Compound for targeted degradation of phosphatidylinositol 3-kinase as well as preparation method and application of compound

Abstract

The invention discloses a series of compounds targeting PI3K protein and a preparation method and application thereof. The structural formula of the compounds is shown as a formula I or pharmaceutically acceptable salts of the compounds. Pharmacological activity tests show that the compound has a good inhibition effect on PI3K kinase activity, has good anti-proliferative activity on various tumor cells, and can significantly degrade PI3K protein. Therefore, the compounds can provide an effective degradation inhibitor for treatment of diseases regulated by PI3K, and are expected to be developed into targeted drugs for treating diseases related to PI3K signal pathways, such as gastric cancer, breast cancer, ovarian cancer, melanoma, colorectal cancer, leukemia and the like. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a compound for targeted degradation of phosphatidylinositol 3-kinase, and a preparation method and application thereof. Background Art

[0002] Phosphatidylinositol 3-kinase (PI3K) is an important signal transduction molecule in cells, which is involved in regulating various physiological processes such as cell growth, proliferation, survival, and metabolism. Abnormal activation of the PI3K signaling pathway is closely related to the occurrence and development of various diseases, especially tumors. Therefore, in-depth research on PI3K targets, signaling pathways, and related inhibitors is of great significance for the development of new anti-tumor drugs. PI3K is a class of heterodimers composed of regulatory subunits and catalytic subunits. Its catalytic subunits include class I p110α, p110β, p110δ, and p110γ. When the receptor tyrosine kinase (RTK) or G protein-coupled receptor (GPCR) on the cell surface is activated by a ligand, PI3K is recruited to the cell membrane, and its catalytic subunit phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-triphosphate (PIP3). As a second messenger, PIP3 can bind to Akt and recruit it to the plasma membrane, where Akt is activated by phosphorylation of rapamycin complex TORC2 (mTORC2) and phosphoinositide-dependent kinase 1 (PDK1) on Ser-473 or threonine residues. Activated Akt can phosphorylate a variety of downstream substrates, such as tuberous sclerosis complex (TSC1-TSC2), thereby activating rapamycin complex TORC1 (mTORC1), ultimately regulating processes such as cell growth, protein synthesis, and cell survival. In addition, Akt can also phosphorylate FOXO family transcription factors, causing them to be transported from the nucleus to the cytoplasm, thereby inhibiting their transcriptional activation of apoptosis-related genes.

[0003] Some PI3K inhibitors lack sufficient selectivity for different subtypes of PI3K and may inhibit multiple subtypes at the same time, leading to increased adverse reactions. For example, Pan-PI3K inhibitors act on the four catalytic subunits of class I PI3K at the same time. Although the therapeutic effect is good, it also brings more adverse events. Long-term use of PI3K inhibitors can easily lead to drug resistance in tumor cells. On the one hand, tumor cells may bypass the effects of PI3K inhibitors by activating other alternative signaling pathways; on the other hand, the PI3K signaling pathway in tumor cells may change through mutations or other mechanisms, making it impossible for inhibitors to effectively bind or inhibit. Some PI3K inhibitors show high toxicity in clinical applications, such as skin toxicity, gastrointestinal toxicity, metabolic disorders, etc., which limits their application dose and range in clinical treatment.

[0004] PI3K targets and their signaling pathways play a key role in the occurrence and development of tumors. Although existing PI3K inhibitors have shown anti-tumor activity to a certain extent, they also have problems such as low selectivity, drug resistance and toxic reactions. By developing more selective inhibitors, adopting combination drug strategies, implementing personalized medicine, and conducting in-depth research on drug resistance mechanisms, it is expected that existing problems will be overcome, and the research and development and clinical application of PI3K targeted drugs will be further promoted, providing more effective treatment options for cancer patients. Summary of the invention

[0005] Purpose of the invention: In view of the problems existing in the above-mentioned prior art, the present invention provides several new compounds for targeted degradation of PI3K protein, which have obvious inhibitory effect on PI3Kα enzyme activity and show good anti-tumor activity. These compounds show strong PI3Kα protein degradation activity, so it is expected to develop targeted degradation drugs for treating diseases related to PI3K signaling pathway, such as gastric cancer, breast cancer, ovarian cancer, leukemia, etc. The present invention also provides the specific preparation method and medical use of the compounds and their intermediates.

[0006] Technical solution: A compound or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound structure is shown in general formula I: ; Linker is a connecting group, and the connecting group is selected from , , ; m is an integer selected from 0 to 25; w -CH2- in the straight chain of the linking group is replaced by one or both of -O- and -CONH-, w is an integer selected from 0 to 5, and m≥w. Preferably, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25.

[0007] In the compound or its pharmaceutically acceptable salt or tautomer, 0 to 5 -CH2- in the straight chain of the linking group are replaced by one or two of 0 to 4 -O-, 0 to 2 -CONH-. Preferably, 0, 1, 2, 3, 4, 5 -CH2- are replaced by one or two of 0, 1, 2, 3, 4, 0, 1, 2 -CONH-. to exist or not to exist;

[0008] Preferably, the compound structure is as follows: .

[0009] The compound or its pharmaceutically acceptable salt, tautomer, the -NH- group in the connecting group and connected.

[0010] Preferably, in the compound or its pharmaceutically acceptable salt or tautomer, the linking group is selected from: , , , , , , , , , ; p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; q is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; r is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; s is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; t is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0011] The compound or its pharmaceutically acceptable salt, tautomer, wherein the pharmaceutically acceptable salt is a salt formed by the compound of general formula I and one or more acids, wherein the acid used for salt formation includes inorganic acids and organic acids, wherein the inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid; the organic acids include acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid and tartaric acid.

[0012] The compound or its pharmaceutically acceptable salt or tautomer, wherein the compound is selected from I-1 to I-21: .

[0013] The preparation method of the compound or its pharmaceutically acceptable salt or tautomer, the reaction route of the compound is as follows: .

[0014] The pharmaceutical composition comprises the compound or its pharmaceutically acceptable salt, tautomer, and a pharmaceutically acceptable carrier.

[0015] Use of the compound or its pharmaceutically acceptable salt, tautomer and stereoisomer or the pharmaceutical composition in the preparation of a PI3K target degradation inhibitor.

[0016] Use of the compound or its pharmaceutically acceptable salt, tautomer and stereoisomer or the pharmaceutical composition in the preparation of drugs for treating diseases regulated by PI3K.

[0017] In the application, the disease regulated by PI3K includes tumor.

[0018] The pharmaceutical composition can be in the form of tablets, capsules, granules, powders, syrups, oral solutions or injections, etc., which are conventional pharmaceutical preparations.

[0019] The present application also provides the use of the compound described in general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a PI3K target degradation inhibitor. Furthermore, the compound or a pharmaceutically acceptable salt thereof can be used for the preparation of a drug for treating a disease regulated by PI3K. Preferably, the disease related to the PI3K signaling pathway is cancer, immune disorder or inflammatory disorder, and cancer mainly includes gastric cancer, breast cancer, prostate cancer, lung cancer, liver cancer, bone cancer, brain cancer, head and neck cancer, intestinal cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer, endometrial cancer, multiple myeloma, etc.

[0020] Principle of the invention: The compound of the present invention is a degrader based on the proteasome system to degrade proteins. When the PROTAC molecule of PI3K binds to the PI3K protein in the cell, the PROTAC molecule will cause the PI3K protein to bind to the ubiquitin ligase, resulting in the ubiquitination of the PI3K protein, and the PI3K protein is marked as a target for degradation. Ubiquitinated PI3K will be recognized by the proteasome and eventually degraded. Since PI3K kinase is a key factor in the occurrence and development of tumors, by promoting the degradation of PI3K protein, the PI3K kinase and non-kinase functions can be effectively inhibited, thereby inhibiting the growth and spread of tumors. Compared with traditional drug target inhibitors, PI3K PROTAC can degrade PI3K protein levels more rapidly, can effectively degrade PI3K protein and has a significant killing effect on various tumor cells, which can effectively solve the problems of lack of effectiveness, safety and drug resistance of clinically targeted PI3K.

[0021] Beneficial effects: Compared with the prior art, the present application provides a series of novel compounds that regulate PI3K protein. After biochemical activity tests, the present application shows that the compounds have a good inhibitory effect on PI3K kinase activity, good anti-proliferative activity on a variety of tumor cells and can significantly degrade PI3K protein. Therefore, these compounds can provide effective degradation inhibitors for the treatment of diseases regulated by PI3K, and are expected to develop targeted drugs for the treatment of diseases related to the PI3K signaling pathway, such as gastric cancer, breast cancer, ovarian cancer, melanoma, colorectal cancer and leukemia. DETAILED DESCRIPTION

[0022] The present application is described in detail below in conjunction with specific embodiments.

[0023] The raw materials used in the synthesis of the present invention were directly purchased or prepared by conventional operations, and the commercially available raw materials were directly used in chemical reactions without special instructions without treatment.

[0024] (1) The synthesis of compound W1 was based on patent CN 113200969 B.

[0025] (2) Synthesis of compound W2:

[0026] 11-Bromoundecanoic acid (1.01 equivalents) and N,N-diisopropylethylamine (3 equivalents) were added to the DMF solution of the raw material W1 (1 equivalent), and the reaction was carried out at 80 degrees Celsius for 5 hours. The reaction was monitored by TLC plate. The reaction was stopped after the raw material was completely reacted. The intermediate W2 was separated by column chromatography with 80% purity and 40% yield, and was directly used in the subsequent reaction without further purification.

[0027] (3) Synthesis of compounds W3 and W4:

[0028] To a DMF solution of the raw material W1 (1 equivalent), 2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxyacetic acid or 1-tert-butyl 5,8,11-trioxa-2-azatridecane dioate (1.01 equivalent), 1-hydroxybenzotriazole (HOBT) (2 equivalents), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (2 equivalents) and triethylamine (3 equivalents) were added, and the reaction was carried out at room temperature for 6 hours. The reaction was monitored by TLC plate. When the raw material was completely reacted, the reaction was stopped. The intermediate M3 or M4 was separated by column chromatography with a yield of 60%.

[0029] M3: 1 H NMR (400 MHz, DMSO- d 6) δ 8.15 (d, J= 1.6 Hz, 1H), 8.07 (dd, J =8.4, 1.7 Hz, 1H), 7.52 (s, 2H), 7.38 (d, J = 8.4 Hz, 1H), 6.73 (t, J = 5.7 Hz,1H), 4.20 (s, 2H), 4.00 – 3.72 (m, 8H), 3.66 (t, J = 4.8 Hz, 4H), 3.60 – 3.48(m, 12H), 3.37 (t, J = 6.1 Hz, 2H), 3.05 (q, J = 6.0 Hz, 2H), 1.36 (s, 9H). Add 1 M hydrochloric acid ethyl acetate solution to the solid or oily product of M3 or M4, and react for two hours in an ice bath. After the reaction is completed, evaporate the solvent under reduced pressure to obtain intermediates W3 and W4, which are directly used in the next reaction.

[0030] (4) Synthesis of compounds W5, W6, and W7:

[0031] To a DMF solution of the raw material W1 (1 equivalent), add succinic acid monomethyl ester or adipate monomethyl ester or suberate monomethyl ester (1.01 equivalent), 1-hydroxybenzotriazole (HOBT) (2 equivalents), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (2 equivalents) and triethylamine (3 equivalents), react at room temperature for 6 hours, monitor the reaction with a TLC plate, and stop the reaction when the raw materials are completely reacted. Column chromatography separation gives the intermediate M5 or M6 or M7 with a yield of 55%.

[0032] M6: 1 H NMR (400 MHz, Chloroform- d ) δ 8.41 (d, J = 1.7 Hz, 1H), 8.22 (dd, J = 8.5, 1.7 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.33 (t, J = 12.3 Hz, 2H), 3.93(s, 8H), 3.77 (dd, J = 5.6, 3.9 Hz, 4H), 3.71 (d, J= 5.6 Hz, 2H), 3.67 (s, 3H), 3.54 (t, J = 5.2 Hz, 2H), 2.43 – 2.35 (m, 4H), 1.72 (d, J = 2.5 Hz, 4H). M7: 1 H NMR (400 MHz, Chloroform- d ) δ 8.41 (d, J = 1.6 Hz, 1H), 8.23 ​​(dd, J = 8.5, 1.6 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 5.43 (s, 2H), 3.93 (s, 8H), 3.78(t, J = 4.7 Hz, 4H), 3.71 (d, J = 5.7 Hz, 2H), 3.67 (s, 3H), 3.55 (s, 2H), 2.38(t, J = 7.6 Hz, 2H), 2.32 (t, J = 7.5 Hz, 2H), 1.73 – 1.60 (m, 4H), 1.38 (t, J =3.7 Hz, 4H). To the tetrahydrofuran aqueous solution (4:1) of the solid or oily substance of M5, M6 or M7, add 3.6 equivalents of lithium hydroxide, react at 50 degrees Celsius for 1 hour, detect the reaction by TLC, and if the raw material is completely reacted, spin-dry the tetrahydrofuran, add water to dissolve the solid, adjust the pH to neutral with 1N hydrochloric acid, extract three times with ethyl acetate, combine the organic phases, spin-dry the solvent to obtain the intermediates W5, W6, and W7, which are directly used in subsequent reactions.

[0033] (5) Synthesis of compounds W8 and W9:

[0034] N-Boc-β-alanine or tert-butyloxycarbonyl-11-aminoundecanoic acid (1.01 equivalent), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (2 equivalents), and N,N-diisopropylethylamine (3 equivalents) were added to a DMF solution of the raw material W1 (1 equivalent), and the reaction was carried out at room temperature for 6 hours. The reaction was monitored by TLC plate. The reaction was stopped when the raw material was completely reacted. The intermediate M8 or M9 was separated by column chromatography with a yield of 65%.

[0035] M8:1 H NMR (400 MHz, DMSO- d 6) δ 8.15 (d, J = 1.7 Hz, 1H), 8.07 (dd, J =8.4, 1.7 Hz, 1H), 7.52 (s, 2H), 7.38 (d, J = 8.4 Hz, 1H), 6.74 (t, J = 5.7 Hz,1H), 3.83 (s, 8H), 3.66 (t, J = 4.7 Hz, 4H), 3.53 (s, 4H), 3.17 (q, J = 6.7 Hz, 2H), 2.90 – 2.52 (m, 2H), 1.37 (s, 9H). Add 1 M hydrochloric acid ethyl acetate solution to the solid or oily product of M8 or M9, and react for two hours in an ice bath. After the reaction is completed, evaporate the solvent under reduced pressure to obtain intermediates W8 and W9, which are directly used in the next reaction.

[0036] Example 1

[0037] (1) Synthesis of 2-amino-N-(8-(3-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-5-oxopentyl)piperazin-1-yl)propoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide (I-1):

[0038] To the DMF solution of intermediate chain L1 (91 mg), HOBT (81 mg), EDCI (93 mg) and triethylamine (122 μl) were added in sequence, stirred at room temperature for 30 minutes, and W1 (126 mg) was added to the above solution, and reacted at room temperature overnight. The reaction was monitored by TLC. After the reaction was completed, the crude product was purified by silica gel column to obtain 105 mg of white solid with a yield of 48%. MS (ESI) m / z 724.75 [M+ H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.87 (s, 1H), 8.16 (d, J =1.6 Hz, 1H), 8.08 (dd, J = 8.3, 1.7 Hz, 1H), 7.85 (dd, J = 6.2, 2.8 Hz, 1H),7.52 (s, 2H), 7.50 – 7.46 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 5.15 (dd, J =13.3, 5.1 Hz, 1H), 4.52 – 4.24 (m, 2H), 3.97 – 3.84 (m, 8H), 3.68 – 3.66 (m,4H), 3.59 -3.56 (m, 4H), 2.97 -2.88 (m, 1H), 2.73 -2.71 (m, 2H), 2.67 – 2.59 (m, 3H), 2.38 -2.27 (m, 1H), 2.06 – 1.97 (m, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 173.32, 171.52, 170.52, 170.13, 168.37,165.10, 165.05, 163.80, 150.95, 144.21, 134.36, 133.96, 133.11, 132.99,129.11, 125.46, 121.49, 119.32, 115.40, 108.37, 66.51, 52.04, 46.96, 43.83,43.79, 31.67, 31.39, 28.20, 23.17. Example 2

[0039] (1) Synthesis of 2-amino-N-(8-(3-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-6-oxoisohexyl)piperazin-1-yl)propoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide (I-2):

[0040] Referring to the synthesis method of I-1, L2 (112 mg), W1 (126 mg) were used to obtain 98 mg of white solid with a yield of 44%. MS (ESI) m / z 738.78 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.82 (s, 1H), 8.15 (d, J =1.7 Hz, 1H), 8.07 (dd, J = 8.4, 1.7 Hz, 1H), 7.83 (dd, J = 6.8, 2.2 Hz, 1H),7.53 (s, 2H), 7.54 – 7.45 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 5.14 (dd, J =13.3, 5.1 Hz, 1H), 4.45 – 4.30 (m, 2H), 3.84 (d, J = 34.7 Hz, 8H), 3.66 (t, J= 4.8 Hz, 4H), 3.56 (s, 4H), 2.96 -2.87 (m, 1H), 2.64 – 2.55 (m, 1H), 2.44(t, J = 7.3 Hz, 4H), 2.38 – 2.32 (m, 1H), 2.06 – 1.99 (m, 1H), 1.87 (p, J =7.4 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 173.30, 171.58, 171.51, 170.99, 170.13,168.32, 165.10, 163.81, 150.96, 144.23, 134.26, 134.21, 133.16, 132.98,129.08, 125.75, 121.47, 119.46, 115.39, 108.36, 66.52, 66.51, 52.04, 47.00,43.79, 35.54, 32.18, 31.68, 23.11, 21.13. Example 3

[0041] (1) Synthesis of 2-amino-N-(8-(3-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-7-oxoheptyl)piperazin-1-yl)propoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide (I-3):

[0042] Referring to the synthesis method of I-1, W5 (100 mg) and lenalidomide (62 mg) were reacted to obtain 50 mg of white solid with a yield of 34%. MS (ESI) m / z 752.65 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.81 (s, 1H), 8.15 (d, J =1.7 Hz, 1H), 8.07 (dd, J = 8.4, 1.7 Hz, 1H), 7.80 (dd, J = 7.1, 1.8 Hz, 1H),7.53 – 7.52 (m, 2H), 7.51 – 7.46 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 5.15 (dd,J = 13.3, 5.1 Hz, 1H), 4.45 – 4.30 (m, 2H), 3.86 -3.78 (m, 8fH), 3.68 -3.65(m, 4H), 3.55 (d, J = 6.0 Hz, 4H), 2.98 – 2.86 (m, 1H), 2.65 – 2.56 (m, 1H), 2.45 – 2.30 (m, 5H), 2.05 – 1.99 (m, 1H), 1.68 -1.57 (m, 4H). 13 C NMR (151 MHz, DMSO-d6) δ 173.33, 171.77, 171.50, 171.24, 168.33,165.10, 163.81, 150.95, 144.21, 134.36, 134.24, 133.15, 132.99, 129.10,119.54, 115.39, 108.37, 66.49, 52.02, 46.98, 36.15, 32.57, 31.67, 25.40,24.80, 23.09. Example 4

[0043] (1) Synthesis of 2-amino-N-(8-(3-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-8-oxooctyl)piperazin-1-yl)propoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide (I-4):

[0044] Referring to the synthesis method of I-1, W6 (105 mg) and lenalidomide (62 mg) were reacted to obtain 60 mg of white solid with a yield of 39%. MS (ESI) m / z 780.65 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.77 (s, 1H), 8.15 (d, J =1.7 Hz, 1H), 8.07 (dd, J = 8.4, 1.7 Hz, 1H), 7.81 (dd, J = 7.0, 2.0 Hz, 1H),7.53 (s, 2H), 7.50 – 7.45 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 5.14 (dd, J =13.3, 5.1 Hz, 1H), 4.43 – 4.30 (m, 2H), 3.81 (s, 8H), 3.67 (d, J = 4.8 Hz,4H), 3.54 (s, 4H), 2.96 -2.87 (m, 1H), 2.64 – 2.56 (m, 1H), 2.36 (t, J = 7.6Hz, 5H), 2.07 – 1.99 (m, 1H), 1.63 -1.52 (m, 4H), 1.34 (s, 4H). 13 C NMR (151 MHz, DMSO-d6) δ 173.30, 171.86, 171.86, 171.52, 171.33,170.12, 165.10, 165.04, 163.81, 150.96, 144.24, 134.29, 132.99, 129.08,125.76, 121.46, 119.46, 115.39, 108.36, 66.51, 66.51, 52.04, 46.98, 43.79,36.25, 32.77, 31.68, 29.00, 28.98, 25.46, 25.13, 23.11. Example 5

[0045] (1) Synthesis of 2-amino-N-(8-(3-(4-(11-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-11-oxoundecyl)piperazin-1-yl)propoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide (I-5):

[0046] L5 (132 mg) and N,N-diisopropylethylamine (116 mg) were added to a DMF solution of W1 (115 mg). o C was reacted overnight, and the reaction was monitored by TLC. The raw material reaction was completed, and the crude product was purified by silica gel column (DCM / MeOH: 2% ~ 8%) to obtain 95 mg of white solid with a yield of 43%. MS (ESI) m / z 752.65 [M + H] + . 1 H NMR (600 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.77 (s, 1H), 8.14 (s,1H), 8.06 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.52 – 7.50 (m, 1H),7.49 (s, 2H), 7.45 (d, J = 4.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 5.14 (dd, J= 13.3, 5.2 Hz, 1H), 4.37 (q, J = 17.4, 15.6 Hz, 2H), 3.79 (s, 8H), 3.66 (t,J = 4.8 Hz, 4H), 3.51 (s, 1H), 2.95 – 2.89 (m, 1H), 2.63 – 2.60 (m, 1H), 2.44 – 2.32 (m, 8H), 2.04 – 1.97 (m, 1H), 1.67 – 1.61 (m, 2H), 1.52 – 1.49 (m,2H), 1.38 – 1.33 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 173.30, 171.82, 171.52, 170.05, 165.14,164.89, 163.79, 150.91, 144.21, 134.30, 134.16, 133.15, 133.07, 129.08,125.71, 121.41, 119.44, 115.35, 108.33, 66.51, 52.03, 46.99, 43.77, 40.57,36.25, 31.68, 27.01, 25.50, 23.14. Example 6

[0047] (1) Synthesis of 2-amino-N-(8-(3-(4-(9-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-9-oxoindolin-1-yl)piperazin-1-yl)propoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide (I-6):

[0048] Referring to the synthesis method of I-5, L6 (241 mg) and W1 (191 mg) were reacted to obtain 125 mg of a light yellow solid with a yield of 32%.

[0049] 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.77 (s, 1H), 8.14 (d, J =1.6 Hz, 1H), 8.06 (dd, J = 8.4, 1.7 Hz, 1H), 7.81 (dd, J = 7.1, 1.9 Hz, 1H),7.53 – 7.45 (m, 4H), 7.37 (d, J = 8.4 Hz, 1H), 5.15 (dd, J = 13.3, 5.1 Hz,1H), 4.46 – 4.28 (m, 2H), 3.91 – 3.59 (m, 12H), 2.97 – 2.87 (m, 1H), 2.64 –2.58 (m, 1H), 2.45 – 2.26 (m, 8H), 2.06 – 2.00 (m, 1H), 1.61 (t, J = 7.2 Hz,2H), 1.46 (s, 2H), 1.34 – 1.25 (m, 9H). 13C NMR (151 MHz, DMSO-d6) δ 173.30, 171.87, 171.52, 170.06, 168.31,165.14, 164.89, 163.79, 150.92, 144.21, 134.30, 134.18, 133.15, 133.07,129.08, 125.73, 121.42, 119.45, 115.35, 108.33, 66.51, 66.50, 52.03, 46.96,43.77, 36.28, 31.68, 29.30, 29.20, 29.10, 27.30, 25.54, 23.14. Example 7

[0050] (1) Synthesis of 2-amino-N-(7-methoxy-8-(3-(4-(8-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-8-oxooctyl)piperazin-1-yl)propoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide (I-7):

[0051] Referring to the synthesis method of I-5, L7 (249 mg) and W1 (191 mg) were reacted to obtain 151 mg of a light yellow solid with a reaction yield of 38%.

[0052] 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.76 (s, 1H), 8.14 (d, J =1.6 Hz, 1H), 8.06 (dd, J = 8.4, 1.7 Hz, 1H), 7.81 (dd, J = 7.1, 1.9 Hz, 1H),7.54 – 7.45 (m, 4H), 7.37 (d, J = 8.4 Hz, 1H), 5.15 (dd, J = 13.3, 5.1 Hz,1H), 4.43 – 4.29 (m, 2H), 3.93 – 3.60 (m, 12H), 3.17 (d, J = 5.1 Hz, 2H),2.97 – 2.88 (m, 1H), 2.64 – 2.58 (m, 1H), 2.39 – 2.26 (m, 8H), 1.61 (t, J =7.1 Hz, 2H), 1.45 (s, 2H), 1.31 – 1.28 (m, 9H). 13 C NMR (151 MHz, DMSO-d6) δ 173.30, 171.87, 171.51, 170.05, 165.14,164.89, 163.79, 150.91, 144.21, 134.29, 134.19, 133.14, 133.08, 129.08,125.74, 121.42, 119.46, 115.35, 108.33, 66.51, 52.02, 46.96, 36.28, 31.68,29.38, 29.21, 29.11, 27.35, 25.55, 23.14. Example 8

[0053] Synthesis of 11-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)undecaneamide (I-8):

[0054] Referring to the synthesis method of I-5, L8 (256 mg) and W1 (191 mg) were reacted to obtain 146 mg of a light yellow solid with a reaction yield of 36%.

[0055] 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.77 (s, 1H), 8.14 (d, J =1.7 Hz, 1H), 8.06 (dd, J = 8.4, 1.7 Hz, 1H), 7.81 (dd, J = 7.0, 1.9 Hz, 1H),7.50 (dd, J = 7.9, 6.1 Hz, 4H), 7.37 (d, J = 8.4 Hz, 1H), 5.15 (dd, J = 13.3,5.1 Hz, 1H), 4.43 – 4.25 (m, 2H), 3.94 – 3.57 (m, 12H), 3.17 (d, J = 5.1 Hz,1H), 2.92 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.66 – 2.56 (m, 1H), 2.41 – 2.24(m, 6H), 2.08 – 1.94 (m, 1H), 1.59 (q, J = 7.1 Hz, 2H), 1.47 (s, 2H), 1.35 –1.20 (m, 13H), 1.21 (d, J = 6.5 Hz, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 173.31, 171.90, 171.51, 170.13, 168.33,164.91, 163.80, 150.94, 134.28, 134.19, 133.13, 129.09, 125.75, 121.46,119.47, 115.37, 108.35, 66.51, 66.50, 52.03, 46.98, 36.27, 31.68, 29.39,29.36, 29.31, 29.22, 29.11, 27.20, 25.54, 23.13, 19.27. Example 9

[0056] Synthesis of 4-((2-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (I-9):

[0057] L9 (166 mg) and HATU (380 mg) were added to the DMF solution of W1, and finally N,N-diisopropylethylamine (194 mg) was added. The reaction was carried out at room temperature for 5 hours. The reaction was monitored by TLC. After the reaction of the raw materials was completed, the crude product was purified by silica gel column (DCM / MeOH: 2% ~ 5%) to obtain 103 mg of yellow solid with a yield of 30%.

[0058] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.16 (d, J = 1.7 Hz, 1H), 8.09 (dd, J = 8.3, 1.7 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.52 (s, 2H), 7.39(d, J = 8.4 Hz, 1H), 7.14 – 7.07 (m, 3H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 4.27 (d, J = 4.6 Hz, 2H), 4.05 – 3.76 (m, 8H), 3.72 – 3.57 (m, 8H), 2.96 –2.83 (m, 1H), 2.64 – 2.53 (m, 2H), 2.11 – 1.98 (m, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 173.26, 170.53, 170.17, 169.29, 167.82,167.20, 165.12, 165.12, 163.81, 150.98, 145.99, 144.25, 136.68, 132.53,121.48, 118.66, 115.41, 111.34, 108.38, 66.52, 66.50, 49.09, 44.23, 43.81,31.47, 22.63. Example 10 Synthesis of 4-((3-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (I-10):

[0059] Referring to the synthesis method of I-9, L10 (173 mg) and W1 (191 mg) were reacted to obtain 97 mg of a yellow solid with a reaction yield of 27%.

[0060] 1 H NMR (400 MHz, Chloroform-d) δ 8.66 (s, 1H), 8.15 (dd, J = 8.5, 1.7Hz, 1H), 7.53 – 7.48 (m, 1H), 7.27 (s, 1H), 7.26 (s, 2H), 7.11 (d, J = 7.1Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.32 (s, 1H), 5.84 (s, 1H), 4.93 (dd, J =13.1, 5.3 Hz, 1H), 3.89 (s, 4H), 3.75 (t, J = 4.8 Hz, 8H), 3.64 (d, J = 18.7Hz, 2H), 3.47 – 3.39 (m, 4H), 3.03 (d, J = 12.3 Hz, 1H), 2.84 – 2.76 (m, 1H), 2.67 (s, 1H), 2.42 (s, 1H), 2.19 – 2.07 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 173.27, 170.97, 170.54, 169.32, 167.80,165.09, 165.05, 163.80, 150.95, 146.90, 144.21, 136.73, 117.79, 115.39,110.90, 109.60, 108.37, 66.51, 49.03, 42.07, 31.45, 29.97, 24.71, 22.64. Embodiment 11 Synthesis of 4-((6-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (I-11):

[0061] Referring to the synthesis method of I-9, L11 (195 mg) and W1 (191 mg) were reacted to obtain 126 mg of a yellow solid with a reaction yield of 33%.

[0062] 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.07 (dd, J = 8.3, 1.7 Hz, 1H), 7.57 (dd, J = 8.6, 7.0 Hz, 1H), 7.52 (s, 2H), 7.38 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.54 (t, J = 6.0 Hz, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 3.91 – 3.73 (m,8H), 3.66 (q, J = 4.7 Hz, 4H), 3.54 (s, 4H), 3.34 – 3.26 (m, 2H), 2.94 – 2.81(m, 1H), 2.63 – 2.53 (m, 1H), 2.37 (t, J = 7.4 Hz, 2H), 2.06 – 2.00 (m, 1H), 1.59 (dp, J = 14.7, 7.3 Hz, 4H), 1.44 – 1.32 (m, J = 5.6 Hz, 2H), 1.29 – 1.20 (m, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 173.24, 171.26, 170.53, 170.11, 169.44,165.10, 165.03, 163.80, 150.96, 146.92, 144.22, 136.74, 133.00, 132.68,121.46, 117.65, 115.39, 110.84, 108.35, 66.51, 49.04, 42.26, 32.72, 31.46,29.04, 26.57, 24.98, 22.65. Example 12 Synthesis of 4-((8-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-8-oxooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (I-12):

[0063] Referring to the synthesis method of I-9, L12 (209 mg) and W1 (193 mg) were reacted to obtain 228 mg of a yellow solid with a reaction yield of 58%.

[0064] 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.15 (d, J = 1.6 Hz, 1H), 8.07 (dd, J = 8.4, 1.7 Hz, 1H), 7.57 (dd, J = 8.6, 7.1 Hz, 1H), 7.53 (s, 2H), 7.38 (d, J = 8.4 Hz, 1H), 6.53 (t, J = 6.0 Hz, 1H), 5.04 (dd, J = 12.9, 5.4Hz, 1H), 3.94 – 3.74 (m, 8H), 3.66 (t, J = 4.8 Hz, 4H), 3.54 (s, 4H), 3.30 (dd, J = 13.4, 6.8 Hz, 2H), 2.95 (s, 1H), 2.94 – 2.81 (m, 1H), 2.62 – 2.54(m, 1H), 2.35 (t, J = 7.5 Hz, 2H), 2.06 – 1.99 (m, 1H), 1.64 – 1.46 (m, 4H),1.40 – 1.26 (m, 6H). 13 C NMR (151 MHz, DMSO-d6) δ 173.25, 171.37, 170.54, 170.12, 169.45,167.77, 165.10, 165.05, 150.96, 146.94, 144.24, 136.75, 132.99, 132.67,120.66, 117.67, 115.39, 110.85, 109.52, 108.35, 66.50, 49.04, 42.31, 32.79,31.45, 29.21, 29.12, 29.05, 26.70, 25.18, 22.63. Embodiment 13 Synthesis of 4-((11-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-11-oxododecanyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (I-13):

[0065] Referring to the synthesis method of I-9, L13 (274 mg) and W1 (191 mg) were reacted to obtain 140 mg of a yellow solid with a reaction yield of 34%.

[0066] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.07 (dd, J = 8.4, 1.7 Hz, 1H), 7.61 – 7.47 (m, 3H), 7.38 (d, J = 8.4 Hz,1H), 7.04 (dd, J = 25.7, 7.8 Hz, 2H), 6.51 (t, J = 5.9 Hz, 1H), 5.04 (dd, J =12.8, 5.4 Hz, 1H), 3.96 – 3.62 (m, 12H), 3.53 (s, 4H), 3.27 (d, J = 6.7 Hz,2H), 2.87 (ddd, J = 17.0, 13.7, 5.3 Hz, 1H), 2.63 – 2.54 (m, 1H), 2.33 (t, J= 7.4 Hz, 2H), 2.02 (ddd, J = 13.6, 7.2, 4.6 Hz, 1H), 1.61 – 1.44 (m, 4H),1.34 – 1.21 (m, 13H). 13C NMR (151 MHz, DMSO-d6) δ 173.26, 171.41, 170.53, 170.11, 169.44,167.78, 165.09, 165.05, 163.80, 150.94, 146.93, 144.20, 136.74, 132.99,132.65, 121.47, 117.65, 115.39, 110.85, 109.49, 108.35, 66.51, 49.03, 43.79,42.31, 40.53, 39.65, 32.83, 31.45, 29.40, 29.35, 29.32, 29.26, 29.19, 29.13,26.76, 25.25, 22.63. Embodiment 14 Synthesis of 4-((2-(2-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (I-14):

[0067] Accurately weigh W3 (79 mg) and 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (46 mg) in a 25 ml round-bottom flask, add 3 ml DMF, add (80 μl) to the above mixture, react at 90 °C for 3 hours, monitor the reaction by TLC, and purify the crude product by silica gel column (DCM / MeOH: 2% ~ 5%) to obtain 41 mg of yellow solid with a yield of 35%.

[0068] 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.05 (dd, J = 8.3, 1.7 Hz, 1H), 7.53 (s, 3H), 7.37 (d, J = 8.3 Hz, 1H), 7.11(s, 1H), 6.99 (d, J = 7.1 Hz, 1H), 6.60 (t, J = 5.7 Hz, 1H), 5.33 (t, J = 5.0Hz, 1H), 4.21 (s, 2H), 3.87 (d, J = 49.6 Hz, 8H), 3.66 (d, J = 5.3 Hz, 4H), 3.62 (s, 4H), 3.57 – 3.44 (m, 8H), 2.08 – 1.93 (m, 4H). 13 C NMR (151 MHz, DMSO-d6) δ 173.23, 170.50, 170.06, 169.43, 167.99,165.03, 164.99, 150.90, 146.81, 136.66, 132.97, 132.49, 117.82, 115.42,111.13, 108.32, 70.30, 70.13, 70.08, 69.27, 66.49, 49.04, 43.74, 42.22,31.45, 22.62. Embodiment 15 Synthesis of 4-((2-(2-(3-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (I-15):

[0069] Referring to the synthesis method of I-9, L15 (216 mg) and W1 (191 mg) were reacted to obtain 125 mg of a yellow solid with a reaction yield of 31%.

[0070] 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.10 (d, J = 30.0 Hz, 2H), 7.63 – 7.31 (m, 4H), 7.06 (dd, J = 39.1, 7.4 Hz, 2H), 6.59 (s, 1H), 5.05 (d,J = 12.5 Hz, 1H), 4.11 – 3.97 (m, 1H), 3.81 (s, 8H), 3.66 (s, 8H), 3.54 (s,8H), 3.46 (s, 2H), 2.96 – 2.78 (m, 1H), 2.59 (s, 3H), 1.99 (s, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 173.25, 170.50, 170.07, 169.65, 169.40,167.73, 165.04, 164.98, 163.77, 150.91, 146.85, 144.15, 136.66, 132.98,132.50, 130.12, 121.48, 117.86, 115.37, 111.14, 109.69, 108.35, 70.20, 69.32,67.37, 66.49, 66.48, 49.04, 43.78, 42.19, 40.48, 39.73 – 39.71 (m), 33.40,31.43, 22.61. Example 16 Synthesis of 4-((2-(2-(2-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (I-16):

[0071] Referring to the synthesis method of I-14, W4 (285 mg) and 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (152 mg) were reacted to obtain 163 mg of a yellow solid with a reaction yield of 39%.

[0072] 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.14 (d, J = 1.7 Hz, 1H), 8.06 (dd, J = 8.3, 1.7 Hz, 1H), 7.53 (d, J = 5.9 Hz, 3H), 7.37 (d, J = 8.4Hz, 1H), 7.08 (s, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.57 (t, J = 5.9 Hz, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.18 (s, 2H), 3.80 (s, 8H), 3.65 (t, J = 4.7Hz, 4H), 3.61 (t, J = 5.4 Hz, 2H), 3.56 (s, 8H), 3.53 – 3.47 (m, 4H), 3.46 –3.41 (m, 2H), 2.93 – 2.82 (m, 1H), 2.68 – 2.52 (m, 2H), 2.10 – 1.98 (m, 1H). Embodiment 17 Synthesis of 4-((15-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxopentadecyl)amino)-2-(2,6-dioxapiperidin-3-yl)isoindoline-1,3-dione (I-17):

[0073] Referring to the synthesis method of I-9, L17 (263 mg) and W1 (191 mg) were reacted to obtain 101 mg of a yellow solid with a reaction yield of 23%.

[0074] 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 1.6 Hz, 1H), 8.08 (dd, J =8.4, 1.7 Hz, 1H), 7.61 – 7.47 (m, 3H), 7.38 (d, J = 8.4 Hz, 1H), 7.12 (d, J =8.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.59 (t, J = 5.8 Hz, 1H), 5.06 (dd, J= 12.9, 5.4 Hz, 1H), 3.82 (s, 8H), 3.66 (q, J = 6.9, 5.8 Hz, 6H), 3.64 – 3.57(m, 4H), 3.59 – 3.51 (m, 5H), 3.55 – 3.49 (m, 2H), 3.49 (s, 6H), 3.45 (q, J =5.6 Hz, 2H), 3.13 (qd, J = 7.4, 4.2 Hz, 3H), 2.89 (ddd, J = 17.4, 14.0, 5.4Hz, 1H), 2.62 (t, J = 6.5 Hz, 2H), 2.09 – 1.96 (m, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 173.25, 170.11, 169.61, 167.76, 165.09,165.02, 150.94, 136.68, 121.47, 117.89, 115.38, 111.14, 109.72, 108.36,70.32, 70.24, 70.17, 69.34, 67.30, 66.50, 53.98, 49.05, 42.22, 42.18, 33.39,31.44, 22.62, 18.51, 17.19, 12.80. Embodiment 18 Synthesis of N1-(3-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-3-oxopropyl)-N4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)succinamide (I-18):

[0075] Referring to the synthesis method of I-9, L1 (217 mg) and W8 (271 mg) were reacted to obtain 120 mg of a white solid with a reaction yield of 25%.

[0076] 1 H NMR (400 MHz, Chloroform-d) δ 11.02 (s, 1H), 9.86 (s, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.07 (dd, J = 8.4, 1.7 Hz, 1H), 7.93 (t, J = 5.6 Hz, 1H), 7.83 (dd, J = 6.7, 2.3 Hz, 1H), 7.54 – 7.42 (m, 4H), 7.38 (d, J = 8.4Hz, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 – 4.27 (m, 2H), 3.92 – 3.63(m, 12H), 3.53 (d, J = 19.2 Hz, 4H), 3.30 (d, J = 11.0 Hz, 2H), 2.92 (ddd, J= 18.0, 13.6, 5.4 Hz, 1H), 2.64 – 2.56 (m, 3H), 2.53 (s, 2H), 2.42 (t, J =7.2 Hz, 2H), 2.38 – 2.29 (m, 1H), 2.07 – 1.99 (m, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 173.49, 173.31, 171.76, 171.50, 168.33,165.09, 165.03, 163.80, 144.21, 134.28, 133.11, 132.99, 129.08, 125.74,125.50, 121.52, 119.37, 117.97, 115.39, 107.97, 103.21, 66.51, 52.03, 40.53,40.34, 40.20, 39.62, 35.58, 33.05, 31.66, 30.87, 23.14, 19.27. Embodiment 19 Synthesis of 4-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholinyl-1,3,5-triazine-2-yl)piperazin-1-yl)-N-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-2-oxoethoxy)ethoxy)ethyl)-4-oxobutanamide (I-19):

[0077] Referring to the synthesis method of I-9, L19 (105 mg) and W5 (120 mg) were reacted to obtain 60 mg of a white solid with a reaction yield of 27%.

[0078] 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.70 (s, 1H), 8.15 (s,1H), 8.08 (d, J = 8.4 Hz, 1H), 7.90 (t, J = 5.7 Hz, 1H), 7.75 (d, J = 7.6 Hz,1H), 7.60 – 7.48 (m, 4H), 7.38 (d, J = 8.3 Hz, 1H), 5.14 (dd, J = 13.3, 5.1Hz, 1H), 4.45 – 4.31 (m, 2H), 4.15 (s, 2H), 3.82 (s, 8H), 3.67 (q, J = 5.2,4.6 Hz, 6H), 3.62 (d, J = 4.6 Hz, 2H), 3.53 (s, 4H), 3.44 (t, J = 6.0 Hz, 2H), 3.26 – 3.14 (m, 3H), 2.91 (ddd, J = 18.1, 13.6, 5.4 Hz, 1H), 2.56 (t, J= 6.9 Hz, 3H), 2.38 – 2.31 (m, 2H), 2.08 – 1.94 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 173.31 (d, J = 466.2 Hz), 172.03, 171.45,170.61, 170.11, 168.90, 168.24, 165.09, 165.03, 163.79, 150.94, 144.20,135.30, 133.36, 133.21, 132.98, 129.12, 126.81, 121.48, 120.21, 115.38,108.36, 70.82, 70.48, 69.92, 69.62, 66.51, 66.49, 62.69, 52.06, 46.95, 40.53,39.03, 31.67, 30.79, 28.33, 23.03. Embodiment 20 Synthesis of 11-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-N-(11-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-11-oxododecanamide (I-20):

[0079] Referring to the synthesis method of I-9, L20 (280 mg) and W2 (242 mg) were reacted to obtain 92 mg of a white solid with a reaction yield of 22%.

[0080] 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.78 (s, 1H), 8.13 (d, J =1.7 Hz, 1H), 8.06 (dd, J = 8.4, 1.7 Hz, 1H), 7.81 (dd, J = 7.0, 1.9 Hz, 1H),7.72 (t, J = 5.7 Hz, 1H), 7.52 (d, J = 8.9 Hz, 2H), 7.52 – 7.43 (m, 2H), 7.37(d, J = 8.4 Hz, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 – 4.27 (m, 2H),3.81 (d, J = 41.1 Hz, 8H), 3.66 (d, J = 4.9 Hz, 5H), 3.16 (d, J = 5.2 Hz,1H), 2.99 (q, J = 6.6 Hz, 2H), 2.95 – 2.85 (m, 1H), 2.69 – 2.52 (m, 1H), 2.45– 2.19 (m, 8H), 2.02 (t, J = 7.3 Hz, 3H), 1.63 – 1.55 (m, 2H), 1.52 – 1.41(m, 4H), 1.39 – 1.31 (m, 3H), 1.32 – 1.22 (m, 20H). 13 C NMR (151 MHz, DMSO-d6) δ 173.30, 172.40, 171.88, 171.49, 170.08,168.33, 165.13, 164.90, 163.78, 150.91, 144.19, 134.29, 133.12, 133.04,129.07, 125.71, 125.69, 121.44, 119.43, 115.35, 108.33, 66.50, 52.03, 46.98,40.53 – 40.51 (m), 40.36, 40.34, 40.06, 39.92, 39.65, 38.78, 36.28, 35.91,31.67, 29.61, 29.45, 29.42, 29.39, 29.36, 29.25, 29.21, 29.19, 29.15, 29.06,26.85, 25.80, 25.56, 23.12. Embodiment 21 Synthesis of N-(11-(4-(4-(2-aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-11-oxododecanyl)-11-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)undecaneamide (I-21):

[0081] Referring to the synthesis method of I-9, L13 (217 mg) and W9 (230 mg) were reacted to obtain 105 mg of a white solid with a reaction yield of 22%.

[0082] 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.15 (s, 1H), 8.07 (d, J =8.4 Hz, 1H), 7.71 (s, 1H), 7.55 (d, J = 13.0 Hz, 3H), 7.38 (d, J = 8.4 Hz,1H), 7.04 (dd, J = 25.3, 7.8 Hz, 2H), 6.52 (s, 1H), 5.05 (dd, J = 13.0, 5.4Hz, 1H), 3.82 (d, J = 38.1 Hz, 8H), 3.66 (s, 4H), 3.53 (s, 4H), 3.32 – 3.23(m, 3H), 3.04 – 2.95 (m, 2H), 2.94 – 2.81 (m, 1H), 2.58 (d, J = 17.1 Hz, 2H), 2.37 – 2.29 (m, 2H), 2.07 – 1.95 (m, 4H), 1.60 – 1.40 (m, 7H), 1.34 – 1.13(m, 23H). 13C NMR (151 MHz, DMSO-d6) δ 173.25, 172.39, 171.39, 170.52, 170.11,169.43, 167.77, 165.09, 165.04, 163.80, 150.95, 146.92, 144.21, 136.73,132.98, 132.64, 121.46, 117.62, 115.39, 110.85, 109.49, 108.34, 66.50, 49.03,42.32, 40.53, 38.77, 35.91, 32.83, 31.44, 29.60, 29.43, 29.41, 29.37, 29.35,29.27, 29.21, 29.19, 29.15, 29.06, 26.83, 26.78, 25.80, 25.26, 22.63. Embodiment 22 Biological evaluation experiment 1. PI3K kinase activity detection The PI3K kinase activity assay used in this experiment uses the ADP-Glo ​​method to perform lipid kinase reactions by incubating lipid substrates with recombinant enzymes and ATP, and measure kinase activity using the ADP-Glo™ Kinase Assay. The ADP-Glo™ Kinase Assay is performed in two steps: First, after the kinase reaction, an ATP depletion reagent is added to terminate the lipid kinase reaction and consume any remaining ATP, leaving only ADP. Second, a detection reagent is added to simultaneously convert ADP to ATP, and a coupled luciferase / luciferin reaction is used to convert the newly synthesized ATP into a fluorescent signal.

[0083] It can be seen from the experimental results that the example compounds of the present invention have strong inhibitory activity on PI3Kα kinase activity. The measured IC 50 The values ​​are shown in Table 1.

[0084] 2. Determination of the inhibitory effect on proliferation of various cancer cells This experiment uses the Cell Counting Kit-8 (CCK8) method to test the inhibitory effect of compounds on the proliferation of various cancer cells. WST-8 is used to quickly detect cell proliferation / toxicity tests. WST is a tetrazolium salt that is reduced by dehydrogenases in living cells in the presence of electron carriers to produce water-soluble orange-yellow formazan. The amount of formazan generated by colorimetry reflects the number of living cells in the experiment. Cells in the logarithmic growth phase are counted at 1×10 5cells / well were inoculated in a 96-well plate and cultured at 37 °C and 5% CO2 until the cells were 90% confluent. Then, the cells were cultured in serum-free DMEM medium, RPMI-1640 medium, F12K medium or other corresponding cell culture medium for 2 h to synchronize the cells. 100 μL of the compound solution of different concentrations was added to the culture plate, and the culture plate was incubated in a 37 °C, 5% CO2 incubator for 72 hours; after the incubation, 10 μL of CCK8 solution was added to each well, and after being placed in a 37 °C incubator for 4 hours, the OD value of each well at OD450 was detected on a microplate reader to calculate the cell proliferation inhibition rate. Inhibition rate = (OD value of the control group - OD value of the experimental group) / OD value of the control group × 100%; after obtaining the data, GraphPad Prism was used to fit the IC 50 .

[0085] It can be seen from the experimental results that the example compounds of the present invention have strong anti-proliferative activity against tumor cell lines. The measured IC 50 The values ​​are shown in Table 2, where the IC 50 Classification by description: "A" means IC 50 The measured value is less than or equal to 5 μM; "B" indicates IC 50 The measured value is less than or equal to 10μM and greater than 5μM; "C" means IC 50 The measured value is less than or equal to 20μM and greater than 10μM. "D" means IC 50 The measured value was greater than 20 μM, “NT” means not tested.

[0086] 3. Determination of PI3K degradation activity in vitro The ability of compounds targeting PI3K protein degradation to degrade PI3K protein was evaluated by western blotting, and western blotting analysis was performed in various tumor cells.

[0087] The experimental results show that the compounds prepared in the examples of the present invention have significant degradation activity on PI3Kα, as shown in Table 3, where “NT” means not tested.

Claims

1. A compound or a pharmaceutically acceptable salt or tautomer thereof, characterized in that: The compound structure is shown in general formula I: ； Linker is a connecting group, and the connecting group is selected from , , ; m is an integer selected from 0 to 25; w -CH2- in the straight chain of the linking group is replaced by one or both of -O- and -CONH-, w is an integer selected from 0 to 5, and m≥w.

2. The compound according to claim 1 or its pharmaceutically acceptable salt or tautomer, characterized in that: In the straight chain of the linking group, 0 to 5 -CH2- are replaced by 0 to 4 -O-, 0 to 2 -CONH-, or both.

3. The compound according to claim 1 or its pharmaceutically acceptable salt or tautomer, characterized in that: The -NH- group in the linking group connected.

4. The compound according to claim 1 or its pharmaceutically acceptable salt or tautomer, characterized in that: The pharmaceutically acceptable salt is a salt formed by a compound of formula I and one or more acids, wherein the acid used for salt formation includes inorganic acids and organic acids, the inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid; the organic acids include acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid and tartaric acid.

5. The compound according to claim 1 or its pharmaceutically acceptable salt or tautomer, characterized in that: The compound is selected from I-1 to I-21: 。 6. A method for preparing the compound according to claim 1 or its pharmaceutically acceptable salt or tautomer, characterized in that: The reaction route of the compound is as follows: 。 7. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 5 or its pharmaceutically acceptable salt, tautomerism and stereoisomer or the pharmaceutical composition according to claim 7 in the preparation of a PI3K target degradation inhibitor.

9. Use of the compound according to any one of claims 1 to 5 or its pharmaceutically acceptable salt, tautomerism and stereoisomer or the pharmaceutical composition according to claim 7 in the preparation of a drug for treating a disease regulated by PI3K.

10. The use according to claim 9, characterized in that: The diseases regulated by PI3K include tumors.

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