was obtained as a yellow solid. LC_MS: (ES + ):m / z 586.10[M+H] + .t R =2.767min.Molecular formula: C 29 H 36 FN5O7, molecular weight: 585.63

[0177] b. The product 2-(2,6-dioxypyridin-3-yl)-5-fluoro-6-{4-[2-(pyridin-4-yl)acetyl]piperazin-1-yl}isoindole-1,3-dione hydrochloride (388 mg 96%) was obtained as a yellow solid. LC_MS: (ES + ):m / z 486.40[M+H] + .t R =1.621min.Molecular formula: C 24 H 28 FN5O5, molecular weight: 485.52

[0178] c. The final product 6-[4-(2-{1-[3-({4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazepan-4-yl)propyl]oxy}quinazolin-7-yl}oxy)propyl]hexahydropyridin-4-yl}acetyl)piperazin-1-yl]-2-(2,6-dioxyylidenehexahydropyridin-3-yl)-5-fluoroisoindole-1,3-dione (18 mg 9%) was obtained. 1 H NMR (400MHz, DMSO) δ11.12(s,1H),10.31(d,J=74.5Hz,1H),9.43(s,1H),8.73(s,1H),8.06(dd,J=6.8,2.5Hz,1H),8.01(s,1H), 7.79(d,J=11.3Hz,1H),7.76-7.71(m,1H),7.54(d,J=9.1Hz,1H),7.49(t,J=11Hz,1H),7.34(s,1H),5.11(dd,J=12.8,5.4Hz,1H ),4.28(q,J=8Hz,4H),4.03(d,J=10.2Hz,2H),3.65(s,5H),3.27(s,4H),3.23(d,J=2.4Hz,4H),3.15(s,3H),3.04-2.98(m,2H), 2.95–2.82(m,2H),2.63–2.53(m,3H),2.38(d,J=5.9Hz,2H),2.30-2.19(m,5H),2.07–1.92(m,5H),1.51–1.36(m,2H).LC_MS:(ES + ):m / z 958.20[M+H] + .t R =1.747min.Molecular formula: C 48 H 54 ClF2N9O8, molecular weight: 958.46. Total hydrogen atoms calculated from H NMR data: 55

[0179] Example 21 Synthesis of Compound 34

[0180] a. 4-[(3-chloro-4-fluorophenyl)amino]-7-[(3-chloropropyl)oxy]-6-{[3-(1,4-oxazin-4-yl)propyl]oxy}quinazoline (100 mg, 0.160 mmol) was dissolved in DMF (3 mL), 2-(2,6-dioxohexahydridine-3-yl)-6-fluoro-5-{4-[2-(piperazin-1-yl)ethyl]piperazin-1-yl}isoindigo-1,3-dione hydrochloride (155 mg, 0.392 mmol) and K PO (250 mg, 1.179 mmol) were added, and the resulting mixture was heated to 55° C. and stirred for 16 hours. LCMS showed the reaction was complete. The resulting mixture was filtered through celite and concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (dichloromethane:methanol:trimethylamine=10:1:0.01 v / v) to give a crude product. The crude product was further purified by preparative thin layer chromatography to give 5-[4-(2-{4-[3-(4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazinane-4-yl)propyl]oxy}quinazolin-7-yl)oxy]propyl]piperazin-1-yl}ethyl)piperazin-1-yl]-2-(2,6-dioxohexahydridine-3-yl)-6-fluoroisoindigo-1,3-dione (35 mg, 19%) as a yellow solid.

[0181] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),10.65(s,1H),8.77(s,1H),8.08–8.01(m,2H),7.82(d,J=11.1Hz,1H),7. 77–7.70(m,1H),7.59(d,J=7.3Hz,1H),7.53(t,J=9.1Hz,1H),7.41(s,1H),5.13(dd,J=12.8,5.4Hz,1H),4.28(q ,J=6.5Hz,4H),3.97(s,5H),3.73(s,3H),3.58–3.52(m,6H),3.50–3.43(m,6H),3.30–3.26(m,2H),3.16–3.19(m ,3H),2.96–2.74(m,5H),2.71–2.52(m,3H),2.48–2.41(m,1H),2.35–2.19(m,5H),2.09–2.02(m,1H).LC_MS:(ES + ):m / z 945.30[M+H] + .t R=1.619min.

[0182] Molecular formula: C 47 H 55 ClF2N 10 O7, molecular weight: 945.46. Total hydrogen atoms calculated from H NMR data: 55

[0183] Example 22 Synthesis of Compound 36

[0184]

[0185] a. 4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazinan-4-yl)propyl]oxy}quinazolin-7-ol (50 mg, 0.116 mmol) and 1,8-dibromooctane (157 mg, 0.579 mmol) were dissolved in DMF (1.5 mL), K2CO3 (48 mg, 0.347 mmol) was added, and the resulting reaction mixture was heated to 50°C and stirred for 16 hours. LCMS showed that the reaction was complete. The resulting mixture was filtered through celite and concentrated under reduced pressure to give a crude product, which was purified by flash gel chromatography (dichloromethane:methanol=15:1 v / v) to give 7-[(8-bromooctyl)oxy]-4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazinan-4-yl)propyl]oxy}quinazoline (42 mg, 40%) as a white solid. LC-MS: (ES+): m / z 625.10 [M+H] + .t R =2.767min.Molecular formula: C 29 H 37 BrClFN4O3, molecular weight: 623.9924

[0186] c. 7-[(8-Bromooctyl)oxy]-4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazinan-4-yl)propyl]oxy}quinazoline (42 mg, 0.067 mmol) was dissolved in DMF (1.5 mL), 2-(2,6-dioxohexahydridine-3-yl)-6-fluoro-5-(piperazin-1-yl)isoindole-1,3-dione hydrochloride (32 mg, 0.081 mmol) and K PO (86 mg, 0.404 mmol) were added, and the resulting mixture was heated to 55° C. and stirred for 16 hours. LCMS showed that the reaction was complete. The resulting mixture was filtered through celite and concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (dichloromethane:methanol=10:1 v / v) to give 5-{4-[9-({4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazinan-4-yl)propyl]oxy}quinazolin-7-yl}oxy)nonyl]piperazin-1-yl}-2-(2,6-dioxohexahydridine-3-yl)-6-fluoroisoindole-1,3-dione (18 mg, 29%) as a yellow solid.

[0187] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.72(s,1H),8.49(s,1H),8.18(d,J=6.7Hz,1H),8.02–7.79(m,2H) ,7.72(d,J=11.3Hz,1H),7.44(q,J=9.2,8.1Hz,2H),7.19(s,1H),5.11(dd,J=12.8,5.4Hz,1H),4.19(dt,J =31.3,6.3Hz,5H),3.62(d,J=6.7Hz,6H),3.51(s,1H),2.89(ddd,J=18.0,13.7,5.4Hz,2H),2.72–2.55(m ,7H),2.35(d,J=6.4Hz,1H),2.02(dp,J=16.8,8.8,6.8Hz,4H),1.80(p,J=6.6Hz,2H),1.54–1.18(m,15H). LC_MS:(ES + ):m / z 903.20[M] + .t R =1.763min.Molecular formula: C 46 H 53 ClF2N8O7, molecular weight: 903.4258. Total number of hydrogen atoms calculated from H NMR data: 53

[0188] Example 23 Synthesis of Compound 43

[0189] The synthetic route is shown in the figure above, and the synthetic operation method is similar to that of compound 15.

[0190] a. The product 4-(2-{4-[2-(2,6-dioxypyridin-3-yl)-1,3-dioxypyridin-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}ethyl)pyridin-1-carboxylic acid 2-methylpropane-2-yl ester (148 mg 86%) was obtained as a yellow sticky solid. LC_MS: (ES + ):m / z554.90[M+H] + .t R =2.063min.Molecular formula: C 29 H 39 N5O6, molecular weight: 553.6600

[0191] b. The product 2-(2,6-dioxypyridin-3-yl)-5-{4-[2-(pyridin-4-yl)ethyl]piperazin-1-yl}isoindole-1,3-dione hydrochloride (109 mg 99%) was obtained as a yellow solid. LC_MS: (ES + ):m / z 454.36[M+H] + .t R =0.707min.Molecular formula: C 24 H 41 N5ClO4, molecular weight: 453.5430+36.4580

[0192] c. The final product, 5-[4-(2-{1-[3-({4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazepan-4-yl)propyl]oxy}quinazolin-7-yl}oxy)propyl]piperidin-4-yl}ethyl)piperazin-1-yl]-2-(2,6-dioxyylidenepiperidin-3-yl)isoindole-1,3-dione (46 mg 23%), was obtained as a yellow solid.

[0193] 1H NMR (400 MHz, DMSO-d6) δ11.09(s,1H),9.71(s,1H),8.51(s,1H),8.17(dd,J=6.9,2.6 Hz,1H),7.94(s,1H),7.85(dt,J=7.6,3.5 Hz,1H),7.70(d,J=8.5 Hz,1H),7.45(t,J=9.1 Hz,1H),7.37(s,1H),7.27(d,J=19.5 Hz,2H),5.08(dd,J=12.9,5.4 Hz,1H),4.24(q,J=5.9 Hz,5H),3.64(s,7H),3.17(s,5H),2.98–2.81(m,4H),2.68–2.53(m,9H),2.25(q,J=8.2,7.5 Hz,3H),2.03(ddd,J=17.6,10.6,6.1 Hz,4H),1.95–1.81(m,2H),1.61(s,2H),1.49(t,J=11.7 Hz,5H).LC_MS:(ES + ):m / z 926.75,[M] + .t R =1.648min.Molecular formula: C 48 H 57 ClFN9O7, molecular weight: 926.4884

[0194] Example 24 Synthesis of Compound 45

[0195] The synthetic route is shown in the figure above, and the synthetic operation method is similar to that of compound 17.

[0196] a. The product 2-methylpropyl-2-yl 4-(2-{4-[2-(2,6-dioxopyridin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-2-oxoethyl)pyridin-1-carboxylate (270 mg 77%) was obtained as a yellow solid. LC_MS: (ES + ):m / z 568.20[M+H] + .t R =2.637min.Molecular formula: C 29 H 37 N5O7, molecular weight: 567.64

[0197] b. The product 2-(2,6-dioxopyridin-3-yl)-5-{4-[2-(pyridin-4-yl)acetyl]piperazine-1-yl}isoindole-1,3-dione hydrochloride (260 mg 98%) was obtained as a yellow solid. LC_MS: (ES + ):m / z 468.55[M+H] + .t R =1.213min.Molecular formula: C 24 H 29 N5O5, molecular weight: 467.53

[0198] c. The final product, 5-[4-(2-{1-[3-({4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazin-4-yl)propyl]oxy}quinazolin-7-yl}oxy)propyl]piperidin-4-yl}acetyl)piperazin-1-yl]-2-(2,6-dioxopyridin-3-yl)isoindole-1,3-dione (35 mg 19%), was obtained as a yellow solid.

[0199] 1 H NMR (400MHz, DMSO) δ11.10(s,1H),10.28(d,J=81.5Hz,1H),9.40(s,1H),8.73(s,1H),8.06(dd,J=6.8,2.5Hz,1H),8.01(s,1H ),7.76–7.71(m,2H),7.53(t,J=9.1Hz,1H),7.38-7.33(m,2H),7.27(dd,J=8.6,1.8Hz,1H),5.09(dd,J=12.9,5.4Hz,1H),4.3 1–4.26(m,4H),4.04(d,J=11.3Hz,2H),3.64(s,5H),3.54(s,4H),3.27-3.21(m,4H),3.15(s,3H),3.05-2.97(m,2H),2.95-2. 82(m,2H),2.62-2.52(m,3H),2.39(d,J=6.0Hz,2H),2.32-2.20(m,5H),2.08–1.92(m,5H),1.44(q,J=12.5Hz,2H).LC_MS:(ES + ):m / z 940.25[M+H] + .t R =1.775min.Molecular formula: C 48 H 55 ClFN9O8, molecular weight: 940.47. Total number of hydrogen atoms calculated from H NMR data: 55

[0200] Example 25 Synthesis of Compound 46

[0201] a. 4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazinan-4-yl)propyl]oxy}quinazolin-7-ol (70 mg, 0.162 mmol) was dissolved in DMF (2 ml). 8-{[(4-methylphenyl)dioxo-λ6-thio]oxy}-3,6-dioxooctyl-1-yl p-toluenesulfonate (445 mg, 0.972 mmol)) and KCO (67 mg, 0.486 mmol) were added. The reaction mixture was heated to 50° C. and stirred for 16 hours. Liquid chromatography-mass spectrometry (LCMS) indicated the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (ethyl acetate:methanol=20:1 v / v) to give 8-({4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazinan-4-yl)propyl]oxy}quinazolin-7-yl}oxy)-3,6-dioxooctyl-1-yl p-toluenesulfonate (100 mg, 86%) as a white solid. LC_MS: (ESI): + ):m / z 720.45[M+H] + .t R =1.828min.Molecular formula: C 34 H 40 ClFN4O8S, molecular weight: 719.2224

[0202] b. 8-({4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazinan-4-yl)propyl]oxy}quinazolin-7-yl}oxy)-3,6-dioxooctyl-1-yl p-toluenesulfonate (100 mg, 0.139 mmol) was dissolved in DMF (1.5 ml). 2-(2,6-dioxohexadihydropyridin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione hydrochloride (63 mg, 0.167 mmol) and potassium phosphate (147 mg, 0.694 mmol) were added, and the mixture was heated to 50° C. and stirred for 16 hours. Liquid chromatography-mass spectrometry (LCMS) showed the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (chloroform:methanol=10:1 v / v) to give 5-{4-[8-({4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazinan-4-yl)propyl]oxy}quinazolin-7-yl}oxy)-3,6-dioxooctyl-1-yl]piperazin-1-yl}-2-(2,6-dioxohexadihydropyridin-3-yl)isoindole-1,3-dione (14 mg 11%) as a yellow solid.

[0203] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.69(s,1H),8.49(s,1H),8.16(s,1H),7.99– 7.80(m,2H),7.62(d,J=8.5Hz,1H),7.43(t,J=9.1Hz,1H),7.30(s,1H),7.24(s,1H) ,7.15(d,J=8.5Hz,1H),5.06(d,J=18.2Hz,1H),4.26(d,J=30.2Hz,5H),3.87(s,3H) ,3.73–3.53(m,14H),2.95–2.81(m,2H),2.60(s,10H),2.13–1.94(m,4H).LC_MS:(ES + ):m / z 889.10[M] + .t R =1.500min.Molecular formula: C 44 H 50 ClFN8O9, molecular weight: 889.3794. Total hydrogen atoms calculated from H NMR data: 50

[0204] Example 26 Synthesis of Compound 47

[0205] a. 4-((3-chloro-4-fluorophenyl)amino)-6-(3-morpholinopropoxy)quinazolin-7-ol (150 mg, 0.346 mmol) and 2-bromo-1-chloroethane (99 mg, 0.693 mmol) were dissolved in DMF (1.5 ml). KCO (143 mg, 1.039 mmol) was added, and the reaction mixture was heated to 50°C and stirred for 16 hours. Liquid chromatography-mass spectrometry indicated the reaction was complete. The resulting mixture was filtered and concentrated under reduced pressure to afford the crude product, which was purified by thin-layer chromatography (ethyl acetate:methanol = 40:1 v / v) to afford 7-[(2-chloroethyl)oxy]-4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazinan-4-yl)propyl]oxy}quinazoline (139 mg, 81%). Liquid chromatography mass spectrometry (LC-MS): (ES+): m / z 496.30 [M+H] + .t R =1.704min.Molecular formula: C 23 H 25 Cl2FN4O3; molecular weight: 495.38.

[0206] b. 7-[(2-chloroethyl)oxy]-4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazin-4-yl)propyl]oxy}quinazoline (139 mg, 0.28 mmol) was dissolved in DMF (2.5 ml). 2-(2,6-dioxohexahydropyridin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione hydrochloride (128 mg, 0.337 mmol) and K2CO3 (298 mg, 1.404 mmol) were added. The reaction mixture was heated to 75°C and stirred for 30 hours. Liquid chromatography-mass spectrometry indicated the reaction was complete. The resulting mixture was filtered and concentrated under reduced pressure to obtain a crude product, which was then purified by thin-layer chromatography (dichloromethane:methanol = 8:1 v / v) to afford the crude product. Further purification by preparative thin layer chromatography gave 5-{4-[2-({4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazin-4-yl)propyl]oxy}quinazolin-7-yl}oxy)ethyl]piperazin-1-yl}-2-(2,6-dioxapiperidin-3-yl)isoindole-1,3-dione (4.5 mg, 4%). 1 H NMR (400MHz, CD3OD) δ8.44(s,1H),8.00(dd,J=6.7,2.6Hz,1H),7.75(s,1H),7.72–7.64(m,2H),7.37(d,J=2.2Hz ,1H),7.29–7.22(m,2H),7.20(s,1H),5.06(dd,J=12.5,5.5Hz,1H),4.57(s,2H),4.38(t,J=5.0Hz,2H),4.26(t, 3.71 (t, J = 8.0 Hz, 4H), 3.64 (s, 1H), 3.56–3.47 (m, 4H), 3.02 (t, J = 5.0 Hz, 2H), 2.92–2.88 (m, 3H), 2.87–2.81 (m, 1H), 2.79–2.74 (m, 1H), 2.73–2.66 (m, 3H), 2.57 (s, 2H), 2.17–2.07 (m, 3H). LC-MS: (ES+): m / z 801.60 [M+H] + .t R =2.886min.Molecular formula: C 40 H 42 ClFN8O7; molecular weight: 801.27. Nuclear magnetic resonance data showed a total of 42 hydrogen atoms.

[0207] Example 27 Synthesis of Compound 48

[0208] The synthetic route is shown in the figure above, and the synthetic operation method is similar to that of compound 47.

[0209] a. The product 4-[(3-chloro-4-fluorophenyl)amino]-7-[(3-chloropropyl)oxy]-6-{[3-(1,4-oxazepan-4-yl)propyl]oxy}quinazoline (107 mg, 60%) was obtained. Liquid chromatography-mass spectrometry (LC-MS): (ES+): m / z 510.35 [M+H] + .t R =1.810min.Molecular formula: C 24 H 27 Cl2FN4O3; molecular weight: 509.40.

[0210] b. The final product 5-{4-[3-({4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazepan-4-yl)propyl]oxy}quinazolin-7-yl}oxy)propyl]piperazin-1-yl}-2-(2,6-dioxypyridin-3-yl)isoindole-1,3-dione (8.1 mg, 5%) was obtained.

[0211] 1 H NMR (400MHz, CD3OD) δ8.69(s,1H),7.96(s,1H),7.94(dd,J=6.6,2.6Hz,1H),7.73(d,J=8.5Hz,1H),7.69-7.61(m,1H), 7.45(d,J=2.1Hz,1H),7.38–7.29(m,2H),7.23(s,1H),5.14(dd,J=12.8,5.5Hz,1H),4.36(t,J=5.4Hz,2H),4.28(t,J= 5.3Hz,2H),4.12-4.05(m,2H),3.82(s,2H),3.69(t,J=8.0Hz,4H),3.51(t,J=16.0Hz,3H),3.38(t,J=12.0Hz,4H),3.35-3.305(m,5H),2.97–2.85(m,2H),2.74-2.59(m,1H),2.43-2.33(m,2H),2.19-2.07(m,3H).LC-MS:(ES+):m / z 815.55[M+H] e .t R =3.096min.Molecular formula: C 41 H 44 ClFN8O7; molecular weight: 815.30. Nuclear magnetic resonance data showed a total of 44 hydrogen atoms.

[0212] Example 28 Synthesis of Compound 49

[0213] The synthetic route is shown in the figure above, and the synthetic operation method is similar to that of compound 47.

[0214] a. The product 7-[(4-chlorobutyl)oxy]-4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazinan-4-yl)propyl]oxy}quinazoline (100 mg, 55%) was obtained. Liquid chromatography-mass spectrometry (LC-MS): (ES+): m / z 524.35 [M+H] + .t R =1.939min.Molecular formula: C 25 H 29 Cl2FN4O3; molecular weight: 523.43.

[0215] b. The final product 5-{4-[4-({4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazin-4-yl)propyl]oxy}quinazolin-7-yl}oxy)butyl]piperazin-1-yl}-2-(2,6-dioxopyridin-3-yl)isoindole-1,3-dione (10.4 mg, 6%) was obtained.

[0216] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.50(s,1H),8.74(s,1H),8.05(dd,J=6.8,2.5Hz,1H),8.02(s,1H ),7.78(d,J=8.4Hz,1H),7.76-7.70(m,1H),7.54(d,J=9.1Hz,1H),7.51–7.46(m,1H),7.40–7.33(m,2H), 5.16–5.02(m,1H),4.30-4.24(m,4H),4.00(s,4H),3.36-3.23(m,9H),3.17(s,3H),2.94-2.84(m,1H),2.71-2.51(m,3H),2.494–2.45(m,3H),2.31–2.23(m,2H),2.08-2.00(m,1H),1.90(s,4H). Liquid chromatography-mass spectrometry (LC-MS): (ES + ):m / z 829.60[M+H] + .t R =1.826min.Molecular formula: C 42 H 46 ClFN8O7, molecular weight: 829.33 NMR data showed that the total number of hydrogen atoms was 46.

[0217] Example 29 Synthesis of Compound 50

[0218] The synthetic route is shown in the figure above, and the synthetic operation method is similar to that of compound 15.

[0219] a. The product 2-methylpropane-2-yl 4-({4-[2-(2,6-dioxohexanedihydropyridin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)hexanedihydropyridine-1-carboxylate (133 mg 63%) was obtained as a yellow solid. Molecular formula: C 28 H 36 FN5O6, molecular weight: 556.64

[0220] b. The product 2-(2,6-dioxohexanedihydropyridin-3-yl)-6-fluoro-5-[4-(hexanedihydropyridin-4-ylmethyl)piperazin-1-yl]isoindole-1,3-dione hydrochloride (102 mg 90%) was obtained as a khaki solid. LC_MS: (ES + ):m / z 458.36[M+H] + .t R =0.721,0.964min.Molecular formula: C 23 H 28 FN5O4, molecular weight: 457.51

[0221] c. The final product, 5-[4-{1-[3-{4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-(1,4-oxazin-4-yl)propyl]oxy}quinazolin-7-yl}oxy)propyl]hexahydropyridin-4-yl}methyl)piperazin-1-yl]-2-(2,6-dioxohexadihydropyridin-3-yl)-6-fluoroisoindole-1,3-dione (19 mg 9%), was obtained as a yellow solid.

[0222] 1H NMR (400MHz, DMSO) δ11.15(s,1H),10.07(d,J=84.8Hz,1H),8.84(s,1H),8.08(s,1H),8.03(dd,J=6.8,2.5Hz,1H),7.85(d,J=11.1Hz ,1H),7.75–7.68(m,1H),7.62(d,J=7.4Hz,1H),7.56(t,J=9.0Hz,1H),7.44(s,1H),5.14(dd,J=12.8,5.4Hz,1H),4.35–4.16(m,4H), 4.03(d,J=11.2Hz,2H),3.81(d,J=9.9Hz,2H),3.75-3.49(m,7H),3.40–3.31(m,2H),3.31-3.05(m,10H),3.03–2.80(m,3H),2.65–2. 53(m,1H),2.34-2.19(m,4H),2.10–2.00(m,1H),1.92(d,J=12.7Hz,2H),1.71–1.52(m,3H),1.43(dd,J=24.4,12.4Hz,2H).LC_MS:(ES + ):m / z 930.25[M+H] + .t R =1.637min.Molecular formula: C 47 H 54 ClF2N9O7, molecular weight: 930.45. Total hydrogen atoms calculated from H NMR data: 54

[0223] Biological Experiment Section

[0224] 1. Bioactivity Assay-Western Blotting

[0225] Methods: Table 1 Types of human tumor cell lines and EGFR mutation sites

[0226] HCC827 cells were seeded into six-well plates. After the cells were completely attached (about 16 hours later), different concentrations of compounds (dissolved in DMSO) or the control compound Gefitinib (whose structural formula is ), and continue to culture for 24 hours (final DMSO concentration is 0.2%). The cells were lysed with RIPA lysis buffer (containing protease inhibitors) and then ultrasonically lysed. Let it stand on ice for 30 minutes, quantify it by BCA method, dilute the protein with 5x protein loading buffer and heat it at 100°C for 10 minutes for denaturation. The protein sample was separated by SDS-PAGE, transferred to a PVDF membrane, blocked with 5% skim milk for 1 hour, and incubated with the primary antibody at 4°C overnight. The membrane was washed with TBST, incubated with the secondary antibody at 1:30000 at room temperature for 30 minutes, and exposed to the chemiluminescence imager (Shanghai Tianneng) after washing. As shown in Figure 1, in HCC827 cells, each compound degraded EGFR to varying degrees at a concentration of 1 μM.

[0227] Methods: The grayscale values ​​of the bands were analyzed using Image J software, and the degradation rate of EGFR protein by each compound at a concentration of 100 nM was calculated. The results are shown in Table 1 below.

[0228] Table 1 Percentage of EGFR protein degradation by a series of compounds

[0229] a From at least two independent tests

[0230] Table 1 shows that compounds 5, 9, 10, 11, 12, 13 and 14, 15, 17, 27, 29, 31, 33, 34, 43, 45, and 46 have relatively significant degradation effects, all >70%. Combined with the degradation effects of the compounds at a concentration of 10 nM in Figure 1, compounds 12 and 14 with better degradation effects were selected and further tested for their half-maximal degradation concentration (DC) of EGFR protein in HCC827 cells. 50 ).

[0231] Figure 2 shows the expression levels of EGFR and related downstream proteins - phosphorylated epidermal growth factor receptor (pEGFR) and phosphorylated protein kinase (pAKT) in HCC827 cells after treatment with different concentrations of compounds 12 and 14 for 24 hours, as well as the expression levels of internal reference proteins - protein kinase (AKT) and β-actin (β-actin). The results show that both compounds 12 and 14 degrade EGFR protein in a concentration-dependent manner. Based on the grayscale value, the DC of compounds 12 and 14 was calculated. 50 , and the results are shown in Table 2 below.

[0232] Table 2 EGFR protein degradation experiment of compounds 12 and 14 DC 50 value

[0233] a From at least two independent tests

[0234] 2. Bioactivity Assay - Selectivity of Compounds 12 and 14

[0235] Western blot experiments were performed to determine the degradation effects of the compounds on the corresponding EGFR in BaF3 (EGFR L858R) mutant cell lines, H1299, H460, Hela and other EGFR wild-type cell lines, and H1975 EGFR L858R / T790M mutant cell lines.

[0236] Methods: BaF3 (EGFR L858R), H1299, H460, Hela, and H1975 cells were seeded into six-well plates and cultured. After the cells were fully adhered, different concentrations of compounds 12 and 14 (dissolved in DMSO solution) were added and cultured for 24 hours (the final DMSO concentration was 0.2%). The cells were lysed with RIPA lysis buffer (containing protease inhibitors), the sample protein was quantified, and a protein immunoblotting experiment was performed. The experimental steps were the same as above, and Figures 3 and 4 show the experimental results. As can be seen from Figure 3, compound 14 effectively degraded EGFR L858R protein in the BaF3 (EGFR L858R) cell line, and the half-degradation concentration DC was obtained by calculating the gray value. 50 As shown in Figure 4, compounds 12 and 14 had no significant degradation effect on wild-type EGFR in H1299, H460, and Hela cells, and L858R / T790M mutant EGFR in H1975 cells at a concentration of 1 μM.

[0237] 3. Bioactivity assay-cell activity experiment

[0238] Method: 5x10 3 (48h) or 2x10 3 HCC827 cells (96h) were seeded in 96-well plates for cultivation. After the cells were completely attached, different concentrations of compound 12, compound 14 and the control compound Gefitinib were added and cultured in a 37°C, 5% CO2 incubator for 48h or 96h. The CCK8 experiment measured cell activity, and the specific steps were as follows: remove the original culture medium, add 100uL CCK8 working solution to each well and continue to culture for 1h, measure the absorbance (OD value) at a wavelength of 450nm using a full-wavelength reader, and calculate the compound concentration with a growth inhibition rate of 50% (GI 50 ), and the results are shown in Figure 5 and Table 3.

[0239] Table 3 Effects of Compound 12, Compound 14, and Gefitinib on GI function of HCC827 cells 50 value

[0240] 4. Bioactivity assay-cell clone formation experiment

[0241] HCC827 cells in the logarithmic growth phase were cultured at a rate of 1×10 3 Cells were seeded in 24-well plates and cultured. After complete cell attachment, various concentrations of compound 14 were added and cultured in a 37°C, 5% CO2 incubator for 7 days. After colony formation, the cells were washed three times with PBS and fixed with 0.5 mL of anhydrous methanol for 30 minutes per well. The methanol was removed, and 0.5 mL of crystal violet stain was added. The cells were stained for 10 minutes, washed with water, and photographed after drying. The number of colonies was counted using Image J software. The experimental results are shown in Figure 6. As can be seen from Figure 6, compound 14 effectively inhibited the colony formation of non-small cell lung cancer HCC827 cells at a concentration of 12.5 nM.

[0242] In addition, we found that although compound 3 had a general degradation effect on EGFR in HCC827 Exon 19 deletion mutant cells (see Table 1), as can be seen in Figure 7, compound 3 had a good degradation effect on EGFR in the H1975 EGFR L858R / T790M mutant cell line, with the degradation rate of EGFR reaching 25.34±13% at a concentration of 10 nM and 46.32±19.66% at a concentration of 100 nM.

[0243] Therefore, compounds 12 and 14 can selectively degrade Exon 19 deletion and L858R mutant EGFR, with no significant effect on wild-type or L858R / T790M mutant EGFR, and have a strong inhibitory effect on EGFR mutation-driven tumor cells. Compound 3 can selectively degrade L858R / T790M mutant EGFR, with no significant effect on wild-type. These compounds can be used to treat a variety of diseases caused by EGFR mutations, including cancer.

[0244] The above embodiments are only intended to help understand the method and core concept of the present invention. It should be noted that, without departing from the principles of the present invention, a number of improvements and modifications may be made to the present invention by those skilled in the art, and such improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof, in: Ring B represents a CRBN ligand, and ring B contains a benzene ring, a five-membered nitrogen-containing heterocycle, and a six-membered nitrogen-containing heterocycle, and the benzene ring portion of ring B is connected to A; A represents a connecting fragment, and the main chain of A contains 6 to 25 atoms other than hydrogen atoms; R1 is selected from H, C1-8 alkyl, C1-8 alkenyl, or a carbon chain containing a 4-8 membered heterocycle on the main chain, and combinations thereof; R5, R6 are independently selected from F, Cl or Br.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The ring B is selected from the following structures: in: R2 and R3 are each independently selected from halogen, cyano, C1-8 alkyl and C1-8 alkoxy; m is an integer from 0 to 3; n is an integer from 0 to 2; l is an integer from 0 to 3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The ring B is R2 is halogen, and m is 0 or 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The A is in a straight chain.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The A includes 1 to 2 4- to 8-membered cycloalkylene groups or 1 to 2 4- to 8-membered heterocycloalkylene groups on the main chain.

6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, characterized in that: The linear A contains 1 to 8 heteroatoms, and the heteroatoms are selected from O or N.

7. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, characterized in that: The 4-8 membered heterocycloalkylene group contains 1-2 heteroatoms, and the heteroatom is N.

8. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, characterized in that: The A includes 1-2 six-membered heterocycloalkylene groups on the main chain, and the six-membered heterocycloalkylene groups contain 1-2 N atoms.

9. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, characterized in that: Said A includes 1-2 4-8 membered heterocycloalkylene groups on the main chain, and said A also includes a carbonyl group on the main chain, and said carbonyl group is connected to a heteroatom in said 4-8 membered heterocycloalkylene group.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The 4-8 membered heterocyclic ring in R1 contains 1-2 heteroatoms, and the heteroatoms are selected from O, S or N.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The A is selected from the following structures: -O(CH2) x -O-, wherein x is an integer of 4-12, y is an integer of 6-12, z is independently an integer of 2-5, p is an integer of 1-5, and q is independently an integer of 2-4.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The A is selected from the following structures: wherein y is an integer of 7-10, z is independently an integer of 2-5, p is an integer of 1-5, and q is independently an integer of 2-4.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The R1 is selected from a C1-8 straight or branched alkyl group or Wherein R7 is a C1-6 alkylene group.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The R1 is selected from methyl or Wherein R7 is -CH2CH2CH2.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R5 is F, R6 is Cl; and / or, R2 and R3 are both halogen.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the compounds shown in the following structures:

17. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof as a proteolysis-targeting chimera PROTAC for epidermal growth factor receptor EGFR.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier.

19. The pharmaceutical composition according to claim 18, characterized in that: The pharmaceutical composition is a pharmaceutical preparation, and the pharmaceutical preparation is selected from tablets, powders, capsules, granules, oral liquids, injections, suppositories, pills, creams, pastes, gels, powders, inhalants, suspensions, dry suspensions, patches, lotions, and nano preparations.

19. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for preparing a drug for treating tumors.

20. The use according to claim 19, characterized in that: The tumor is selected from one or more combinations of esophageal cancer, gastric cancer, glioblastoma, anal cancer, head and neck epithelial cancer, head and neck squamous cell carcinoma, breast cancer, lung cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, brain metastasis, solid tumor, oropharyngeal cancer, bronchial tumor and skin cancer.

21. A method for treating a disease responsive to degradation of an EGFR mutant protein, characterized in that: The method comprises administering an effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof to an animal or human in need of treatment.

22. The method according to claim 21, characterized in that: The disease responsive to degradation of EGFR mutant protein is selected from esophageal cancer, gastric cancer, glioblastoma, anal cancer, head and neck epithelial cancer, head and neck squamous cell carcinoma, breast cancer, lung cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, brain metastases, solid tumors, oropharyngeal cancer, bronchial tumors and skin cancer. One or more combinations thereof.

23. The method according to claim 21, characterized in that: The disease responsive to degradation of EGFR mutant protein is lung cancer; preferably non-small cell lung cancer.

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