Compound for targeted degradation of PI3K protein as well as preparation method and application of compound

Abstract

The invention discloses a compound for targeted degradation of PI3K protein as well as a preparation method and application of the compound. The structural general formula of the compound is as shown in a formula I in the specification. Biochemical activity tests show that the compounds have a good inhibition effect on PI3K enzyme activity and can significantly degrade PI3K protein, so that the compounds can provide effective and better-selectivity degradation inhibitors for treatment of diseases regulated by PI3K, and are expected to be developed into drugs for treating diseases related to PI3K signal pathways, such as PI3K signal pathways, PI3K signal pathways, PI3K signal pathways, PI3K signal pathways, PI3K signal pathways, PI3K signal pathways and PI3K signal pathways. The target drugs can be used for treating gastric cancer, breast cancer, ovarian cancer, leukemia and the like. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a compound for targeted degradation of PI3K protein, or a pharmaceutically acceptable salt thereof and a preparation method and application thereof, and belongs to the field of pharmaceutical chemistry. Background Art

[0002] The PI3K / Akt / mTOR axis is an important signaling pathway in mammalian tumor immunity, which is closely related to cell proliferation, cell cycle progression, cell survival, cell growth and angiogenesis. The activation of this pathway is closely related to tumor cell apoptosis, migration, tumor development and drug resistance. PI3K protein is a highly conserved lipid kinase family that can integrate growth factors, cytokines and other environmental signals, convert them into intracellular signals, regulate multiple signaling pathways and thus regulate various physiological functions. Activating mutations and amplifications of PI3K protein are often found in various cancers, making it a major drug target for anticancer therapy. A common mechanism of PI3K protein activation in cancer is PIK3CA gene mutation. PIK3CA mutations are most commonly found in gynecological malignancies, breast adenocarcinomas and head and neck cancers. Other tumor types, including lung, bladder and colorectal adenocarcinomas, as well as overgrowth syndromes, often carry PIK3CA activating mutations. Like other driver oncogenes, mutation preferences are also observed in tumors. For example, head and neck cancers are more likely to carry E542K or E545K hotspot mutations located in the helical domain. PIK3CA amplification is also common in cancer types. Mutations in other genes can also lead to overactivation of the PI3K pathway. Loss, nonsense, and loss-of-function missense mutations of PTEN are common in many cancers, including prostate and breast cancer, glioblastoma, and melanoma. Although PTEN loss leads to PIP3 accumulation and increased PI3K activity, it should be emphasized that this effect appears to be mediated to a greater extent by P110β. Mutations in PIK3R1, the gene encoding the p85 regulatory subunit, also lead to activation of PI3K signaling. Although uncommon, it also exists in uterine cancer, ovarian cancer, and prostate cancer.

[0003] Clinical data show that pan-PI3K inhibitors have serious adverse reactions due to their non-selectivity. The PI3Kα pathway itself is a classic response pathway for insulin signals. After PI3Kα is inhibited, the normal glucose metabolism signal response is blocked, resulting in compensatory insulin secretion and increased blood sugar. PI3Kδ and γ are involved in immune cell signal transduction. These signaling pathways are essential for the maturation and normal function of immune cells. Inhibition of their signals will lead to decreased immune function and increase the risk of infection for users. Non-selective PI3Kδ / PI3Kγ inhibitors can trigger autoimmune and inflammatory responses. Liver toxicity caused by poor metabolic pathways also restricts the application of PI3K inhibitors. The main metabolite of Gilead's PI3Kδ selective inhibitor idelalisib has the effect of inhibiting the liver enzyme CYP3A4, causing liver toxicity. The combination of idelalisib and CD20 monoclonal antibody has been observed to have severe liver toxicity in the early stage of medication. So far in 2021, PI3K inhibitors have been withdrawn from the market or withdrawn from indications three times. PI3K inhibitors are facing the test of clinical effectiveness and safety. Therefore, solving the problem of lack of effectiveness and safety of clinically targeted PI3K has become an urgent need. Summary of the invention

[0004] Objectives of the invention: The first objective of the present invention is to provide a compound for targeted degradation of PI3K protein, or a pharmaceutically acceptable salt thereof. The second objective of the present invention is to provide a method for preparing the compound for targeted degradation of PI3K protein, or a pharmaceutically acceptable salt thereof. The third objective of the present invention is to provide a pharmaceutical composition comprising the compound for targeted degradation of PI3K protein, or a pharmaceutically acceptable salt thereof. The fourth objective of the present invention is to provide the compound for targeted degradation of PI3K protein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound for targeted degradation of PI3K protein, or a pharmaceutically acceptable salt thereof, in the preparation of PI3K protein target degradation inhibitors or drugs for diseases regulated by PI3K, especially in the preparation of tumor drugs regulated by PI3K protein.

[0005] Technical solution: The compound for targeted degradation of PI3K protein described in the present invention, or a pharmaceutically acceptable salt thereof, has a general structural formula as shown in Formula I:

[0006]

[0007] Wherein, R is selected from H, -CH3; linker is a connecting group, and linker is selected from a straight chain or branched alkylene chain with a total length of 1 to 11 atoms.

[0008] Furthermore, the linear or branched alkylene chain consists of one or more of -CH2-, -O-, -CO-, -CONH-, -S- or -N-.

[0009] Furthermore, the linear or branched alkylene chain consists of one or more of -CH2-, -O-, -CO-, -CONH- or -N-.

[0010] Furthermore, the pharmaceutically acceptable salt is an acid addition salt of the compound of formula I, wherein the acid used for salt formation includes an inorganic acid and / or an organic acid.

[0011] Furthermore, the inorganic acid is hydrochloric acid, sulfuric acid, phosphoric acid or methanesulfonic acid, preferably hydrochloric acid.

[0012] Furthermore, the organic acid is 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 or tartaric acid.

[0013] Furthermore, the compound is selected from any one of the following:

[0014]

[0015]

[0016]

[0017] The compound for targeting degradation of PI3K protein of the present invention, or the preparation method of a pharmaceutically acceptable salt thereof, is synthesized according to the following reaction route:

[0018]

[0019] Wherein, R is selected from H, -CH3; R1 is Br, linker is a connecting group, and linker is selected from a straight or branched alkylene chain with a total length of 1 to 11 atoms.

[0020] The present invention also includes a pharmaceutical composition comprising the compound for targeting degradation of PI3K protein described in the present invention, or a pharmaceutically acceptable salt, tautomer and stereoisomer, metabolite, metabolic precursor, solvent compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0021] Furthermore, the pharmaceutical composition can be in the form of conventional pharmaceutical preparations such as tablets, capsules, granules, powders, syrups, oral solutions or injections.

[0022] The compound for targeting and degrading PI3K protein of the present invention, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention is used in the preparation of a PI3K protein target degradation inhibitor or a drug for a disease regulated by PI3K.

[0023] Furthermore, the compound for targeted degradation of PI3K protein of the present invention, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention is used in the preparation of drugs for tumors, immune disorders or inflammatory disorders regulated by PI3K protein.

[0024] Furthermore, tumors mainly include 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.

[0025] Principle of the invention: The compound of the present invention targets the degradation of PI3K protein. When the PROTAC molecule of PI3K binds to the intracellular PI3K, the PROTAC molecule will cause PI3K to bind to the ubiquitin ligase, resulting in PI3K ubiquitination and marking it as a target for degradation. The ubiquitinated PI3K will be recognized by the proteasome and eventually degraded. Since PI3K protein is a key factor in the occurrence and development of tumors, by promoting PI3K degradation, the function of PI3K protein 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 protein.

[0026] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0027] The present invention provides a novel compound for regulating PI3K protein. After biochemical activity tests, the compounds have good inhibitory activity and protein degradation activity against PI3Kα, inhibitory activity against a variety of tumor cells, and are more sensitive to cells carrying PI3K mutations. Therefore, these compounds can provide effective and more selective 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, leukemia, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 is a graph showing the growth curve of the MCF7 xenograft tumor in Example 10;

[0029] Figure 2 is a graph showing the weight gain of MCF7 mice in Example 10;

[0030] Figure 3 is a graph showing the growth curve of the T47D xenograft tumor in Example 10;

[0031] Figure 4 This is a graph of the weight gain of T47D mice in Example 10. DETAILED DESCRIPTION

[0032] The technical solution of the present invention is further described below in conjunction with the accompanying drawings.

[0033] 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 treatment unless otherwise specified.

[0034] Example 1

[0035] (1) Synthesis of Compound M1

[0036] The structural formula of compound M1 is shown below:

[0037]

[0038] The preparation process was synthesized according to the reference (Scott, William J et al. "Discovery and SAR of Novel 2,3-Dihydroimidazo[1,2-c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80-6946)." ChemMedChem vol.11,14(2016):1517-30.).

[0039] (2) Synthesis of Compound M

[0040] Synthesized according to the following route:

[0041]

[0042] To a round-bottom flask were added raw material M1 (2.0 g, 4.36 mmol), 2-aminopyrimidine-5-carboxylic acid (732 mg, 5.23 mmol) and PyBOP (2.72 g, 5.23 mmol, molecular formula is C 18 H 28 F6N6OP2, CAS: 128625-52-5), dissolved in 10 mL N, N-dimethylformamide (DMF), then added 3 mL N, N-diisopropylethylamine (DIPEA), stirred at room temperature for 12 hours, monitored the reaction with a TLC plate, and stopped the reaction after the raw materials reacted. Added 500 mL of water, extracted the solid, and obtained a light yellow solid compound M (2.33 g), with a yield of 92%.

[0043] The light yellow solid compound M was subjected to mass spectrometry analysis. The result was: MS (ESI) m / z 580.66 [M+H] + .

[0044] From the above analysis, it can be seen that the structure of the light yellow solid compound M is shown in the following formula:

[0045]

[0046] (3) Synthesis of Compound A

[0047] Synthesized according to the following route:

[0048]

[0049] Add 30 mL of 2 mol / L ethyl acetate hydrochloric acid solution (Shanghai Anaiji Chemical Co., Ltd.) to the raw material compound M (2 g), stir at room temperature for 2 hours, monitor the reaction with a TLC plate, and stop the reaction when the raw material is completely reacted. Take out the solid to obtain a light yellow hydrochloride solid A (1.98 g), with a yield of 92%.

[0050] The hydrochloride solid A was subjected to mass spectrometry analysis, and the result was: MS (ESI) m / z 480.55 [M+H] + .

[0051] From the above analysis, it can be seen that the structure of hydrochloride solid A is shown as follows:

[0052]

[0053] Example 2

[0054] A series of compounds of general formula I were synthesized according to the following route:

[0055]

[0056] 1. Synthesis of Compound I-1:

[0057] Synthesis of 5-bromo-N-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentanamide (B-1):

[0058] Lenalidomide (1 eq, 5 mmol) was dissolved in 20 mL of tetrahydrofuran, and 5-bromovaleryl chloride (1.5 eq, 7.5 mmol) was slowly added dropwise under ice bath. The mixture was reacted at room temperature for 12 h. After the reaction was completed, a white solid (B-1) was obtained by filtration with a yield of 98%.

[0059] The obtained white solid product (B-1) was subjected to H NMR spectrum analysis, and the results were: 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.80(s,1H),7.81(dd,J=2.0,7.0Hz,1H),7.55–7.44(m,2H),5.15(dd,J=5.1,13.3Hz,1H),4.47–4.28(m ,2H),3.57(t,J=6.5Hz,2H),2.92(ddd,J=5.4,13.6,17.3Hz,1H),2.71 –2.54(m,1H),2.45–2.25(m,3H),2.10–1.98(m,1H),1.91–1.63(m,4H).

[0060] From the above analysis, it can be seen that the structure of the white solid product (B-1) is shown below:

[0061]

[0062] The intermediate compound A (120 mg, 1.0 eq.) prepared in Example 1 and 5-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentanamide (B-1) (116 mg, 1.1 eq.) were dissolved in 3 mL of dimethyl sulfoxide solution (DMSO), and N,N-diisopropylethylamine (DIPEA) (97 mg, 3.0 eq.) was added to the reaction bottle as a base, and the reaction was carried out at 80° C. for 12 h. The reaction was monitored by TLC, and 15 mL of ethyl acetate was added after the reaction was completed, and the solid was extracted and further purified by silica gel column chromatography with a mobile phase of 1:5 methanol / dichloromethane (plus 1‰ triethylamine) to obtain a white solid compound I-1 (100 mg) with a yield of 49%.

[0063] The white solid compound I-1 was analyzed by hydrogen nuclear magnetic spectrum. The results were as follows: 1H NMR (400MHz, DMSO-d6) δ12.79 (s, 1H), 11.03 (s, 1H), 9.97 (s, 1H), 8.90 (s, 2H), 7.83–7.81 (m, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.52–7.47 (m, 2H), 7.36 (s, 2H), 7.04 (d, J = 8.8 Hz, 1H),5.18–5.13(m,1H),4.46–4.32(m,2H),4.17–4.01(m,6H),3.92(s,3H),3.09–2.8 8(m,9H),2.67–2.58(m,2H),2.43–2.33(m,6H),2.05–1.95(m,3H),1.74–1.61(m,4H).

[0064] The white solid compound I-1 was analyzed by NMR carbon spectrum, and the results were:13 C NMR(151MHz,DMSO-d6)δ175.86,173.31,171.51,168.29,165.08,160.39,150.3 9,135.07,135.06,134.27,134.25,133.16,131.47,129.06,125.77,125.73,12 2.00,122.00,119.71,119.53,119.50,110.91,61.23,61.21,53,85,52.05,51.41,49.72,49.69,47.13,45.93,45.43,40.57,35.59,31.69,28.50,23.16,8.94.

[0065] The white solid compound I-1 was subjected to mass spectrometry analysis. The result was: MS (ESI) m / z 821.40 [M+H] + .

[0066] From the above analysis, it can be seen that the structure of the white solid compound I-1 is shown in the following formula:

[0067]

[0068] 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.

[0069] Example 3 Synthesis of Compound I-2

[0070] Synthesis of 6-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hexanamide (B-2):

[0071] Referring to the synthesis method of B-1 in Example 2, 5-bromovaleryl chloride was replaced by 6-bromovaleryl chloride to obtain a white solid (B-2) with a yield of 97%.

[0072] The obtained white solid product (B-2) was subjected to H NMR spectrum analysis, and the results were: 1H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 9.79 (s, 1H), 7.81 (dd, J = 1.9, 7.1Hz, 1H), 7. 61–7.36(m,2H),5.15(dd,J=5.1,13.3Hz,1H),4.48–4.27(m,2H),3.73–3.49(m,2H) ,2.92(ddd,J=5.3,13.6,17.3Hz,1H),2.61(dt,J=3.5,17.2Hz,1H),2.42–2.27(m,3 H),2.09–1.97(m,1H),1.87–1.69(m,2H),1.64(p,J=7.4Hz,2H),1.52–1.37(m,2H).

[0073] From the above analysis, it can be seen that the structure of the white solid product (B-2) is shown below:

[0074]

[0075] Referring to the synthesis method of I-1 in Example 2, the difference is that B-1 in Example 2 is replaced by 6-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-4-yl)pentanamide (B-2) (120 mg, 1.1 eq.), and the rest is the same as Example 2 to obtain a white solid compound I-2 (98 mg) with a yield of 47%.

[0076] The white solid compound I-2 was analyzed by nuclear magnetic hydrogen spectrum, and the results were: 1 H NMR(400MHz,DMSO-d6)δ12.76(s,1H),11.05(s,1H),9.89(s,1H),8.90(s,2H),7. 83(d,J=7.0Hz,1H),7.60(d,J=8.8Hz,1H),7.49(d,J=7.0Hz,2H),7.37(s,2H),7. 02(d,J=8.8Hz,1H),5.18–5.13(m,1H),4.44–4.31(m,2H),4.16(s,2H),4.07–4.0 0(m,4H),3.91(s,3H),3.07–2.88(m,10H),2.41–2.31(m,6H),2.04–1.17(m,10H).

[0077] The white solid compound I-2 was analyzed by NMR carbon spectrum, and the results were: 13C NMR(151MHz,DMSO-d6)δ175.88,173.32,171.70,171.52,168.30,165.09,160.40 ,154.96,150.48,135.11,135.10,134.28,134.14,133.15,131.44,129.08,125.6 9,121.97,121.95,119.76,119.46,110.87,67.28,61.22,61.19,53.88,52.03,51.44,49.77,47.03,46.04,45.42,40.57,40.24,39.82,35.98,31.68,23.15,9.00.

[0078] The white solid compound I-2 was subjected to mass spectrometry analysis. The result was: MS (ESI) m / z 835.70 [M+H] + .

[0079] From the above analysis, it can be seen that the structure of the white solid compound I-2 is shown as follows:

[0080]

[0081] 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.

[0082] Example 4 Synthesis of Compound I-3

[0083] Synthesis of 7-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)heptylamide (B-3):

[0084] Referring to the synthesis method of B-1 in Example 2, 5-bromovaleryl chloride was replaced by 7-bromovaleryl chloride to obtain a white solid (B-3) with a yield of 98%.

[0085] The obtained white solid product (B-3) was subjected to H NMR spectrum analysis, and the results were: 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.77(s,1H),7.81(dd,J=2.0,6.9Hz,1H),7.56–7.43(m,2H),5.15(dd,J=5.1,13.3Hz,1H),4.45–4.28(m ,2H),3.64(t,J=6.6Hz,2H),2.98–2.84(m,1H),2.70–2.56(m,1H),2.40 –2.27(m,3H),2.10–1.99(m,1H),1.78–1.56(m,4H),1.53–1.29(m,4H).

[0086] From the above analysis, it can be seen that the structure of the white solid product (B-3) is shown below:

[0087]

[0088] Referring to the synthesis method of I-1 in Example 2, the difference is that B-1 in Example 1 is replaced by 7-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-4-yl)pentanamide (B-3) (124 mg, 1.1 eq.), and the rest is the same as in Example 2 to obtain a white solid compound I-3 (117 mg) with a yield of 55%.

[0089] The white solid compound I-3 was analyzed by H NMR spectrum, and the results were: 1 H NMR(400MHz,DMSO-d6)δ12.75(s,1H),11.05(s,1H),9.84(s,1H),8.90(s,2H),7.82–7 .80(m,1H),7.58(d,J=8.8Hz,1H),7.51–7.46(m,2H),7.36(s,2H),7.01(d,J=8.8Hz,1 H),5.17–5.13(m,1H),4.42–4.30(m,2H),4.14(t,J=6.0Hz,2H),4.05–4.00(m,4H),3. 90(s,3H),2.97–2.58(m,8H),2.38–2.34(m,8H),2.04–1.95(m,4H),1.62–1.23(m,8H).

[0090] The white solid compound I-3 was analyzed by NMR carbon spectrum, and the results were: 13C NMR(151MHz,DMSO-d6)δ175.84,173.30,171.82,171.52,168.30,165.08,160.37,1 54.87,150.91,150.51,135.11,134.31,134.17,133.15,131.35,129.07,125.72,12 1.85,119.80,119.44,110.79,107.39,67.35,61.16,53.82,52.03,47.02,45.37,40.57,36.19,31.68,28.89,28.87,28.87,28.85,26.83,26.80,25.45,25.42,23.14.

[0091] The white solid compound I-3 was subjected to mass spectrometry analysis. The result was: MS (ESI) m / z 849.70 [M+H] + .

[0092] From the above analysis, it can be seen that the structure of the white solid compound I-3 is shown in the following formula:

[0093]

[0094] 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.

[0095] Example 5 Synthesis of Compound I-4

[0096] Synthesis of 8-bromo-N-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)octanamide (B-4):

[0097] Referring to the synthesis method of B-1 in Example 2, 5-bromovaleryl chloride was replaced by 8-bromovaleryl chloride to obtain a white solid (B-4) with a yield of 95%.

[0098] The obtained white solid product (B-4) was subjected to H NMR spectrum analysis, and the results were: 1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.76(s,1H),7.81(dt,J=1.4,6.9Hz,1H),7 .54–7.44(m,2H),5.15(dd,J=5.1,13.3Hz,1H),4.45–4.27(m,2H),3.53(t,J=6.7 Hz,2H),2.92(ddd,J=5.4,13.5,17.2Hz,1H),2.70–2.56(m,1H),2.43–2.28(m,3H ),2.10–1.97(m,1H),1.80(p,J=6.8Hz,2H),1.66–1.54(m,2H),1.45–1.30(m,6H).

[0099] From the above analysis, it can be seen that the structure of the white solid product (B-4) is shown below:

[0100]

[0101] Referring to the synthesis method of I-1 in Example 2, the difference is that B-1 in Example 1 is replaced by 8-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-4-yl)pentanamide (B-4) (128 mg, 1.1 eq.), and the rest is the same as in Example 2 to obtain a white solid compound I-4 (112 mg) with a yield of 52%.

[0102] The white solid compound I-4 was analyzed by H NMR spectrum, and the results were: 1 H NMR(400MHz,DMSO-d6)δ12.75(s,1H),11.06(s,1H),9.79(s,1H),8.90(s,2H),7.82–7.80 (m,1H),7.58(d,J=8.8Hz,1H),7.51–7.46(m,2H),7.36(s,2H),7.02(d,J=8.8Hz,1H),5.17 –5.13(m,1H),4.41–4.29(m,2H),4.16–3.99(m,6H),3.90(s,3H),2.97–2.88(m,2H),2.67– 2.54(m,4H),2.44–2.28(m,11H),2.04–1.93(m,3H),1.61–1.58(m,2H),1.42–1.15(m,8H).

[0103] The white solid compound I-4 was analyzed by NMR carbon spectrum, and the results were: 13C NMR(151MHz,DMSO-d6)δ173.30,171.85,171.52,171.50,168.30,165.10,160.39,154 .90,150.92,150.52,134.30,134.16,133.15,131.36,131.35,129.07,125.70,121.8 5,119.82,119.44,110.79,107.37,67.41,61.15,53.84,52.02,46.97,46.12,45.37,40.57,40.39,40.24,40.11,39.97,39.81,39.66,36.24,31.68,29.03,25.48,23.14.

[0104] The white solid compound I-4 was subjected to mass spectrometry analysis. The result was: MS (ESI) m / z 863.70 [M+H] + .

[0105] From the above analysis, it can be seen that the structure of the white solid compound I-4 is shown in the following formula:

[0106]

[0107] 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.

[0108] Example 6 Synthesis of Compound I-5

[0109] Synthesis of 11-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)undecylamide (B-5):

[0110] Referring to the synthesis method of B-1 in Example 2, 5-bromovaleryl chloride was replaced by 11-bromovaleryl chloride to obtain a white solid (B-5) with a yield of 95%.

[0111] The obtained white solid product (B-5) was subjected to H NMR spectrum analysis, and the results were: 1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.75(s,1H),7.81(dd,J=2.0,6.9Hz,1H),7 .59–7.39(m,2H),5.15(dd,J=5.1,13.3Hz,1H),4.48–4.27(m,2H),3.51(t,J=6.7 Hz,2H),2.92(ddd,J=5.4,13.6,17.3Hz,1H),2.73–2.55(m,1H),2.35(t,J=7.3Hz ,3H),2.03(s,1H),1.78(p,J=6.8Hz,2H),1.65–1.56(m,2H),1.40–1.26(m,12H).

[0112] From the above analysis, it can be seen that the structure of the white solid product (B-5) is shown below:

[0113]

[0114] Referring to the synthesis method of I-1 in Example 2, the difference is that B-1 in Example 2 is replaced by 11-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-4-yl)pentanamide (B-5) (139 mg, 1.1 eq.), and the rest is the same as in Example 2 to obtain a white solid compound I-5 (95 mg) with a yield of 42%.

[0115] The white solid compound I-5 was analyzed by H NMR spectrum, and the results were: 1 H NMR(400MHz,DMSO-d6)δ12.77(s,1H),11.05(s,1H),9.85(s,1H),8.90(s,2H),7.82–7.79 (m,1H),7.61(d,J=8.8Hz,1H),7.52–7.46(m,2H),7.37(s,2H),7.03(d,J=8.8Hz,1H),5.17 –5.13(m,1H),4.42–4.30(m,2H),4.08–4.01(m,6H),3.91(s,3H),3.08–2.88(m,12H),2.67 –2.54(m,4H),2.37–2.32(m,6H),2.04–1.91(m,3H),1.61–1.60(m,3H),1.33–1.26(m,8H).

[0116] The white solid compound I-5 was analyzed by NMR carbon spectrum, and the results were: 13C NMR(151MHz,DMSO-d6)δ175.86,173.31,171.91,171.50,168.31,165.08,160.39,154.95, 150.44,135.08,134.34,134.20,133.13,131.43,129.05,125.74,121.98,121.97,121.96 ,119.74,119.41,110.89,61.22,61.20,52.03,47.06,45.88,45.41,40.57,40.39,40.25,39.96,39.82,36.24,31.68,30.32,29.30,29.25,29.20,29.11,28.50,25.55,23.15,8.92.

[0117] The white solid compound I-5 was subjected to mass spectrometry analysis. The result was: MS (ESI) m / z 905.75 [M+H] + .

[0118] From the above analysis, it can be seen that the structure of the white solid compound I-5 is shown in the following formula:

[0119]

[0120] 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.

[0121] Example 7 Synthesis of Compound I-6

[0122] Synthesis of 10-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)decylamide (B-6):

[0123] Referring to the synthesis method of B-1 in Example 2, 5-bromovaleryl chloride was replaced by 10-bromovaleryl chloride to obtain a white solid (B-6) with a yield of 95%.

[0124] The obtained white solid product (B-6) was subjected to H NMR spectrum analysis, and the results were: 1H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 9.75 (s, 1H), 7.81 (dd, J = 2.1, 6.9Hz, 1H), 7.55–7.43(m,2H),5.15(dd,J=5.1,13.3Hz,1H),4.44–4.28(m,2H),3.52(t,J=6 .7Hz,2H),2.99–2.84(m,1H),2.72–2.56(m,1H),2.34(h,J=8.2,8.8Hz,3H),2.1 0–2.00(m,1H),1.78(p,J=6.8Hz,2H),1.60(t,J=7.3Hz,2H),1.43–1.26(m,10H).

[0125] From the above analysis, it can be seen that the structure of the white solid product (B-6) is shown below:

[0126]

[0127] Referring to the synthesis method of I-1 in Example 2, the difference is that B-1 prepared in Example 1 is replaced by 10-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-4-yl)pentanamide (B-6) (135 mg, 1.1 eq.), and the rest is the same as in Example 2 to obtain a white solid compound I-6 (100 mg) with a yield of 45%.

[0128] The white solid compound I-6 was analyzed by H NMR spectrum, and the results were: 1 H NMR(400MHz,DMSO-d6)δ12.75(s,1H),11.04(s,1H),9.76(s,1H),8.90(s,2H),7.81–7.79 (m,1H),7.59(d,J=8.1Hz,1H),7.52–7.46(m,2H),7.33(s,2H),7.02(d,J=8.1Hz,1H),5.17 –5.12(m,1H),4.41–4.30(m,2H),4.16–4.02(m,6H),3.91(s,3H),2.97–2.88(m,2H),2.67– 2.58(m,3H),2.37–2.32(m,9H),2.04–1.94(m,4H),1.60–1.58(m,2H),1.44–1.24(m,14H).

[0129] The white solid compound I-6 was analyzed by NMR carbon spectrum, and the results were: 13C NMR(151MHz,DMSO-d6)δ179.36,175.86,173.30,171.86,171.85,171.52,168.30,165.09 ,160.39,160.38,160.36,134.29,134.17,133.14,131.36,129.09,129.08,125.72,125. 71,121.88,119.45,110.81,61.15,53.84,52.01,46.95,40.47,40.37,40.11,39.83,39.82,39.80,39.69,36.26,31.68,29.30,29.28,29.25,29.18,29.09,27.13,25.53,23.14.

[0130] The white solid compound I-6 was subjected to mass spectrometry analysis. The result was: MS (ESI) m / z 891.60 [M+H] + .

[0131] From the above analysis, it can be seen that the structure of the white solid compound I-6 is shown in the following formula:

[0132]

[0133] 2-amino-N-(8-(3-(4-(10-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-10-oxodecanyl)piperazin-1-yl)propoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide.

[0134] Example 8 Synthesis of Compound I-7

[0135] Synthesis of 9-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)nonanamide (B-7):

[0136] Referring to the synthesis method of B-1 in Example 2, 5-bromovaleryl chloride was replaced by 9-bromovaleryl chloride to obtain a white solid (B-7) with a yield of 92%.

[0137] The obtained white solid product (B-7) was subjected to H NMR spectrum analysis, and the results were: 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.75(s,1H),7.81(dd,J=2.0,6.9Hz,1H),7.60–7.42(m,2H),5.15(dd,J=5.1,13.3Hz,1H),4.44–4.26( m,2H),3.66–3.47(m,2H),2.98–2.85(m,1H),2.71–2.55(m,1H),2.41– 2.26(m,3H),2.12–1.96(m,1H),1.91–1.55(m,4H),1.42–1.27(m,8H).

[0138] From the above analysis, it can be seen that the structure of the white solid product (B-7) is shown below:

[0139]

[0140] Referring to the synthesis method of I-1 in Example 2, the difference is that B-1 prepared in Example 1 is replaced by 9-bromo-N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-4-yl)pentanamide (B-7) (131 mg, 1.1 eq.), and the rest is the same as in Example 2 to obtain white solid compound I-7 (125 mg) with a yield of 57%.

[0141] The white solid compound I-7 was analyzed by H NMR spectrum, and the results were: 1 H NMR(400MHz,DMSO-d6)δ12.74(s,1H),11.03(s,1H),9.79(s,1H),8.90(s,2H),7 .82–7.80(m,1H),7.58(d,J=8.8Hz,1H),7.52–7.46(m,2H),7.33(s,2H),7.01(d, J=8.8Hz,1H),5.17–5.12(m,1H),4.41–4.30(m,2H),4.16–3.99(m,6H),3.91(s,3 H),3.05–2.58(m,8H),2.37–2.33(m,6H),2.05–1.95(m,4H),1.62–1.15(m,14H).

[0142] The white solid compound I-7 was analyzed by NMR carbon spectrum, and the results were: 13C NMR (151MHz, DMSO-d6) δ175.87,173.30,171.87,171.52,168.31,165.11,160.46,160. 44,160.41,160.40,160.38,154.88,150.52,134.32,134.18,133.15,129.08,125.72,1 25.70,121.82,119.44,107.37,67.30,61.17,53.80,52.02,46.99,46.05,45.36,40.57,40.37,40.10,39.96,39.81,39.65,36.25,31.69,29.11,29.05,26.98,25.51,23.15.

[0143] The white solid compound I-7 was subjected to mass spectrometry analysis. The result was: MS (ESI) m / z 877.60 [M+H] + .

[0144] From the above analysis, it can be seen that the structure of the white solid compound I-7 is shown in the following formula:

[0145]

[0146] 2-amino-N-(8-(3-(4-(9-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)-9-oxoindoline)piperazin-1-yl)propoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide.

[0147] Example 9 Synthesis of Compound I-8

[0148] Synthesis of 8-bromo-N-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentanamide (B-8):

[0149] 3-(4-amino-1-oxoisoindol-2-yl)-1-methylpiperidine-2,6-dione (1 eq, 5 mmol) was dissolved in 20 mL of tetrahydrofuran, and 8-bromovaleryl chloride (1.5 eq, 7.5 mmol) was slowly added dropwise under ice bath. The mixture was reacted at room temperature for 12 h. After the reaction was completed, a white solid (B-8) was obtained by filtration with a yield of 95%.

[0150] The obtained white solid product (B-8) was subjected to H NMR spectrum analysis, and the results were: 1H NMR(400MHz, DMSO-d6)δ9.42(s,1H),7.84(dd,J=7.5,2.0Hz,1H),7.45(t,J=7.5Hz,1H),7.36 (dd,J=7.6,2.1Hz,1H),4.45(d,J=9.5Hz,1H),4.37–4.29(m,2H),3.59(s,2H),2.87(s,3H),2 .59(d,J=3.9Hz,2H),2.49–2.37(m,2H),2.18(s,1H),2.13(s,1H),2.05(d,J=12.5Hz,1H),1. 97(d,J=12.3Hz,1H),1.62(s,2H),1.54(d,J=2.3Hz,2H),1.37(s,2H),1.32(d,J=1.4Hz,2H).

[0151] From the above analysis, it can be seen that the structure of the white solid product (B-8) is shown below:

[0152]

[0153] Referring to the synthesis method of I-1 in Example 2, the difference is that B-1 prepared in Example 1 is replaced by 8-bromo-N-(2-(1-methyl-2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-4-yl)pentanamide (B-8) (131 mg, 1.1 eq.), and the rest is the same as in Example 2 to obtain a white solid compound I-8 (142 mg) with a yield of 65%.

[0154] The white solid compound I-8 was analyzed by H NMR spectrum, and the results were: 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),9.81(s,1H),8.90(s,2H),7.80(d,J=7.4Hz ,1H),7.59–7.58(m,1H),7.52–7.50(m,2H),7.35(s,2H),7.02(d,J=7.4Hz,1H),5. 24–5.20(m,1H),4.41–4.29(m,2H),4.14–3.90(m,8H),3.01(s,3H),2.78–2.74(m, 2H),2.67–2.57(m,3H),2.37–2.15(m,8H),2.05–1.96(m,4H),1.59–1.23(m,14H).

[0155] The white solid compound I-8 was analyzed by NMR carbon spectrum, and the results were: 13C NMR(151MHz,DMSO-d6)δ172.34,171.83,171.17,168.30,165.10,160.40,160.39,154, 90,154.89,150.92,150.55,150.53,134.31,134.23,133.15,129.09,125.79,121.86,1 19.82,119.50,110.81,110.80,67.40,61.15,53.83,52.53,46.98,45.38,45.36,40.57,40.26,40.11,39.97,39.83,39.81,39.69,36.23,31.86,29.02,27.04,25.47,22.36.

[0156] The white solid compound I-8 was subjected to mass spectrometry analysis. The result was: MS (ESI) m / z 877.40 [M+H] + .

[0157] From the above analysis, it can be seen that the structure of the white solid compound I-8 is shown in the following formula:

[0158]

[0159] 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.

[0160] Example 10

[0161] (I) PI3K kinase activity detection

[0162] The PI3K kinase activity test method used in this experiment adopts the ADP-Glo ​​method, which is to incubate lipid substrates with recombinant enzymes and ATP to perform lipid kinase reactions and use ADP-Glo TM Kinase assays measure kinase activity. ADP-Glo TM The kinase assay is performed in two steps: First, after the kinase reaction, an ATP depleting 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 convert the newly synthesized ATP to a fluorescent signal using a coupled luciferase / luciferin reaction.

[0163] The compounds of Examples 2 to 9 were tested and the IC 50The values ​​are shown in Table 1, where the DC of the compound 50 Classification by description: "A" means DC 50 The measured value is less than or equal to 10nM; "B" means DC 50 The measured value is less than or equal to 100nM and greater than 10nM; "C" means DC 50 The measured value is less than or equal to 500nM and greater than 100nM. "D" means DC 50 The measured value is greater than 500 nM. From the experimental results in Table 1, it can be seen that the IC values ​​of compounds I-1 to I-8 prepared in Examples 2 to 9 are 50 The values ​​are all A, indicating that compounds I-1 to I-8 prepared in Examples 2 to 9 have strong inhibitory activity on PI3Kα kinase activity.

[0164] (II) Determination of PI3K degradation activity in vitro

[0165] The ability of compounds I-1 to I-7 prepared in Examples 2 to 8 to degrade PI3K protein was evaluated by Western blotting, and Western blotting analysis was performed in various tumor cells (human breast cancer cells MCF7, human breast ductal carcinoma cells T47D). The results are shown in Table 1. 50 Classification by description: "A" means DC 50 The measured value is less than or equal to 10nM; "B" means DC 50 The measured value is less than or equal to 100nM and greater than 10nM; "C" means DC 50 The measured value is less than or equal to 500nM and greater than 100nM. "D" means DC 50 Measured values ​​were greater than 500 nM; "NT" means not tested.

[0166] The experimental results showed that the compounds I-1 to I-7 prepared in Examples 2 to 9 had significant degradation activity against PI3Kα, and the optimal compound I-7 had a significant degradation activity against DCs of human breast cancer cells MCF7 and human breast ductal carcinoma cells T47D. 50 The values ​​are all A, indicating that compound I-7 also has excellent selectivity for other PI3K subtype kinases. The results are shown in Table 1.

[0167] Table 1 IC of the compounds prepared in Examples 2 to 9 against PI3K kinase activity 50 and degradation of active DC 50

[0168] Example <![CDATA[PIK3CA IC 50 (nM)]]> <![CDATA[MCF7 DC 50 (nM)]]> <![CDATA[T47D DC 50 (nM)]]> 2 A NT NT 3 A NT NT 4 A NT A 5 A NT A 6 A NT A 7 A NT A 8 A A A 9 A NT NT

[0169] (III) Determination of the inhibitory effect on proliferation of various cancer cells

[0170] This experiment uses the Cell Counting Kit-8 (CCK8) method to test the inhibitory effects of compounds I-1 to I-8 prepared in Examples 2 to 9 on the proliferation of various cancer cells (human breast cancer cells MCF7, human breast ductal cancer cells T47D). 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 produced by colorimetry reflects the number of living cells in the experiment. Cells in the logarithmic growth phase are cultured at 1×10 5 cells / well were inoculated in a 96-well plate and cultured at 37°C and 5% CO2 until the cells were 90% confluent, and then cultured with serum-free DMEM medium, RPMI-1640 medium, F12K medium or other corresponding cell culture medium for 2 hours to synchronize the cells. 100 μL of the compound solution of different concentrations to be tested 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, GraphPadPrism fitted the IC 50 The results are shown in Table 2. Among them, "++++" means IC 50 The measured value is less than or equal to 10nM; "+++" indicates IC 50 The measured value is less than or equal to 100nM and greater than 10nM; "++" indicates IC 50 The measured value is less than or equal to 500nM and greater than 100nM; "+" indicates IC 50 The measured value is greater than 500nM; "-" indicates IC 50 Not determined.

[0171] Table 2 Antiproliferative activity of the compounds of the present application on MCF7 and T47D cells

[0172] Example <![CDATA[MCF7 IC 50 (nM)]]> <![CDATA[T47D IC 50 (nM) <!-- 15 -->]]> 2 - ++++ 3 +++ ++++ 4 +++ ++++ 5 ++++ ++++ 6 ++++ ++++ 7 ++++ ++++ 8 ++++ ++++ 9 +++ -

[0173] As can be seen from Table 2, Examples 2-9 have excellent anti-proliferative activity against MCF7 and T47D breast cancer tumor cell lines.

[0174] (IV) Determination of the anti-breast cancer activity of compounds in vivo

[0175] 1. Test consumables

[0176] Source, strain, and strain: SPF BALB / c nude mice were provided by Changzhou Cavens Laboratory Animal Co., Ltd. Laboratory Animal Production License: SCXK (Su) 2016-0010; Laboratory Animal Use License: SYXK (Su) 2017-0040. Age: 4-6 weeks at the time of purchase, 6-8 weeks at the start of administration. Body weight: 16-18g at the time of purchase, 18-20g at the start of administration. Gender: male. Number of animals per group: 5. Human breast cancer cells MCF7 and T47D were provided by the Shanghai Institute of Cell Biology, Chinese Academy of Sciences, and cultured in EMEM medium containing 10% fetal bovine serum.

[0177] Experimental method: The human breast cancer cell MCF7 xenograft tumor model was established by inoculating human breast cancer cell MCF7 subcutaneously in the axilla of nude mice. MCF7 cells in the logarithmic growth phase were taken and inoculated subcutaneously in the right axilla of 28 BALB / c nude mice under sterile conditions. The cell inoculation amount was 5×10 6 Use a vernier caliper to measure the diameter of the transplanted tumor. When the tumor grows to 85 mm 3 Around 20 tumor-bearing nude mice with good growth status and uniform tumor size were selected and randomly divided into 4 groups, 5 mice in each group, namely model control group, positive control group (copanlisib), oral administration group and intraperitoneal administration group. The model control group was given normal saline every day; the positive control group was given the positive drug copanlisib (10 mg / kg) by intraperitoneal injection once every two days; the intraperitoneal administration group was given compound I-7 (20 mg / kg) by intraperitoneal injection once a day; the oral administration group was given compound I-7 (20 mg / kg) by oral gavage once a day, and all groups were conducted for a total of 21 days. At the same time, the tumor volume and animal weight of the nude mice were measured and recorded every other day. The results are as follows Figure 1-2 shown.

[0178] Tumors in the vigorous growth stage were taken and human breast ductal carcinoma T47D cells were inoculated subcutaneously in the right axilla of 35 BALB / c nude mice under sterile conditions. The cell inoculation amount was 5×10 6 The diameter of the transplanted tumor in nude mice was measured with a vernier caliper. When the tumor grew to 85 mm 3Around 30 tumor-bearing nude mice with good growth status and good tumor size uniformity were selected and divided into 5 groups, with 5 mice in each group. The medication was the same as the above process, namely (1) model group, (2) intraperitoneal administration control group (10 mg / kg) (copanlisib 10 mg / kg, IP), (3) compound I-7 intraperitoneal group (20 mg / kg) (I-7 20 mg / kg, IP), (4) compound I-7 oral group (20 mg / kg), (5) compound I-7 oral group (40 mg / kg) (I-7 40 mg / kg, IP). The anti-tumor effect of the test substance was dynamically observed by measuring the tumor diameter. The tumor diameter was measured every other day, and the body weight of the nude mice was weighed while measuring the tumor diameter. The nude mice were euthanized 21 days after administration, and the tumor mass was surgically removed. The results are as follows Figure 3-4 shown.

[0179] Figure 1 This is the growth curve of MCF7 xenograft tumor. Figure 2 This is a graph of mouse weight gain. Figure 3 This is the growth curve of T47D xenograft tumor. Figure 4 The results show that the compound I-7 prepared in the test drug example 8 has a significant inhibitory effect on tumor growth, and the compound has no significant effect on the weight of the animals.

Claims

1. A compound for targeting degradation of PI3K protein, or a pharmaceutically acceptable salt thereof, characterized in that: The general structural formula of the compound is shown in Formula I: Wherein, R is selected from H, -CH3; linker is a connecting group, and linker is selected from a straight chain or branched alkylene chain with a total length of 1 to 11 atoms.

2. The compound for targeting degradation of PI3K protein according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The linear or branched alkylene chain consists of one or more of -CH2-, -O-, -CO-, -CONH-, -S- or -N-.

3. The compound for targeting degradation of PI3K protein according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The linear or branched alkylene chain consists of one or more of -CH2-, -O-, -CO-, -CONH- or -N-.

4. The compound for targeting degradation of PI3K protein according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt is an acid addition salt of the compound of formula I, wherein the acid used for salt formation includes inorganic acid and / or organic acid.

5. The compound for targeting degradation of PI3K protein according to claim 4, or a pharmaceutically acceptable salt thereof, characterized in that: The inorganic acid is hydrochloric acid, sulfuric acid, phosphoric acid or methanesulfonic acid, and the organic acid is 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 or tartaric acid.

6. The compound for targeting degradation of PI3K protein according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from any one of the following:

7. A method for preparing a compound for targeting degradation of PI3K protein according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that: Synthesized according to the following reaction route: Wherein, R is selected from H, -CH3; R1 is Br, linker is a connecting group, and linker is selected from a straight or branched alkylene chain with a total length of 1 to 11 atoms.

8. A pharmaceutical composition, characterized in that A compound for targeting degradation of PI3K protein comprising any one of claims 1 to 6, or a pharmaceutically acceptable salt, tautomer and stereoisomer, metabolite, metabolic precursor, solvent compound or prodrug thereof, and a pharmaceutically acceptable carrier.

9. Use of the compound for targeted degradation of PI3K protein according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a PI3K protein target degradation inhibitor or a drug for a disease regulated by PI3K.

10. The method according to claim 9, characterized in that Use of the compound for targeted degradation of PI3K protein according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of drugs for tumors, immune disorders or inflammatory disorders regulated by PI3K protein.

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