Protein-targeting degradation chimeras and use thereof

Abstract

Disclosed are protein-targeting degradation chimeras and the use thereof. The protein-targeting degradation chimeras have a new chemical structure, exhibit a great degradation effect on the BCL6 protein, can be used for preparing BCL6 degrader drugs, and has the potential to be developed into a drug for treating diseases that can be treated or alleviated by means of the degradation of the BCL6 protein. The diseases that can be treated or alleviated by means of the degradation of the BCL6 protein comprise cancers such as Hodgkin lymphoma, B-cell-derived non-Hodgkin lymphoma, T-cell-derived non-Hodgkin lymphoma, NK / T-cell-derived non-Hodgkin lymphoma and diffuse large B-cell lymphoma.

Description

Protein-targeting degradation chimeras and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry, and particularly relates to a kind of protein-targeting degradation chimeras and uses thereof. BACKGROUND

[0002] B-cell lymphoma 6 (BCL6) plays an important role in humoral immune response, and is a human gene of about 24 kb, encoding a BCL6 protein of about 95 kD. The BCL6 protein is a member of the POZ / BTB / Zinc finger protein family, mainly composed of three parts: 1) the POZ / BTB domain at the amino terminus: this is the main functional region for transcriptional repression. When BCL6 exerts transcriptional repression, the BTB domain spontaneously forms a dimer, and three important transcriptional co-repressors SMRT, BCOR or NCOR bind to the BTB binding site by competitive binding, and jointly exert transcriptional repression. This process is involved in the transcriptional regulation in the early stage of germinal center (GC) formation. 2) the middle region (also known as the RD2 domain) contains three PEST domains, which mainly function to recruit auxiliary factors such as MTA3 or CTBP1, and play a role in maintaining protein stability. 3) the zinc finger domain at the carboxy terminus is composed of six identical zinc finger structures, which mainly function to bind DNA, and are a prerequisite for BCL6 to exert transcriptional repression.

[0003] BCL6 is a transcriptional repressor that recruits co-repressors through its BTB domain. BCL6 protein is overexpressed in lymphoma, breast cancer, ovarian cancer, non-small cell lung cancer and glioma, and is closely related to poor prognosis of patients. When BCL6 protein is highly expressed, the p53 tumor suppressor gene is almost absent. In the GC response, chromosomal translocation and point mutation of BCL6 can cause persistent high expression of BCL6 protein, promote malignant proliferation of B cells, and further cause the occurrence of B-cell lymphoma. Most non-Hodgkin lymphoma (NHL) originates from GC, among which diffuse large B-cell lymphoma (DLBCL) is the most common subtype, and BCL6 is considered to be an oncogenic driver of DLBCL. Many preclinical studies have also shown that blocking the interaction between BCL6-BTB domain and its transcriptional co-repressor can inhibit GC formation and NHL cell proliferation, which is an effective strategy for treating NHL, and has good safety, without causing toxic side effects and inflammation driven by macrophages.

[0004] BCL6 is a highly potential cancer treatment target, including but not limited to Hodgkin lymphoma, B-cell derived non-Hodgkin lymphoma, T-cell derived non-Hodgkin lymphoma, NK / T-cell derived non-Hodgkin lymphoma or diffuse large B-cell lymphoma. There are about 18 BCL6 drugs under research, including small molecule inhibitors (8 types), protein targeting degradation chimeras (5 types) and molecular glue (5 types), and only the PROTAC drug (BMS-986458) of BMS has entered phase I clinical study. Therefore, it is still urgent and necessary to develop a small molecule degrading agent with novel structure, good drug property and safety, and capable of quickly and efficiently degrading BCL6. SUMMARY

[0005] The purpose of the present application is to provide a BCL6 protein targeting degradation chimera and uses thereof.

[0006] The above purposes of the present application are achieved by the following technical solutions.

[0007] A compound or a pharmaceutically acceptable salt or solvate thereof having a chemical structure as shown in formula I:

[0008] POI-L-E3L

[0009] I

[0010] Wherein:

[0011] L is a Linker connecting POI and E3L;

[0012] E3L is independently selected from:

[0013] Wherein:

[0014] R1, R2, R 3、 R4, R5, R 6、 R7, R8, R 9、 R 10 , R 11 , R 12 , R 13 , R 14 , R 15、 R 16 , R 17 , R 18、 R 19 , R 20 , R 21 are independently selected from -H, halogen, -C1-C3alkyl, -C1-C3haloalkyl, -C1-C3alkoxy;

[0015] R 22 is independently selected from -H, -C1-C3alkyl;

[0016] POI is independently selected from:

[0017] wherein:

[0018] R 23 is independently selected from -H, halogen;

[0019] R 24 , R 25 is independently selected from -H, -C1-C3alkyl;

[0020] L is independently selected from:

[0021] wherein:

[0022] n = 1, 2 or 3.

[0023] A compound represented by one of the following chemical structures:

[0024] A pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, solvate thereof.

[0025] Use of the above-mentioned compound or a pharmaceutically acceptable salt, solvate thereof for the manufacture of a BCL6 protein degrading agent.

[0026] Use of the above-mentioned compound or a pharmaceutically acceptable salt, solvate thereof for the manufacture of a medicament for treating a disease which is treated or alleviated by degrading BCL6 protein.

[0027] Preferably, the disease is cancer.

[0028] More preferably, the cancer is Hodgkin lymphoma, B-cell derived non-Hodgkin lymphoma, T-cell derived non-Hodgkin lymphoma, NK / T-cell derived non-Hodgkin lymphoma or diffuse large B-cell lymphoma.

[0029] Use of the above-mentioned pharmaceutical composition for the manufacture of a medicament for treating a disease which is treated or alleviated by degrading BCL6 protein.

[0030] Preferably, the disease is cancer.

[0031] More preferably, the cancer is Hodgkin lymphoma, B-cell derived non-Hodgkin lymphoma, T-cell derived non-Hodgkin lymphoma, NK / T-cell derived non-Hodgkin lymphoma or diffuse large B-cell lymphoma.

[0032] A method of treating a disease, administering to an individual having the disease a therapeutically effective amount of any of the compounds or pharmaceutically acceptable salts, solvates thereof described above, or administering a therapeutically effective amount of the pharmaceutical composition described above; wherein the disease is a disease treated or ameliorated by degrading BCL6 protein.

[0033] Preferably, the disease is cancer.

[0034] More preferably, the cancer is Hodgkin lymphoma, B-cell derived non-Hodgkin lymphoma, T-cell derived non-Hodgkin lymphoma, NK / T-cell derived non-Hodgkin lymphoma or diffuse large B-cell lymphoma. Beneficial effects:

[0035] The compound or pharmaceutically acceptable salt, solvate thereof provided by the present application is a protein-targeted degradation chimera, which has a novel chemical structure; the compound or pharmaceutically acceptable salt, solvate thereof has excellent degradation effect on BCL6 protein, and can be used for preparing a BCL6 degradation agent drug, and has the prospect of developing into a drug for treating a disease treated or ameliorated by degrading BCL6 protein, including cancers such as Hodgkin lymphoma, B-cell derived non-Hodgkin lymphoma, T-cell derived non-Hodgkin lymphoma, NK / T-cell derived non-Hodgkin lymphoma and diffuse large B-cell lymphoma. DETAILED DESCRIPTION

[0036] The essential content of the present application will be specifically described below in combination with examples, but the protection scope of the present application is not limited by this.

[0037] Synthetic route 1:

[0038] Intermediate 11 is synthesized according to synthetic route 1.

[0039] Synthetic route 1. Reagents and conditions: (a) 1,2-dibromoethane, K2CO3, DMF, rt, 3 h; (b) BBr3, DCM, 0 °C, 4 h; (c) Cs2CO3, CH3CN, 60 °C, 1 h; (d) KNO3, H2SO4, 0 °C, 4 h; (e) ethyl diazoacetate, DBU, EtOH, DMF, rt, 16 h; (f) NaOH, H2O, 115 °C, 24 h; (g) 2-bromo-N-methylacetamide, Cs2CO3, DMF, rt, 3 h; (h) Fe, NH4Cl, EtOH, H2O, 80 °C, 3 h; (i) DIPEA, DMSO, 100 °C, 3 h.

[0040] Intermediate 11 is synthesized according to synthetic route 1.

[0041] 1-(2-bromoethyl)-7-methoxyindoline-2,3-dione (2)

[0042] 1-(2-bromoethyl)-7-methoxyindoline-2,3-dione (2)

[0043] To a round bottom flask containing 1a (5.00 g, 28.22 mmol), 1,2-dibromoethane 1b (10.6 g, 56.45 mmol), potassium carbonate (7.80 g, 56.45 mmol) was added 35 mL of DMF solution, stirred at room temperature for 3 h, TLC monitoring reaction was completed. Added 350 mL of water stirred for half an hour, suction filtration, water washing, drying to get red solid intermediate 2 (6.80 g, yield: 84.8%). 1 H NMR (300 MHz, DMSO-d6) δ 7.45 (d, J = 8.1 Hz, 1H), 7.16 (dt, J = 15.4, 7.4 Hz, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.91 (s, 3H), 3.66 (t, J = 6.8 Hz, 2H). ESI-MS: m / z: [M+H] + 283.98.

[0044] 1-(2-bromoethyl)-7-methoxyindoline-2,3-dione (2)

[0045] 1-(2-bromoethyl)-7-methoxyindoline-2,3-dione (2)

[0046] To a round bottom flask containing 1a (5.00 g, 28.22 mmol), 1,2-dibromoethane 1b (10.6 g, 56.45 mmol), potassium carbonate (7.80 g, 56.45 mmol) was added 35 mL of DMF solution, stirred at room temperature for 3 h, TLC monitoring reaction was completed. Added 350 mL of water stirred for half an hour, suction filtration, water washing, drying to get red solid intermediate 2 (6.80 g, yield: 84.8%). 1 H NMR (300 MHz, DMSO-d6) δ 7.45 (d, J = 8.1 Hz, 1H), 7.16 (dt, J = 15.4, 7.4 Hz, 2H), 4.20 (t, J = 6.9 Hz, 2H), 3.91 (s, 3H), 3.66 (t, J = 6.8 Hz, 2H). ESI-MS: m / z: [M+H]+ 269.97.

[0047] 2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-5,6-dione (4)

[0048] 2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-5,6-dione (4)

[0049] Intermediate 3 (1.00 g, 3.70 mmol) was added to a round-bottom flask, 30 mL of acetonitrile solution was added, then cesium carbonate (2.41 g, 7.41 mmol) was added, and the reaction was heated at 60 °C for 1 h, and TLC was used to monitor the end of the reaction. After removing the heat, the reaction solution was allowed to cool to room temperature, and then filtered, washed with ethyl acetate, concentrated, and the residue was purified by column chromatography (eluent system: petroleum ether: ethyl acetate = 4:1, v / v) to obtain intermediate 4 as a red solid (0.57 g, yield: 81.8%). 1 H NMR (300 MHz, DMSO-d6) δ 7.24 - 7.11 (m, 2H), 6.99 (t, J = 7.8 Hz, 1H), 4.32 (t, J = 4.7 Hz, 2H), 3.79 (t, J = 4.9 Hz, 2H). ESI-MS: m / z: [M+H] + 190.04.

[0050] 2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-5,6-dione (5)

[0051] 2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-5,6-dione (5)

[0052] Intermediate 4 (2.40 g, 12.69 mmol) was added to a round-bottom flask, stirred in an ice bath for 15 min, and then 20 mL of concentrated sulfuric acid solution was slowly added, stirred in an ice bath for 0.5 h, and then potassium nitrate (1.28 g, 12.69 mmol) was slowly added, and the reaction was allowed to proceed at room temperature for 6 h, and TLC was used to monitor the end of the reaction. The reaction solution was slowly poured into stirring ice water, and then ethyl acetate was added, and the organic phase was extracted three times, and then concentrated under reduced pressure, and the residue was purified by column chromatography (eluent system: petroleum ether: ethyl acetate = 4:1, v / v) to obtain intermediate 5 as an orange-red solid (1.80 g, yield: 60.6%). 1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 4.41 (t, J = 4.7 Hz, 2H), 3.86 (t, J = 4.6 Hz, 2H). ESI-MS: m / z: [M+H] + 235.03.

[0053] 6-hydroxy-9-nitro-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-5-one (7)

[0054] 6-hydroxy-9-nitro-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-5-one (7)

[0055] Intermediate 5 (1.10 g, 4.70 mmol) was added to a round bottom flask, EtOH:DMF = 20 mL:4 mL of mixed solvent was added, argon was replaced, DBU (107 mg, 0.70 mmol) was quickly added, argon was replaced, the solution quickly became thick, the solution changed from orange red to brown yellow (about 15 minutes), ethyl diazoacetate (1.07 g, 9.40 mmol) was quickly added, argon was replaced, stirred at room temperature for 16 h. After monitoring the end of the reaction by TLC, most of the ethanol was removed under reduced pressure, dilute hydrochloric acid (16 mL, 1.2 M) was slowly added dropwise with a dropping funnel, 20 mL of water was added, stirred at room temperature for 2 hours. Ethyl acetate was added, extracted twice, the organic phase was combined and concentrated under reduced pressure to give crude intermediate 6 as an orange yellow oil (1.40 g, yield: 93.0%). ESI-MS: m / z: [M+H] + 321.06.

[0056] 6-hydroxy-9-nitro-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-5-one (7)

[0057] 6-hydroxy-9-nitro-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-5-one (7)

[0058] Intermediate 6 (1.40 g, 4.40 mmol) was added to a round bottom flask, sodium hydroxide solid (0.35 g, 8.80 mmol) was added, followed by 44 mL of water, stirred at 115 °C for 24 h, TLC monitored the end of the reaction. Slowly drop 1M dilute hydrochloric acid solution to adjust pH to 2-3, suction filtration, water washing, the filter cake was dried to give the crude intermediate 7 as a yellow solid (0.78 g, yield: 71.9%). ESI-MS: m / z: [M+H] + 249.05.

[0059] N-methyl-2-((9-nitro-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)acetamide (8)

[0060] N-methyl-2-((9-nitro-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)acetamide (8)

[0061] Intermediate 7 (1.00 g, 4.03 mmol) was added to a round bottom flask, followed by 7a (0.74 g, 4.83 mmol), and cesium carbonate (2.63 g, 8.06 mmol), followed by DMF (15 mL), stirred at room temperature for 4 h, TLC monitored the end of the reaction. First add 50 mL of water, suction filtration, water washing, the filter cake was dried, to the filtrate added equal volume of ethyl acetate and water liquid-liquid extraction 3 times, combined organic layer and low pressure concentration to remove the solvent, the residue was combined with the filter, purified by column chromatography (elution system was dichloromethane:methanol = 60:1, v / v) to give intermediate 8 as a white solid (0.48 g, yield: 37.3%). 1 H NMR (300 MHz, DMSO-d6) δ 8.27 (d, J = 2.5 Hz, 1H), 7.96 (s, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.54 (s, 1H), 4.62 (s, 2H), 4.48 (t, J = 4.8 Hz, 2H), 4.25 (t, J = 4.8 Hz, 2H), 2.69 (d, J = 4.6 Hz, 3H). ESI-MS: m / z: [M+H] + 320.08.

[0062] 2-(9-amino-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N- methylacetamide (9)

[0063] 2-((9-amino-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(9)

[0064] Add 8 (0.40 g, 1.25 mmol) to a round-bottom flask containing anhydrous ethanol:water = 20 mL:4 mL, add ammonium chloride (0.35 g, 6.26 mmol), and add reduced iron powder (0.34 g, 6.26 mmol) while stirring. Heat the mixture at 80 °C for 3 h, and monitor the reaction for completion by TLC. Remove heating and allow the reaction solution to cool to room temperature. Add 2 mL of ammonia-methanol solution to adjust the pH to greater than 7. Filter with diatomaceous earth, wash with dichloromethane:methanol = 20:1 (1000 mL), collect the filtrate, and concentrate under low pressure to obtain a pale yellow solid 9 (0.24 g, yield: 67.0%). ESI-MS: m / z: [M+H] + 290.11.

[0065] 2-((9-((2,5-dichloropyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)-N-methylacetamide (11)

[0066] 2-((9-((2,5-dichloropyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(11)

[0067] Intermediate 9 (0.40 g, 1.38 mmol), starting material 10 (0.51 g, 2.77 mmol), and DIPEA (0.54 g, 4.15 mmol) were added to a round-bottom flask, followed by 8 mL of DMSO solution. The mixture was stirred at 100 °C for 3 h, and the reaction was monitored by TLC until complete. 35 mL of water was added, and the mixture was stirred for half an hour. The mixture was then filtered, washed with water, and dried to obtain a pale yellow solid, intermediate 11 (0.43 g, yield: 71.6%). ESI-MS: m / z: [M+H] + 436.04.

[0068] Synthesis Route 2:

[0069] Examples 1-3 were synthesized according to synthetic route 2.

[0070] Synthetic Route 2: Reagents and Conditions: (a) NaBH(OAc)3, DCE, rt, 3h; (b) H2, Pd / C, EtOH, rt, 16h; (c) DIPEA, DMSO, 100℃, 3h; (d) TFA, DCM, rt, 1h; (e) DIPEA, NMP, 170℃, microwave, 3h.

[0071] 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (21)

[0072] tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate(21)

[0073] Synthetic Method 1: Intermediate 20a (151 mg, 0.81 mmol) and 20b (100 mg, 0.40 mmol) were added to a round-bottom flask containing 4 mL of anhydrous 1,2-dichloroethane solution. The mixture was stirred at room temperature for 15 minutes, then NaBH(OAc)3 (171 mg, 0.81 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The reaction solution was concentrated under low pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (elution system: dichloromethane:methanol = 100:1, v / v) to give intermediate 21 as a white solid (201 mg, yield: 59.4%). 1 H NMR (300MHz, DMSO-d6) δ7.36(qd,J=6.7,2.6Hz,5H),5.08(s,2H),3.32(dd,J=12.5,7.6Hz,6H),2.28(t,J=5.0Hz,4 H),2.13(d,J=6.8Hz,2H),2.01(s,1H),1.70(d,J=12.1Hz,3H),1.41(s,9H),1.28–1.16(m,1H).ESI-MS:m / z:[M+H] + 418.26.

[0074] 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (22)

[0075] tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate(22)

[0076] General synthesis method 2: Intermediate 21 (201 mg, 0.48 mmol) was dissolved in a round-bottom flask containing 5 mL of anhydrous ethanol solution, palladium-carbon (30 mg, 15% m / m) was added, hydrogen was replaced, stirred at room temperature for 16 hours, TLC monitored the reaction to complete. The reaction was filtered through celite, washed with dichloromethane, the filtrate was concentrated at low pressure, and the residue was purified by column chromatography (eluent system dichloromethane:methanol = 100:1, v / v) to obtain intermediate 22 as a white oil (108 mg, yield: 79.2%). ESI-MS: m / z: [M+H] + 283.23.

[0077] tert-butyl-4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (24a)

[0078] tert-butyl-4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (24a)

[0079] General synthesis method 3: Intermediate 23a (400 mg, 1.45 mmol) and 22 (534 mg, 1.88 mmol) were added to a round-bottom flask containing 6 mL of DMSO solution, then DIPEA (374 mg, 2.90 mmol) was added, stirred at 100°C for 3 hours, TLC monitored the reaction to complete. After the reaction was cooled to room temperature, it was extracted with ethyl acetate, the organic layer was washed with saturated brine, then dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent system dichloromethane:methanol = 100:1, v / v) to obtain intermediate 24a as a yellow solid (690 mg, yield: 88.3%). 1 H NMR (300 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.69 (dd, J = 8.5, 7.1 Hz, 1H), 7.34 (dd, J = 8.0, 4.1 Hz, 2H), 5.11 (dd, J = 13.1, 5.7 Hz, 1H), 3.70 (d, J = 11.7 Hz, 1H), 2.88 (s, 2H), 2.56 (s, 6H), 2.32 (s, 3H), 2.21 (d, J = 6.8 Hz, 1H), 2.03 (d, J = 8.9 Hz, 1H), 1.83 (d, J = 13.2 Hz, 2H), 1.41 (s, 9H), 1.37 - 1.23 (m, 3H). ESI-MS: m / z: [M+H]+ 540.27.

[0080] 4-((1-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (24b)

[0081] tert-butyl-4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (24b)

[0082] Following General Synthesis 3, 23b (400 mg, 1.45 mmol) was used as the reactant to give the target product 24b (690 mg, yield: 88.3%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 7.68 (dd, J = 8.5, 7.1 Hz, 1H), 7.33 (dd, J = 7.8, 5.4 Hz, 2H), 5.09 (dd, J = 12.7, 5.3 Hz, 1H), 2.88 (t, J = 12.4 Hz, 3H), 2.62 (s, 1H), 2.56 (s, 1H), 2.43 (s, 3H), 2.23 (d, J = 6.8 Hz, 2H), 2.02 (d, J = 11.4 Hz, 1H), 1.81 (t, J = 16.9 Hz, 3H), 1.42 - 1.30 (m, 2H), 1.25 (s, 9H), 1.24 (d, J = 4.4 Hz, 1H). ESI-MS: m / z: [M+H] + 540.27.

[0083] 4-((1-(2-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (24c)

[0084] tert-butyl-4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (24c)

[0085] Following General Synthesis Procedure 3, using 23c (400 mg, 1.36 mmol) as the starting material, the target product 24c was obtained as a yellow solid (670 mg, yield: 91.3%). 1 H NMR (300 MHz, DMSO-d6) δ 11.15 (s, 1H), 7.73 (d, J = 11.4 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 5.12 (dd, J = 12.9, 5.3 Hz, 1H), 3.61 (d, J = 12.0 Hz, 2H), 2.88 (dd, J = 15.4, 7.6 Hz, 3H), 2.65 - 2.53 (m, 2H), 2.30 (d, J = 6.2 Hz, 4H), 2.19 (d, J = 6.8 Hz, 2H), 2.07 - 2.00 (m, 1H), 1.83 (d, J = 13.3 Hz, 2H), 1.41 (d, J = 4.4 Hz, 10H), 1.26 (d, J = 9.7 Hz, 2H). ESI-MS: m / z: [M+H] + 558.26.

[0086] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindoline-1,3-dione (25b)

[0087] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindoline-1,3-dione (25b)

[0088] General Synthesis Procedure 4: Intermediate 24a (300 mg, 0.56 mmol) was added to a round bottom flask containing 5 mL dichloromethane solution, trifluoroacetic acid (1.5 mL) was added, stirred at room temperature for 1 hour, TLC monitored the reaction was completed. Concentrated under reduced pressure, intermediate 25a was obtained as a yellow oil (230 mg, yield: 94.1%). ESI-MS: m / z: [M+H] + 440.22.

[0089] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindoline-1,3-dione (25b)

[0090] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindoline-1,3-dione (25b)

[0091] Following General Synthesis 4, 24b (300 mg, 0.56 mmol) was used as the starting material to give the target product 25b (230 mg, yield: 94.1%) as yellow oil. ESI-MS: m / z: [M+H] + 440.22.

[0092] 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindoline-1,3-dione(25c)

[0093] 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindoline-1,3-dione(25c)

[0094] Following General Synthesis 4, 24c (300 mg, 0.54 mmol) was used as the starting material to give the target product 25c (210 mg, yield: 85.3%) as yellow oil. ESI-MS: m / z: [M+H] + 458.21.

[0095] Example 1

[0096] 2-((9-((5-chloro-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 1)

[0097] 2-((9-((5-chloro-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 1)

[0098] Synthetic General Procedure 5: Intermediate 25a (121 mg, 0.28 mmol) and 11 (60 mg, 0.14 mmol) were added to a round bottom flask containing 5 mL of NMP solution, followed by the addition of DIPEA (71 mg, 0.55 mmol), and the reaction was subjected to microwave irradiation at 170 °C for 3 h. The reaction was monitored by TLC until completion. After the reaction was cooled to room temperature, it was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography (eluent: dichloromethane:methanol = 20:1, v / v) to give the target product, Example 1, as a yellow solid (18 mg, yield: 15.6%). 1 H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.79 (s, 1H), 8.03 (d, J = 13.0 Hz, 2H), 7.75 - 7.54 (m, 2H), 7.32 (d, J = 10.8 Hz, 3H), 7.10 (s, 1H), 5.09 (dd, J = 13.6, 5.2 Hz, 1H), 4.60 (s, 2H), 4.38 (s, 2H), 4.16 (s, 2H), 3.66 (s, 6H), 2.84 (d, J = 12.9 Hz, 3H), 2.66 (d, J = 4.4 Hz, 6H), 2.40 (s, 3H), 2.22 (s, 2H), 2.01 (d, J = 9.9 Hz, 1H), 1.83 (d, J = 13.1 Hz, 3H), 1.27 (d, J = 31.9 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 173.38, 170.60, 167.93, 167.61, 159.58, 155.68, 155.15, 147.59, 142.95, 136.25, 134.43, 134.15, 124.42, 120.38, 118.91, 116.78, 114.88, 113.51, 112.48, 109.28, 102.71, 68.34, 64.20, 53.42, 51.49, 49.23, 44.34, 32.53, 31.47, 30.99, 25.93, 22.57. HRMS (ESI): calcd for C 41 H 43 ClN 10 O8[M+H] + 839.2954, found 839.3023. Purity: 96.63% by HPLC (MeOH / H2O = 80:20, t R = 4.042 min).

[0099] Example 2

[0100] 2-((9-((5-chloro-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 2)

[0101] 2-((9-((5-chloro-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 2)

[0102] Following General Synthesis 5, 25b (121 mg, 0.28 mmol) was used as the starting material to give the target product Example 2 (18 mg, yield: 15.6%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.78 (s, 1H), 8.07 (s, 1H), 7.98 (d, J = 4.8 Hz, 1H), 7.71 - 7.58 (m, 2H), 7.41 - 7.30 (m, 2H), 7.24 (d, J = 8.6 Hz, 1H), 7.12 (s, 1H), 5.08 (dd, J = 12.7, 5.4 Hz, 1H), 4.61 (s, 2H), 4.40 (t, J = 4.7 Hz, 2H), 4.19 (d, J = 4.6 Hz, 2H), 4.06 (d, J = 12.9 Hz, 2H), 3.66 (s, 4H), 2.94 (dt, J = 24.8, 12.4 Hz, 3H), 2.70 - 2.55 (m, 4H), 2.41 (s, 3H), 2.19 (s, 2H), 2.10 - 1.99 (m, 1H), 1.84 (d, J = 13.2 Hz, 2H), 1.31 - 1.12 (m, 3H). 13C NMR (75 MHz, DMSO-d6) δ 173.31, 170.62, 168.14, 167.94, 167.46, 159.61, 155.71, 155.50, 155.15, 155.07, 147.63, 142.96, 134.54, 134.45, 125.50, 120.38, 118.96, 118.07, 117.84, 113.69, 112.47, 109.30, 108.23, 102.73, 68.45, 64.22, 53.40, 49.24, 47.76, 44.37, 40.74, 32.89, 31.50, 30.13, 25.92, 22.70. HRMS (ESI): calcd for C 41 H 43 ClN 10 O8[M+H] + 839.2954, found 839.3026. Purity: 98.43% by HPLC (MeOH / H2O = 80:20, t R = 4.012 min).

[0103] Example 3

[0104] 2-((9-((5-chloro-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 3)

[0105] 2-((9-((5-chloro-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 3)

[0106] Following General Synthesis 5, 25c (126 mg, 0.28 mmol) was used as the starting material to obtain the target product, Example 3 (21 mg, yield: 17.8%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.80 (s, 1H), 8.07 (s, 1H), 7.99 (d, J = 4.8 Hz, 1H), 7.72 (d, J = 11.4 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.13 (s, 1H), 5.11 (dd, J = 13.0, 5.3 Hz, 1H), 4.61 (s, 2H), 4.40 (s, 2H), 4.18 (s, 2H), 3.63 (d, J = 14.9 Hz, 6H), 2.91 (t, J = 12.3 Hz, 3H), 2.67 (d, J = 4.6 Hz, 3H), 2.61 (d, J = 14.8 Hz, 2H), 2.42 (s, 3H), 2.23 (s, 2H), 2.03 (d, J = 7.8 Hz, 1H), 1.86 (d, J = 12.6 Hz, 2H), 1.25 (s, 4H). 13 C NMR (75 MHz, DMSO-d6) δ 173.27, 170.43, 167.95, 167.21, 166.72, 155.73, 155.16, 155.07, 147.63, 142.96, 134.43, 129.30, 120.39, 118.98, 113.68, 112.51, 109.32, 102.79, 68.44, 64.22, 53.34, 50.40, 49.54, 44.24, 31.46, 30.71, 25.93, 22.58. HRMS (ESI): calcd for C 41 H 42 ClFN 10 O8[M+H] + 857.2860, found 857.2930. Purity: 95.79% by HPLC (MeOH / H2O = 80:20, t R = 4.172 min).

[0107] Synthesis Route 3:

[0108] Example 4 was synthesized according to Synthesis Route 3.

[0109] Synthesis route 3: Reagents and conditions: (a) Pd(OAc)2, Xantphos, Cs2CO3, dioxane, 110 °C, 10 h; (b) LiOH, MeOH, H2O, 40 °C, 10 h; (c) EDCI, HOBt, DIPEA, DMF, 25 °C, 10 h; (d) TFA, DCM, rt, 1 h; (e) DIPEA, NMP, 170 °C, microwave, 3 h.

[0110] 4-((1-(3-Fluoro-4-(methoxycarbonyl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (26)

[0111] 4-((1-(3-Fluoro-4-(methoxycarbonyl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (26)

[0112] General synthesis 6: Intermediate 22a (360 mg, 1.54 mmol) and 22 (482 mg, 1.70 mmol) were added to a sealed tube containing 10 mL of dry dioxane, followed by the addition of cesium carbonate (1.01 g, 3.09 mmol), palladium acetate (17 mg, 0.08 mmol), XantPhos (89 mg, 0.15 mmol), and argon was purged. The reaction was heated at 110 °C for 16 h, and the reaction was monitored by TLC. After the reaction was cooled to room temperature, it was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography (eluent: dichloromethane:methanol = 100:1, v / v) to give intermediate 26 as a white solid (390 mg, yield: 58.0%). ESI-MS: m / z: [M+H] + 436.25.

[0113] 4-(4-((4-(tert-Butoxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-fluorobenzoic acid (27)

[0114] 4-(4-((4-(tert-Butoxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-fluorobenzoic acid (27)

[0115] General synthesis method 7: Intermediate 26 (200 mg, 0.46 mmol) was added to a round-bottom flask containing a mixture solution of methanol: water = 8 mL: 2 mL, then lithium hydroxide (55 mg, 2.30 mmol) was added, and the reaction was carried out at 40 °C for 10 hours, and TLC was used to monitor the completion of the reaction. After the reaction was cooled to room temperature, dilute hydrochloric acid was added to adjust the pH of the solution to 5-6, and extraction was performed using ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent system: dichloromethane:methanol = 100:1, v / v) to obtain intermediate 27 as a white solid (180 mg, yield: 93.0%). ESI-MS: m / z: [M+H] + 421.24.

[0116] tert-butyl-4-((1-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate(28)

[0117] tert-butyl-4-((1-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate(28)

[0118] General synthesis method 8: Intermediate 27 (180 mg, 0.43 mmol) was added to a round-bottom flask containing 5 mL of DMF solution, then DIPEA (276 mg, 2.14 mmol), EDCI (123 mg, 0.64 mmol), and HOBt (87 mg, 0.64 mmol) were sequentially added, and the mixture was stirred at room temperature for half an hour. Then 27a (83 mg, 0.51 mmol) was added, and the reaction was carried out at room temperature overnight, and TLC was used to monitor the completion of the reaction. Extraction was performed using ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent system: dichloromethane:methanol = 50:1, v / v) to obtain intermediate 28 as a white solid (160 mg, yield: 70.5%). ESI-MS: m / z: [M+H] + 532.28.

[0119] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)benzamide(29)

[0120] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)benzamide (29)

[0121] Following General Synthesis Procedure 4, 28 (200 mg, 0.38 mmol) was used as the starting material to give the target product 29 (130 mg, yield: 80.1%) as a white oil. ESI-MS: m / z: [M+H] + 432.23.

[0122] Example 4

[0123] 4-(4-((4-(5-chloro-4-((6-(2-(methylamino)-2-oxoethoxy)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-9-yl)amino)pyrimidin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (Example 4)

[0124] 4-(4-((4-(5-chloro-4-((6-(2-(methylamino)-2-oxoethoxy)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-9-yl)amino)pyrimidin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (Example 4)

[0125] Following General Synthesis Procedure 5, 29 (119 mg, 0.28 mmol) was used as the starting material to give the target product Example 4 (25 mg, yield: 21.9%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.79 (s, 1H), 8.07 (s, 1H), 8.00 (q, J = 4.1, 3.7 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.66 (t, J = 8.9 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.12 (s, 1H), 6.43 (dd, J = 9.1, 2.2 Hz, 1H), 6.35 (d, J = 15.1 Hz, 1H), 4.74 (dt, J = 12.4, 6.4 Hz, 1H), 4.60 (s, 2H), 4.51 (d, J = 12.0 Hz, 2H), 4.41 (d, J = 4.4 Hz, 2H), 4.21 - 4.16 (m, 2H), 4.03 (d, J = 12.9 Hz, 1H), 3.17 (s, 2H), 2.97 (t, J = 11.9 Hz, 2H), 2.67 (d, J = 4.6 Hz, 3H), 2.15 (d, J = 11.7 Hz, 2H), 1.86 (m, 1H), 1.76 (m, 2H), 1.32 (m, 1H). HRMS (ESI): calcd for C 40 H 44 ClFN 10 O7[M+H] + 831.3067, found 831.3149. Purity: 96.19% by HPLC (MeOH / H2O = 80:20, t R = 4.022 min).

[0126] Synthesis Route 4:

[0127] Examples 5-6 were synthesized according to Synthesis Route 4.

[0128] Synthesis Route 4: Reagents and conditions: (a) NaBH(OAc)3, DCE, rt, 12 h; (b) TFA, DCM, rt, 3 h; (c) DIPEA, DMSO, 100 °C, 3 h; (d) H2, Pd / C, EtOH, rt, 16 h; (e) DIPEA, NMP, microwave, 170 °C, 3 h.

[0129] 4-((4-(2-((tert-Butoxycarbonyl)amino)ethyl)piperidin-1-yl)methyl)piperidine-1- carboxylic acid benzyl ester (31a)

[0130] benzyl-4-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)methyl)piperidine-1-carboxylate (31b)

[0131] Following General Synthesis 1, using intermediate 30b (400 mg, 2.00 mmol) as the starting material, the target product 31b (610 mg, yield: 75.8%) was obtained as a white solid. ESI-MS: m / z: [M+H] + 460.31.

[0132] 4-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)methyl)piperidine-1-carboxylate (31b)

[0133] benzyl-4-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)methyl)piperidine-1-carboxylate (31b)

[0134] Following General Synthesis 1, using intermediate 30b (400 mg, 2.00 mmol) as the starting material, the target product 31b (610 mg, yield: 75.8%) was obtained as a white solid. ESI-MS: m / z: [M+H] + 432.28.

[0135] 4-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)methyl)piperidine-1-carboxylate (31b)

[0136] benzyl 4-((4-(2-aminoethyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (32a)

[0137] Following General Synthesis 4, using intermediate 31a (400 mg, 0.87 mmol) as the starting material, the target product 32a (290 mg, yield: 92.7%) was obtained as a white oil. ESI-MS: m / z: [M+H] + 360.26.

[0138] 4-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)methyl)piperidine-1-carboxylate (31b)

[0139] benzyl 4-((4-aminopiperidin-1-yl)methyl)piperidine-1-carboxylate(32b)

[0140] Following General Synthesis Procedure 4, using Intermediate 31b (400 mg, 0.87 mmol) as the starting material, the target product 32b was obtained as a white oil (270 mg, yield: 93.6%). ESI-MS: m / z: [M+H] + 332.23.

[0141] benzyl 4-((4-(2-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperidin-1-yl)methyl)piperidine-1-carboxylate(33a)

[0142] Benzyl-4-((4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperidin-1-yl)methyl)piperidine-1-carboxylate(33a)

[0143] Following General Synthesis Procedure 3, using 23a (400 mg, 1.45 mmol) as the starting material, the target product 33a was obtained as a yellow solid (840 mg, yield: 94.2%). ESI-MS: m / z: [M+H] + 616.31.

[0144] benzyl 4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)piperidin-1-yl)methyl)piperidine-1-carboxylate(33b)

[0145] Benzyl-4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)piperidin-1-yl)methyl)piperidine-1-carboxylate(33b)

[0146] Following General Synthesis Procedure 3, using 23a (400 mg, 1.45 mmol) as the starting material, the target product 33b was obtained as a yellow solid (810 mg, yield: 95.2%). ESI-MS: m / z: [M+H] + 588.27.

[0147] 2-(2,6-dioxopiperidin-3-yl)-4-((2-(1-(piperidin-4-ylmethyl)piperidin-4-yl)ethyl)amino)isoindoline-1,3-dione (34a)

[0148] 2-(2,6-dioxopiperidin-3-yl)-4-((2-(1-(piperidin-4-ylmethyl)piperidin-4-yl)ethyl)amino)isoindoline-1,3-dione (34a)

[0149] Following General Synthesis 2, using 33a (300 mg, 0.49 mmol) as the starting material, the target product 34a (190 mg, yield: 81.0%) was obtained as a yellow oil. ESI-MS: m / z: [M+H] + 482.27.

[0150] 2-(2,6-dioxopiperidin-3-yl)-4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)amino)isoindoline-1,3-dione (34b)

[0151] 2-(2,6-dioxopiperidin-3-yl)-4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)amino)isoindoline-1,3-dione (34b)

[0152] Following General Synthesis 2, using 33b (300 mg, 0.49 mmol) as the starting material, the target product 34b (180 mg, yield: 76.7%) was obtained as a yellow oil. ESI-MS: m / z: [M+H] + 454.24.

[0153] Example 5

[0154] 2-((9-((5-chloro-2-(4-((4-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4- ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 5)

[0155] 2-((9-((5-chloro-2-(4-((4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4- ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 5)

[0156] Following General Synthesis 5, 34a (132 mg, 0.28 mmol) was used as the starting material to give the target product Example 5 (18 mg, yield: 9.1%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.77 (s, 1H), 8.03 (d, J = 11.6 Hz, 2H), 7.64 - 7.55 (m, 2H), 7.41 (d, J = 2.2 Hz, 1H), 7.13 - 7.09 (m, 2H), 7.05 (d, J = 7.1 Hz, 1H), 6.54 (s, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.61 (s, 2H), 4.50 (d, J = 12.5 Hz, 2H), 4.40 (d, J = 5.4 Hz, 2H), 4.20 (d, J = 4.7 Hz, 2H), 2.89 (d, J = 14.4 Hz, 5H), 2.68 (d, J = 4.6 Hz, 5H), 2.57 (s, 4H), 2.09 - 1.97 (m, 3H), 1.73 (s, 2H), 1.54 (s, 2H), 1.26 (d, J = 4.4 Hz, 8H). HRMS (ESI): calcd for C 44 H 49 ClN 10 O8[M+H] + 881.3423, found 881.3478. Purity: 97.53% by HPLC (MeOH / H2O = 80:20, t R = 3.998 min).

[0157] Example 6

[0158] 2-((9-((5-chloro-2-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 6)

[0159] 2-((9-((5-chloro-2-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 6)

[0160] Following General Synthesis 5, 34b (125 mg, 0.28 mmol) was used as the starting material to give the target product Example 6 (13 mg, yield: 11.1%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.00 (s, 1H), 8.28 (d, J = 10.7 Hz, 2H), 7.89 - 7.81 (m, 2H), 7.67 (d, J = 2.2 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.36 (s, 1H), 7.31 (d, J = 7.0 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 5.33 (dd, J = 12.9, 5.4 Hz, 1H), 4.86 (s, 2H), 4.76 (d, J = 12.7 Hz, 2H), 4.65 (d, J = 5.3 Hz, 2H), 4.45 (d, J = 4.8 Hz, 2H), 3.12 (t, J = 11.5 Hz, 3H), 2.94 (d, J = 4.6 Hz, 3H), 2.88 (s, 1H), 2.81 (s, 1H), 2.41 (s, 3H), 2.23 (dd, J = 17.8, 9.7 Hz, 3H), 2.01 (d, J = 12.6 Hz, 2H), 1.76 (s, 2H), 1.59 - 1.47 (m, 5H), 1.29 (d, J = 12.3 Hz, 2H). HRMS (ESI): calcd for C 42 H 45 ClN10 O8[M+H] + 853.3110, found 853.3174. Purity: 96.13% by HPLC (MeOH / H2O = 80:20, t R = 4.018 min).

[0161] Synthesis route 5:

[0162] Examples 7-9 were synthesized according to synthesis route 5.

[0163] Synthesis route 5: Reagents and conditions: (a) NaBH(OAc)3, DCE, rt, 3 h; (b) H2, Pd / C, EtOH, rt, 16 h; (c) DIPEA, DMSO, 100 °C, 3 h; (d) TFA, DCM, rt, 1 h; (e) DIPEA, DMSO, 100 °C, 10 h; (f) DIPEA, EDCI, HOBt, DMF, rt, 12 h.

[0164] 1-(5-chloro-4-((6-(2-(methylamino)-2-oxoethoxy)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-9-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid(35)

[0165] 1-(5-chloro-4-((6-(2-(methylamino)-2-oxoethoxy)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-9-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid(35)

[0166] Intermediate 11 (300 mg, 0.69 mmol), starting material 12i (178 mg, 1.39 mmol), DIPEA (151 mg, 1.17 mmol) were added to a round bottom flask, 8 mL of DMSO solution was added, stirred at 100 °C for 10 h, TLC monitoring reaction was completed. Slowly drop the dilute hydrochloric acid to adjust the solution pH to 2-5, then add 50 mL of water and stir for ten minutes, suction filtration, water washing, drying to get yellow solid 35 (310 mg, yield: 85.2%). ESI-MS: m / z: [M+H] + 259.15.

[0167] 4-(1-((Benzyl oxy)carbonyl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (21c)

[0168] tert-butyl 4-(1-((benzyloxy)carbonyl)piperidin-4-yl)piperazine-1-carboxylate (21c)

[0169] Following General Synthesis 1, using intermediate 20c (400 mg, 1.71 mmol) as the starting material, the target product 21c (410 mg, yield: 59.2%) was obtained as a white oil. ESI-MS: m / z: [M+H] + 404.25.

[0170] 4-((1-((BENZYLOXY)CARBONYL)AZETIDIN-3-YL)METHYL)PIPERAZINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER (21D)

[0171] tert-butyl 4-((1-((benzyloxy)carbonyl)azetidin-3-yl)methyl)piperazine-1-carboxylate (21d)

[0172] Following General Synthesis 1, using intermediate 20d (400 mg, 1.82 mmol) as the starting material, the target product 21d (440 mg, yield: 61.9%) was obtained as a white oil. ESI-MS: m / z: [M+H] + 389.23.

[0173] 4-(PIPERIDIN-4-YL)PIPERAZINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER (22C)

[0174] tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (22c)

[0175] Following General Synthesis 2, using 21c (300 mg, 0.74 mmol) as the starting material, the target product 22c (170 mg, yield: 84.9%) was obtained as a colorless oil. ESI-MS: m / z: [M+H] + 270.21.

[0176] 4-(AZETIDIN-3-YLMETHYL)PIPERAZINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER (22D)

[0177] tert-butyl 4-(azetidin-3-ylmethyl)piperazine-1-carboxylate (22d)

[0178] Following General Synthesis Procedure 2, 21d (300 mg, 0.77 mmol) was used as the starting material to obtain the target product 22d (180 mg, yield: 91.5%) as colorless oil. ESI-MS: m / z: [M+H] + 256.19.

[0179] tert-butyl-4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carboxylate(24c)

[0180] tert-butyl-4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carboxylate(24c)

[0181] Following General Synthesis Procedure 3, 23b (400 mg, 1.45 mmol) was used as the starting material to obtain the target product 24c (590 mg, yield: 77.5%) as yellow solid. 1 H NMR (300 MHz, DMSO-d6) d 7.67 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.7, 2.3 Hz, 1H), 5.08 (dd, J = 12.6, 5.3 Hz, 1H), 4.08 (d, J = 13.2 Hz, 2H), 2.92 (dt, J = 25.2, 9.1 Hz, 3H), 2.63 (s, 1H), 2.56 (d, J = 3.8 Hz, 2H), 2.45 (t, J = 4.8 Hz, 4H), 2.03 (d, J = 12.1 Hz, 1H), 1.84 (d, J = 12.4 Hz, 2H), 1.40 (s, 11H). ESI-MS: m / z: [M+H] + 526.26.

[0182] tert-butyl-4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carboxylate(24c)

[0183] tert-butyl-4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carboxylate (24d)

[0184] Following General Synthesis Procedure 3, 23b (400 mg, 1.45 mmol) was used as the starting material to give the target product 24d (610 mg, yield: 82.3%) as a yellow solid. ESI-MS: m / z: [M+H] + 526.26.

[0185] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperazin-1-yl)piperidin-1-yl)isoindoline-1,3-dione (25c)

[0186] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperazin-1-yl)piperidin-1-yl)isoindoline-1,3-dione (25c)

[0187] Following General Synthesis Procedure 4, 24c (300 mg, 0.57 mmol) was used as the starting material to give the target product 25c (205 mg, yield: 84.4%) as a yellow oil. ESI-MS: m / z: [M+H] + 426.21.

[0188] 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-ylmethyl)azetidin-1-yl)isoindoline-1,3-dione (25d)

[0189] 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-ylmethyl)azetidin-1-yl)isoindoline-1,3-dione (25d)

[0190] Following General Synthesis Procedure 4, 24d (300 mg, 0.56 mmol) was used as the starting material to give the target product 25d (195 mg, yield: 85.8%) as a yellow oil. ESI-MS: m / z: [M+H] + 412.19.

[0191] Example 7

[0192] 2-((9-((5-chloro-2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 7)

[0193] 2-((9-((5-chloro-2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 7)

[0194] Synthetic General Procedure 9: Intermediate 35 (60 mg, 0.11 mmol) was added to a round bottom flask containing 5 mL of DMF, followed by the addition of DIPEA (71 mg, 0.55 mmol), EDCI (32 mg, 0.16 mmol), HOBt (23 mg, 0.16 mmol), stirred at room temperature for half an hour, then 25b (100 mg, 0.23 mmol) was added, and the reaction was allowed to proceed at room temperature overnight, with TLC monitoring of the completion of the reaction. Extraction was performed three times using ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography (eluent: dichloromethane:methanol = 15:1, v / v) to obtain the target product, Example 7, as a yellow solid (16 mg, yield: 14.8%). 1H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.78 (s, 1H), 8.07 (s, 1H), 7.99 (d, J = 4.8 Hz, 1H), 7.66 (s, 1H), 7.41 (s, 1H), 7.33 (s, 2H), 7.25 (d, J = 8.7 Hz, 1H), 7.12 (s, 1H), 5.09 (d, J = 7.3 Hz, 1H), 4.60 (s, 2H), 4.54 - 4.46 (m, 2H), 4.40 (s, 2H), 4.19 (s, 2H), 4.05 (s, 2H), 3.57 (s, 2H), 3.46 (s, 2H), 3.01 - 2.91 (m, 7H), 2.70 - 2.59 (m, 5H), 2.18 (s, 2H), 2.07 - 2.00 (m, 2H), 1.82 (d, J = 12.7 Hz, 4H), 1.67 (d, J = 12.8 Hz, 3H), 1.50 (d, J = 12.3 Hz, 2H). HRMS (ESI): calcd for C 47 H 52 ClN 11 O9[M+H] + 950.3638, found 950.3706. Purity: 94.88% by HPLC (MeOH / H2O = 80:20, t R = 3.903 min).

[0195] Example 8

[0196] 2-((9-((5-chloro-2-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 8)

[0197] 2-((9-((5-chloro-2-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 8)

[0198] Following general synthesis 9, 35 (60 mg, 0.11 mmol) was used as the starting material to give the target product Example 8 (13 mg, yield: 12.2%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.78 (s, 1H), 8.07 (s, 1H), 7.98 (d, J = 5.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 8.7, 2.2 Hz, 1H), 7.12 (s, 1H), 5.09 (dd, J = 12.8, 5.3 Hz, 1H), 4.60 (s, 2H), 4.50 (d, J = 12.7 Hz, 2H), 4.40 (t, J = 4.7 Hz, 2H), 4.19 (t, J = 4.7 Hz, 2H), 4.10 (d, J = 12.7 Hz, 2H), 3.55 (s, 2H), 3.44 (s, 2H), 3.03 - 2.89 (m, 6H), 2.67 (d, J = 4.6 Hz, 3H), 2.63 (s, 1H), 2.57 (s, 2H), 2.45 (s, 2H), 2.03 (d, J = 11.9 Hz, 1H), 1.85 (d, J = 12.1 Hz, 2H), 1.66 (d, J = 12.5 Hz, 2H), 1.59 - 1.38 (m, 5H), 1.26 (s, 1H). HRMS (ESI): calcd for C 46 H 50 ClN 11 O9[M+H] + 936.3481, found 936.3531. Purity: 96.43% by HPLC (MeOH / H2O = 80:20, t R = 3.993 min).

[0199] Example 9

[0200] 2-((9-((5-chloro-2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazepino[2,3,4- ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 9)

[0201] 2-((9-((5-chloro-2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4- ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 9)

[0202] Following General Synthesis 9, 35 (60 mg, 0.11 mmol) was used as the starting material to give the target product Example 9 (10 mg, yield: 9.6%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.77 (s, 1H), 8.05 (s, 1H), 7.96 (d, J = 4.8 Hz, 1H), 7.56 (dd, J = 5.3, 3.1 Hz, 2H), 7.38 (d, J = 2.2 Hz, 1H), 7.09 (s, 1H), 7.03 (s, 1H), 6.90 (dd, J = 8.6, 2.1 Hz, 1H), 5.03 (dd, J = 12.7, 5.3 Hz, 1H), 4.64 (s, 1H), 4.58 (s, 2H), 4.48 (d, J = 12.7 Hz, 2H), 4.37 (d, J = 5.4 Hz, 2H), 4.17 (d, J = 5.4 Hz, 2H), 3.59 (s, 2H), 3.48 (d, J = 13.8 Hz, 4H), 3.22 (s, 2H), 2.94 (t, J = 12.8 Hz, 4H), 2.64 (d, J = 4.6 Hz, 3H), 2.59 (s, 1H), 2.33 (d, J = 22.3 Hz, 5H), 1.96 (dt, J = 13.4, 6.6 Hz, 2H), 1.65 (d, J = 12.4 Hz, 2H), 1.47 (d, J = 10.8 Hz, 2H), 1.23 (s, 1H). HRMS (ESI): calcd for C 45 H 48 ClN 11 O9[M+H] + 922.3325, found 922.3402. Purity: 95.49% by HPLC (MeOH / H2O = 80:20, t R = 4.001 min).

[0203] Synthesis route 6:

[0204] Examples 10-11 were synthesized according to synthesis route 6.

[0205] Synthesis route 6: Reagents and conditions: (a) (PPh3)3RhCl, EtOH, 80 °C, 18 h; (b) KI, pyridine, 115 °C, 12 h; (c) TFA, DCM, rt, 3 h; (d) AcOH, NaBH(OAc)3, DCE, rt, 3 h; (e) TFA, DCM, rt, 3 h; (f) EDCI, HOBt, DIPEA, DMF, rt, 12 h.

[0206] 2-(tert-butyl) 5,6-dimethyl isoindoline-2,5,6-tricarboxylate (37)

[0207] 2-(tert-butyl) 5,6-dimethyl isoindoline-2,5,6-tricarboxylate (37)

[0208] Intermediate 36a (3.40 g, 17.59 mmol) and 36b (10.00 g, 70.37 mmol) were added to a round bottom flask containing 50 mL of anhydrous ethanol solution, then (PPh3)3RhCl (163 mg, 0.18 mmol) was added, argon was replaced, 85 °C was refluxed for 18 hours, TLC was used to monitor the completion of the reaction. Ethyl acetate was used for extraction, the organic layer was washed with saturated brine, then anhydrous sodium sulfate was added for drying, concentrated under reduced pressure, and the residue was purified by column chromatography (elution system: petroleum ether: ethyl acetate = 20: 1, v / v) to obtain the target product 37 as a white solid (1.00 g, yield: 17.0%). 1 H NMR (300 MHz, DMSO-d6) δ 7.72 (d, J = 9.7 Hz, 2H), 4.67 (d, J = 4.7 Hz, 4H), 3.84 (s, 6H), 1.49 (s, 9H). ESI-MS: m / z: [M+H] + 336.14.

[0209] 6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4- f]isoindole-2(lH)-carboxylic acid tert-butyl ester (38)

[0210] tert-butyl-6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-carboxylate(38)

[0211] Intermediate 37 (820 mg, 2.45 mmol) and 27a (523 mg, 3.18 mmol) were added to a round bottom flask containing 5 mL of pyridine solution, then potassium iodide (1.22 g, 7.34 mmol) was added, and refluxed at 115 °C overnight, TLC was used to monitor the completion of the reaction. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate and 1 M aqueous citric acid solution, the organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (elution system: dichloromethane:methanol = 100:1, v / v) to obtain the target product 38 as a yellow solid (460 mg, yield: 47.1%). 1 H NMR (300 MHz, DMSO-d6) δ 11.15 (s, 1H), 7.91 (d, J = 1.7 Hz, 2H), 5.17 (dd, J = 12.8, 5.3 Hz, 1H), 4.74 (d, J = 7.1 Hz, 4H), 2.92 (ddd, J = 17.0, 13.8, 5.4 Hz, 1H), 2.60 (t, J = 16.2 Hz, 2H), 2.15 - 2.03 (m, 1H), 1.49 (s, 9H). ESI-MS: m / z: [M+H] + 400.14.

[0212] 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione(39a)

[0213] 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione(39a)

[0214] According to General Synthesis 4, using 38 (400 mg, 1.00 mmol) as the raw material for the reaction, the target product 39a was obtained as a yellow oil (275 mg, yield: 91.8%). ESI-MS: m / z: [M+H] + 300.09.

[0215] 4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)- yl)methyl)piperidine-1-carboxylate (40)

[0216] 4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)- yl)methyl)piperidine-1-carboxylate (40)

[0217] Following General Synthesis 1, intermediate 39a (450 mg, 1.50 mmol) as the starting material, the target product 40 was obtained as a white solid (345 mg, yield: 46.2%). 1 H NMR (300 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.81 - 7.77 (m, 2H), 5.20 - 5.10 (m, 1H), 3.96 (d, J = 13.6 Hz, 6H), 3.85 (d, J = 13.2 Hz, 4H), 2.59 (d, J = 5.4 Hz, 2H), 2.41 (t, J = 4.0 Hz, 1H), 2.14 - 2.01 (m, 1H), 1.78 (t, J = 6.5 Hz, 5H), 1.41 - 1.40 (m, 9H). ESI-MS: m / z: [M+H] + 497.23.

[0218] 2-(2,6-dioxopiperidin-3-yl)-6-(piperidin-4-ylmethyl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (41)

[0219] 2-(2,6-dioxopiperidin-3-yl)-6-(piperidin-4-ylmethyl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (41)

[0220] Following General Synthesis 4, intermediate 40 (190 mg, 0.38 mmol) as the starting material, the target product 41 was obtained as a white oil (115 mg, yield: 75.8%). ESI-MS: m / z: [M+H] + 397.18.

[0221] Example 10

[0222] 2-((9-((5-chloro-2-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-1,2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindole-2-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 10)

[0223] 2-((9-((5-chloro-2-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-1,2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindole-2-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 10)

[0224] Following General Synthesis 9, 35 (60 mg, 0.11 mmol) was used as the starting material to obtain the target product Example 10 (9 mg, yield: 9.8%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.80 (s, 1H), 8.08 (s, 1H), 7.97 (d, J = 5.2 Hz, 1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.10 (s, 1H), 5.18 (dd, J = 12.9, 4.3 Hz, 3H), 4.79 (s, 2H), 4.57 (d, J = 11.8 Hz, 4H), 4.39 (t, J = 4.8 Hz, 2H), 4.17 (t, J = 4.8 Hz, 2H), 3.04 - 2.86 (m, 4H), 2.63 (d, J = 4.8 Hz, 5H), 2.15 - 2.06 (m, 1H), 1.84 (d, J = 12.5 Hz, 2H), 1.56 (d, J = 12.3 Hz, 2H). 13C NMR (75 MHz, DMSO-d6) δ 173.35, 173.27, 170.34, 167.91, 167.41, 159.53, 155.76, 155.23, 155.06, 147.61, 144.91, 144.23, 142.95, 134.54, 131.44, 131.39, 120.37, 119.18, 118.94, 118.85, 113.66, 112.36, 109.31, 102.52, 68.42, 64.20, 52.44, 52.25, 49.57, 44.05, 31.45, 27.71, 25.85, 22.53. HRMS (ESI): calcd for C 39 H 36 ClN9O9[M+Na] + 832.2325, found 832.2228. Purity: 96.41% by HPLC (MeOH / H2O = 80:20, t R = 4.301 min).

[0225] Example 11

[0226] 2-((9-((5-chloro-2-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 11)

[0227] 2-((9-((5-chloro-2-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 11)

[0228] Following general procedure 9, 35 (60 mg, 0.11 mmol) was used as the starting material to obtain the target product Example 11 (12 mg, yield: 11.7%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.79 (s, 1H), 8.07 (d, J = 1.1 Hz, 1H), 8.00 (d, J = 5.1 Hz, 1H), 7.79 (d, J = 17.3 Hz, 2H), 7.59 (d, J = 2.2 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.12 (s, 1H), 5.16 (dd, J = 12.7, 5.3 Hz, 1H), 4.61 (s, 2H), 4.51 (d, J = 12.0 Hz, 2H), 4.40 (d, J = 4.8 Hz, 2H), 4.22 - 4.17 (m, 2H), 4.00 (s, 4H), 2.95 (q, J = 15.7, 14.1 Hz, 6H), 2.70 - 2.66 (m, 4H), 2.59 (s, 5H), 2.13 - 2.05 (m, 1H), 1.91 - 1.73 (m, 3H), 1.65 (s, 2H), 1.51 (s, 3H), 1.26 (s, 1H). HRMS (ESI): calcd for C 47 H 52 ClN 11 O9[M+H] + 907.3216, found 907.3258. Purity: 97.32% by HPLC (MeOH / H2O = 80:20, t R = 4.108 min).

[0229] Synthesis route 7:

[0230] Examples 12-16 were synthesized according to synthesis route 7.

[0231] Synthesis route 7: Reagents and conditions: (a) DIPEA, DMSO, 100 °C, 3 h; (b) TFA, DCM, rt, 1 h; (c) NaBH(OAc)3, DCE, rt, 5 h; (d) TFA, DCM, rt, 1 h; (e) DIPEA, EDCI, HOBt, DMF, rt, 12 h.

[0232] 6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (43a)

[0233] tert-butyl-6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(43a)

[0234] Following General Synthesis 3, using 23b (400 mg, 1.45 mmol) as the starting material, the target product 43a (614 mg, yield: 93.3%) was obtained as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 2.1 Hz, 1H), 6.52 (dd, J = 8.3, 2.2 Hz, 1H), 4.93 (dd, J = 12.8, 5.3 Hz, 1H), 4.07 - 4.01 (m, 4H), 3.98 - 3.88 (m, 4H), 2.85 - 2.67 (m, 1H), 2.48 (s, 1H), 2.42 (s, 1H), 1.88 (d, J = 11.6 Hz, 1H), 1.28 - 1.22 (m, 9H). ESI-MS: m / z: [M+H] + 455.18.

[0235] 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate(43b)

[0236] tert-butyl-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate(43b)

[0237] Following General Synthesis 3, using 23b (400 mg, 1.45 mmol) as the starting material, the target product 43b (643 mg, yield: 92.0%) was obtained as a yellow solid. ESI-MS: m / z: [M+H] + 483.22.

[0238] tert-butyl-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate(43b)

[0239] tert-butyl-7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (43c)

[0240] Following General Synthesis 3, using 23b (400 mg, 1.45 mmol) as the starting material, the target product 43c (610 mg, yield: 87.3%) was obtained as a yellow solid. ESI-MS: m / z: [M+H] + 483.22.

[0241] 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (43d)

[0242] tert-butyl-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (43d)

[0243] Following General Synthesis 3, using 23b (400 mg, 1.45 mmol) as the starting material, the target product 43d (594 mg, yield: 82.6%) was obtained as a yellow solid. ESI-MS: m / z: [M+H] + 497.23.

[0244] tert-butyl-9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (43e)

[0245] tert-butyl-9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (43e)

[0246] Following General Synthesis 3, using 23b (400 mg, 1.45 mmol) as the starting material, the target product 43e (605 mg, yield: 81.8%) was obtained as a yellow solid. ESI-MS: m / z: [M+H] + 511.25.

[0247] 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (44b)

[0248] 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (44b)

[0249] Following the general synthesis protocol 4, take 43a (300 mg, 0.59 mmol) as the raw material for reaction to obtain the target product 44a (187 mg, yield: 79.9%) in yellow oil. ESI-MS: m / z: [M+H] + 355.13.

[0250] 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (44b)

[0251] 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (44b)

[0252] Following the general synthesis protocol 4, take 43b (300 mg, 0.62 mmol) as the raw material for reaction to obtain the target product 44b (171 mg, yield: 71.9%) in yellow oil. ESI-MS: m / z: [M+H] + 383.16.

[0253] 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (44b)

[0254] 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (44b)

[0255] Following the general synthesis protocol 4, take 43c (300 mg, 0.62 mmol) as the raw material for reaction to obtain the target product 44c (183 mg, yield: 77.0%) in yellow oil. ESI-MS: m / z: [M+H] +383.16.

[0256] 2-(2,6-dioxopiperidin-3-yl)-5-(2,8-diazaspiro[4.5]decan-2-yl)isoindoline-1,3-dione (44d)

[0257] 2-(2,6-dioxopiperidin-3-yl)-5-(2,8-diazaspiro[4.5]decan-2-yl)isoindoline-1,3-dione (44d)

[0258] Following general synthesis 4, using 43d (300 mg, 0.60 mmol) as the reactant, the target product 44d (212 mg, yield: 88.5%) was obtained as yellow oil. ESI-MS: m / z: [M+H] + 397.18.

[0259] 2-(2,6-dioxopiperidin-3-yl)-5-(3,9-diazaspiro[5.5]undecan-3-yl)isoindoline-1,3-dione (44e)

[0260] 2-(2,6-dioxopiperidin-3-yl)-5-(3,9-diazaspiro[5.5]undecan-3-yl)isoindoline-1,3-dione (44e)

[0261] Following general synthesis 4, using 43e (300 mg, 0.59 mmol) as the reactant, the target product 44e (215 mg, yield: 89.2%) was obtained as yellow oil. ESI-MS: m / z: [M+H] + 411.20.

[0262] tert-butyl-4-((6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-carboxylate (45a)

[0263] tert-butyl-4-((6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-carboxylate (45a)

[0264] Following general synthetic method 1, using intermediate 44a (300 mg, 0.85 mmol) as the reactant, the target product, a yellow solid 45a (248 mg, yield: 53.1%), was obtained. ESI-MS: m / z: [M+H] + 552.27.

[0265] 4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (45b)

[0266] tert-butyl-4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate(45b)

[0267] Following general synthetic method 1, using intermediate 44b (300 mg, 0.78 mmol) as the reactant, the target product, a yellow solid 45b (263 mg, yield: 57.8%), was obtained. ESI-MS: m / z: [M+H] + 580.30.

[0268] 4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[4.4]nonane-2-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (45c)

[0269] tert-butyl-4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)piperidine-1-carboxylate(45c)

[0270] Following general synthetic method 1, using intermediate 44c (300 mg, 0.78 mmol) as the reactant, the target product, a yellow solid 45c (211 mg, yield: 46.4%), was obtained. ESI-MS: m / z: [M+H] + 580.30.

[0271] 4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,8-diazaspiro[4.5]decan-8- yl)methyl)piperidine-1-carboxylate (45d)

[0272] 4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,8-diazaspiro[4.5]decan-8- yl)methyl)piperidine-1-carboxylate (45d)

[0273] Following General Synthesis 1, using intermediate 44d (300 mg, 0.76 mmol) as the starting material, the target product 45d (224 mg, yield: 49.9%) was obtained as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.20 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 6.91 (dd, J = 8.6, 2.2 Hz, 1H), 5.17 (dd, J = 12.5, 5.3 Hz, 1H), 3.97 (s, 2H), 3.57 (s, 3H), 3.31 - 3.25 (m, 1H), 2.98 (d, J = 12.4 Hz, 1H), 2.71 (s, 2H), 2.66 (s, 2H), 2.35 (s, 2H), 2.19 (d, J = 6.7 Hz, 5H), 1.95 - 1.87 (m, 1H), 1.71 (d, J = 16.3 Hz, 7H), 1.50 (d, J = 2.0 Hz, 3H), 1.48 (s, 9H). ESI-MS: m / z: [M+H] + 594.32.

[0274] 4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,8-diazaspiro[4.5]decan-8- yl)methyl)piperidine-1-carboxylate (45d)

[0275] 4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,8-diazaspiro[4.5]decan-8- yl)methyl)piperidine-1-carboxylate (45d)

[0276] Following General Synthesis 1, using intermediate 44e (300 mg, 0.73 mmol) as the starting material, the target product 45e (232 mg, yield: 52.2%) was obtained as a yellow solid. ESI-MS: m / z: [M+H] + 608.34.

[0277] 2-(2,6-dioxopiperidin-3-yl)-5-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (46b)

[0278] 2-(2,6-dioxopiperidin-3-yl)-5-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (46b)

[0279] Following General Synthesis 4, using 45a (300 mg, 0.54 mmol) as the starting material, the target product 46a (213 mg, yield: 86.7%) was obtained as a yellow oil. ESI-MS: m / z: [M+H] + 452.22.

[0280] 2-(2,6-dioxopiperidin-3-yl)-5-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (46b)

[0281] 2-(2,6-dioxopiperidin-3-yl)-5-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (46b)

[0282] Following General Synthesis 4, using 45b (300 mg, 0.52 mmol) as the starting material, the target product 46b (233 mg, yield: 93.9%) was obtained as a yellow oil. ESI-MS: m / z: [M+H] + 480.25.

[0283] 2-(2,6-dioxopiperidin-3-yl)-5-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (46b)

[0284] 2-(2,6-dioxopiperidin-3-yl)-5-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[4.4]nonan-2-yl)isoindoline-1,3-dione (46c)

[0285] Following the general synthesis protocol 4, 45c (300 mg, 0.54 mmol) was used as the reactant to give the target product 46c (221 mg, yield: 89.0%) as yellow oil. ESI-MS: m / z: [M+H] + 480.25.

[0286] 2-(2,6-dioxopiperidin-3-yl)-5-(8-(piperidin-4-ylmethyl)-2,8-diazaspiro[4.5]decan-2-yl)isoindoline-1,3-dione (46d)

[0287] 2-(2,6-dioxopiperidin-3-yl)-5-(8-(piperidin-4-ylmethyl)-2,8-diazaspiro[4.5]decan-2-yl)isoindoline-1,3-dione (46d)

[0288] Following the general synthesis protocol 4, 45d (300 mg, 0.50 mmol) was used as the reactant to give the target product 46d (217 mg, yield: 87.0%) as yellow oil. ESI-MS: m / z: [M+H] + 494.27.

[0289] 2-(2,6-dioxopiperidin-3-yl)-5-(9-(piperidin-4-ylmethyl)-3,9-diazaspiro[5.5]undecan-3-yl)isoindoline-1,3-dione (46e)

[0290] 2-(2,6-dioxopiperidin-3-yl)-5-(9-(piperidin-4-ylmethyl)-3,9-diazaspiro[5.5]undecan-3-yl)isoindoline-1,3-dione (46e)

[0291] Following the general synthesis protocol 4, 45e (300 mg, 0.73 mmol) was used as the reactant to give the target product 46e (232 mg, yield: 52.2%) as yellow solid. ESI-MS: m / z: [M+H] +508.28.

[0292] Example 12

[0293] 2-((9-((5-chloro-2-(4-(4-((6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 12)

[0294] 2-((9-((5-chloro-2-(4-(4-((6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 12)

[0295] Following General Synthesis 9, 46a (60 mg, 0.11 mmol) was used as the starting material to obtain the target product Example 12 (13 mg, yield: 11.9%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.78 (s, 1H), 8.07 (s, 1H), 7.98 (q, J = 4.6, 3.8 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.12 (s, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.66 (dd, J = 8.4, 2.0 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.60 (s, 2H), 4.50 (d, J = 12.4 Hz, 2H), 4.39 (d, J = 5.3 Hz, 2H), 4.34 (s, 1H), 4.22 - 4.16 (m, 2H), 4.12 (s, 4H), 4.01 (d, J = 12.7 Hz, 1H), 3.30 (s, 5H), 3.08 - 2.88 (m, 5H), 2.67 (d, J = 4.6 Hz, 3H), 2.62 (s, 1H), 2.56 (s, 1H), 2.28 (s, 2H), 2.08 - 1.96 (m, 1H), 1.80 - 1.59 (m, 4H), 1.59 - 1.36 (m, 3H), 1.26 (s, 2H). HRMS (ESI): calcd for C 48 H 52 ClN 11 O9[M+H] + 962.3638, found 962.3704. Purity: 95.22% by HPLC (MeOH / H2O = 80:20, t R = 3.901 min).

[0296] Example 13

[0297] 2-((9-((5-chloro-2-(4-(4-((2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)- 2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4- yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazepino[2,3,4-ij]quinolin-6-yl)oxy)-N- methylacetamide (Example 13)

[0298] 2-((9-((5-chloro-2-(4-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 13)

[0299] Following General Synthesis 9, 46b (60 mg, 0.11 mmol) was used as the starting material to give the target product Example 13 (8 mg, yield: 7.1%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.77 (s, 1H), 8.05 (s, 1H), 7.97 (d, J = 4.8 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.10 (s, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.64 (dd, J = 8.4, 2.1 Hz, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 4.58 (s, 2H), 4.48 (d, J = 11.7 Hz, 2H), 4.38 (s, 2H), 4.17 (d, J = 4.8 Hz, 2H), 4.01 (d, J = 12.8 Hz, 1H), 3.74 (s, 4H), 3.05 - 2.80 (m, 6H), 2.65 (d, J = 4.6 Hz, 3H), 2.60 (s, 1H), 2.54 (s, 3H), 2.29 (d, J = 11.7 Hz, 3H), 2.11 (s, 2H), 2.02 - 1.96 (m, 1H), 1.75 (s, 6H), 1.63 (d, J = 14.0 Hz, 3H), 1.47 (s, 2H), 1.23 (s, 1H). HRMS (ESI): calcd for C 50 H 56 ClN 11 O9[M+H] + 990.3951, found 990.4034. Purity: 96.64% by HPLC (MeOH / H2O = 80:20, t R= 3.817 min).

[0300] Example 14

[0301] 2-((9-((5-chloro-2-(4-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 14)

[0302] 2-((9-((5-chloro-2-(4-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 14)

[0303] Following General Synthesis 9, 46c (60 mg, 0.11 mmol) was used as the starting material to obtain the target product, Example 14 (14 mg, yield: 12.5%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.56 (s, 1H), 7.83 (s, 1H), 7.76 (d, J = 4.9 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.17 (d, J = 2.2 Hz, 1H), 6.88 (s, 1H), 6.68 (s, 1H), 6.58 (d, J = 8.7 Hz, 1H), 4.84 (dd, J = 12.5, 5.4 Hz, 1H), 4.36 (s, 2H), 4.27 (d, J = 12.2 Hz, 2H), 4.19 - 4.15 (m, 2H), 4.12 (s, 1H), 3.98 - 3.92 (m, 2H), 3.79 (d, J = 12.4 Hz, 1H), 3.23 (d, J = 6.7 Hz, 3H), 3.17 (s, 2H), 2.85 - 2.60 (m, 6H), 2.43 (d, J = 4.6 Hz, 5H), 2.33 (s, 5H), 2.06 (s, 1H), 1.86 - 1.74 (m, 3H), 1.62 - 1.38 (m, 7H), 1.31 - 1.20 (m, 2H), 1.02 (s, 1H). HRMS (ESI): calcd for C 50 H 56 ClN 11 O9[M+H] + 990.3951, found 990.4016. Purity: 95.82% by HPLC (MeOH / H2O = 80:20, t R = 3.842 min).

[0304] Example 15

[0305] 2-((9-((5-chloro-2-(4-(4-((2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)- 2,8-diazaspiro[4.5]dec-8-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4- yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazepino[2,3,4-ij]quinolin-6-yl)oxy)-N- methylacetamide (Example 15)

[0306] 2-((9-((5-chloro-2-(4-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 15)

[0307] Following General Synthesis 9, 46d (60 mg, 0.11 mmol) was used as the starting material to give the target product Example 15 (11 mg, yield: 9.6%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.79 (s, 1H), 8.10 - 8.05 (m, 1H), 8.00 (d, J = 4.8 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.12 (s, 1H), 6.94 (d, J = 2.1 Hz, 1H), 6.83 (dd, J = 8.7, 2.1 Hz, 1H), 5.08 (dd, J = 12.6, 5.4 Hz, 1H), 4.60 (s, 2H), 4.51 (d, J = 12.5 Hz, 2H), 4.41 (d, J = 4.5 Hz, 2H), 4.37 (s, 1H), 4.19 (t, J = 4.7 Hz, 2H), 4.03 (d, J = 12.7 Hz, 1H), 3.49 (s, 3H), 3.40 (s, 3H), 3.31 (s, 1H), 3.10 - 2.85 (m, 6H), 2.67 (d, J = 4.6 Hz, 3H), 2.62 (s, 1H), 2.57 (s, 3H), 2.40 - 2.12 (m, 2H), 2.06 - 1.98 (m, 1H), 1.94 - 1.87 (m, 2H), 1.79 (d, J = 13.8 Hz, 3H), 1.65 (d, J = 12.0 Hz, 6H), 1.51 (d, J = 6.6 Hz, 2H), 1.26 (s, 1H). HRMS (ESI): calcd for C 51 H 58 ClN 11 O9[M+H] +1004.4108, found 1004.4176. Purity: 95.02% by HPLC (MeOH / H20 = 80:20, t R = 3.813 min).

[0308] Example 16

[0309] 2-((9-((5-chloro-2-(4-(4-((9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 16)

[0310] 2-((9-((5-chloro-2-(4-(4-((9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 16)

[0311] Following General Synthesis 9, 46e (60 mg, 0.11 mmol) was used as the starting material to obtain the target product, Example 16 (17 mg, yield: 14.7%) as a yellow solid. 1H NMR (300MHz, DMSO-d6) δ11.12(s,1H),8.80(s,1H),8.07(s,1H),8.00(q,J=4.2Hz,1H),7.67(d,J=8.5Hz,1H),7.59(d,J=2.2Hz,1H),7.40(d, J=2.0Hz,1H),7.32(d,J=2.1Hz,1H),7.24(d,J=8.9Hz,1H),7.12(s,1H),5.09(dd,J=12.8,5.4Hz,1H),4.60(s,2H),4.51(d,J=12.4Hz,2H),4 .40(t,J=4.3Hz,2H),4.36(s,1H),4.18(t,J=4.2Hz,2H),4.02(d,J=12.3Hz,1H),3.47(s,6H),2.96(s,2H),2.67(d,J=4.6Hz,3H),2.63(s,1H ),2.57(s,2H),2.36(s,4H),2.17(s,2H),2.06–1.98(m,2H),1.77(d,J=14.7Hz,4H),1.65(d,J=13.8Hz,2H),1.52(s,11H).HRMS(ESI):calcd for C 52 H 60 ClN 11 O9[M+H] + 1018.4264, found 1018.4340. Purity: 95.29% by HPLC (MeOH / H2O = 80:20, t R =3.702 min).

[0312] Synthesis Route 8:

[0313] Examples 17-18 were synthesized according to synthetic route 8.

[0314] Synthetic Route 8: Reagents and Conditions: (a) Cs₂CO₃, Xantphos, Pd₂(dba)₃, dioxane, 100℃, 4h; (b) Cs₂CO₃, PdCl₂(dppf)CH₂Cl₂, dioxane, 100℃, 4h; (c) H₂, Pd / C, THF, 12h; (d) TFA, DCM, 3h; (e) NaBH(OAc)₃, DCE, 6h; (f) TFA, DCM, 3h; (g) EDCI, HOBt, DIPEA, DMF, 12h.

[0315] 7-(4-bromo-2-fluorophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (48a)

[0316] tert-butyl 7-(4-bromo-2-fluorophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate(48a)

[0317] Synthetic Method 10: Intermediate 47 (500 mg, 1.66 mmol) and 47a (376 mg, 1.66 mmol) were added to a sealed tube containing 10 mL of anhydrous dioxane solution. Cesium carbonate (1.08 g, 3.32 mmol), Pd2(dba)3 (106 mg, 0.12 mmol), and XantPhos (144 mg, 0.25 mmol) were then added sequentially. The mixture was purged with argon and reacted at 100 °C for 4 hours. The reaction was monitored by TLC until complete. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (elution system: dichloromethane:methanol = 100:1, v / v) to obtain intermediate 48a as a white solid (560 mg, yield: 84.4%). ESI-MS: m / z: [M+H] + 399.10.

[0318] 2-(4-bromo-2-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (48b)

[0319] tert-butyl 2-(4-bromo-2-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate(48b)

[0320] Following general synthetic method 10, using 47b (500 mg, 1.66 mmol) as the reactant, the target product, a white solid 48b (490 mg, yield: 71.3%), was obtained. ESI-MS: m / z: [M+H] + 413.12.

[0321] 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (50a)

[0322] tert-butyl-7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate(50a)

[0323] Synthetic Method 11: Intermediates 48a (560 mg, 1.40 mmol) and 49 (761 mg, 1.82 mmol) were added to a sealed tube containing a 6 mL:2 mL dioxane:water mixture. Cesium carbonate (1.08 g, 3.32 mmol) and PdCl2(dppf)CH2Cl2 (110 mg, 0.14 mmol) were then added sequentially. The mixture was purged with argon and reacted at 100 °C for 4 hours. The reaction was monitored by TLC until complete. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (elution system: petroleum ether:ethyl acetate = 5:1, v / v) to give intermediate 50a as a white solid (750 mg, yield: 87.7%). 1 H NMR (300MHz, DMSO-d6) δ7.77(d,J=8.2Hz,1H),7.50(d,J=2.0Hz,1H),7.47(q,J=1.9Hz,2H),7.45(t,J=1.9Hz,2H ),7.42–7.40(m,2H),7.38(d,J=1.7Hz,2H),7.37(d,J=1.3Hz,1H),7.35–7.32(m,1H),7.28(dd,J=8.4,2.1Hz,1H ),6.76(dd,J=9.9,8.5Hz,1H),6.57(d,J=8.1Hz,1H),5.43(d,J=12.6Hz,4H),3.49(td,J=7.0,2.6Hz,2H),3.41( s,1H),3.35(d,J=6.3Hz,3H),3.28(d,J=4.4Hz,2H),1.98–1.85(m,4H),1.45(d,J=2.7Hz,9H).ESI-MS:m / z:[M+H] + 610.30.

[0324] 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (50b)

[0325] tert-butyl-2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate (50b)

[0326] Following General Synthesis 11, using 48b (540 mg, 1.31 mmol) as the starting material, the target product 50b (710 mg, yield: 87.1%) was obtained as a white solid. ESI-MS: m / z: [M+H] + 624.32.

[0327] 7-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (51a)

[0328] tert-butyl-7-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (51a)

[0329] General Synthesis 12: Intermediate 50a (750 mg, 1.23 mmol) was added to a round bottom flask containing 10 mL of tetrahydrofuran solution, palladium on carbon (150 mg, 20% m / m) was added, hydrogen was replaced, stirred at room temperature for 16 hours, TLC monitored the reaction was completed. The reaction liquid was filtered through diatomite, washed with dichloromethane, the filtrate was concentrated at low pressure, the residue was purified by column chromatography (elution system dichloromethane:methanol = 100:1, v / v) to obtain intermediate 51a as a white oil (451 mg, yield: 85.1%). ESI-MS: m / z: [M+H] + 432.22.

[0330] 2-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (51b)

[0331] tert-butyl-2-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate (51b)

[0332] Following the general synthesis protocol 12, 50b (680 mg, 1.09 mmol) was used as the reactant to afford the target product 51b (462 mg, yield: 95.1%) as a white oil. ESI-MS: m / z: [M+H] + 446.24.

[0333] 3-(3-Fluoro-4-(2,7-diazaspiro[4.4]nonan-2-yl)phenyl)piperidine-2,6-dione (52a)

[0334] 3-(3-Fluoro-4-(2,7-diazaspiro[4.4]nonan-2-yl)phenyl)piperidine-2,6-dione (52a)

[0335] Following the general synthesis protocol 4, 51a (440 mg, 1.02 mmol) was used as the reactant to afford the target product 52a (315 mg, yield: 93.2%) as a white oil. ESI-MS: m / z: [M+H] + 332.17.

[0336] 3-(3-Fluoro-4-(2,8-diazaspiro[4.5]decan-2-yl)phenyl)piperidine-2,6-dione (52b)

[0337] 3-(3-Fluoro-4-(2,8-diazaspiro[4.5]decan-2-yl)phenyl)piperidine-2,6-dione (52b)

[0338] Following the general synthesis protocol 4, 51b (430 mg, 0.96 mmol) was used as the reactant to afford the target product 52b (322 mg, yield: 96.6%) as a white oil. ESI-MS: m / z: [M+H] + 346.18.

[0339] tert-Butyl-4-((7-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)piperidine-1-carboxylate (53a)

[0340] tert-Butyl-4-((7-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)piperidine-1-carboxylate (53a)

[0341] Following General Synthesis 1, using Intermediate 52a (300 mg, 0.90 mmol) as the starting material, the target product 53a (302 mg, yield: 63.1%) was obtained as a white solid. ESI-MS: m / z: [M+H] + 529.31.

[0342] tert-butyl-4-((2-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)piperidine-1-carboxylate(53b)

[0343] tert-butyl-4-((2-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)piperidine-1-carboxylate(53b)

[0344] Following General Synthesis 1, using Intermediate 52b (300 mg, 0.87 mmol) as the starting material, the target product 53b (290 mg, yield: 61.5%) was obtained as a white solid. ESI-MS: m / z: [M+H] + 543.33.

[0345] 3-(3-Fluoro-4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)piperidine-2,6-dione(54a)

[0346] 3-(3-Fluoro-4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)piperidine-2,6-dione(54a)

[0347] Following General Synthesis 4, using 53a (290 mg, 0.55 mmol) as the starting material, the target product 54a (210 mg, yield: 89.3%) was obtained as a white oil. ESI-MS: m / z: [M+H] + 429.26.

[0348] 3-(3-Fluoro-4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)piperidine-2,6-dione(54a)

[0349] 3-(3-fluoro-4-(8-(piperidin-4-ylmethyl)-2,8-diazaspiro[4.5]decan-2-yl)phenyl)piperidine-2,6-dione (54b)

[0350] Following General Synthesis 4, using 53b (270 mg, 0.50 mmol) as the starting material, the target product 54b was obtained as a white oil (192 mg, yield: 87.2%). ESI-MS: m / z: [M+H] + 443.27.

[0351] Example 17

[0352] 2-((9-((5-chloro-2-(4-(4-((7-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 17)

[0353] 2-((9-((5-chloro-2-(4-(4-((7-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 17)

[0354] Following General Synthesis 9, using 54a (60 mg, 0.11 mmol) as the starting material, the target product 17 was obtained as a white solid (10 mg, yield: 9.4%). 1H NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.79 (s, 1H), 8.06 (s, 1H), 7.99 (d, J = 5.1 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.12 (s, 1H), 7.02 - 6.83 (m, 2H), 6.65 (t, J = 9.0 Hz, 1H), 4.60 (s, 2H), 4.50 (d, J = 12.6 Hz, 2H), 4.40 (t, J = 4.6 Hz, 2H), 4.35 (s, 1H), 4.18 (t, J = 4.5 Hz, 2H), 4.03 (d, J = 13.0 Hz, 1H), 3.74 (dd, J = 11.4, 4.8 Hz, 1H), 3.39 (s, 3H), 3.33 (s, 4H), 3.25 (d, J = 8.3 Hz, 1H), 3.00 (dt, J = 23.8, 13.0 Hz, 5H), 2.67 (d, J = 4.7 Hz, 4H), 2.61 (d, J = 5.5 Hz, 3H), 2.34 - 2.11 (m, 2H), 2.03 - 1.89 (m, 3H), 1.85 - 1.73 (m, 4H), 1.64 (d, J = 9.6 Hz, 2H), 1.56 - 1.43 (m, 2H), 1.26 (d, J = 3.6 Hz, 2H). HRMS (ESI): calcd for C 48 H 56 ClFN 10 O7[M+H] + 939.4006, found 939.4068. Purity: 95.55% by HPLC (MeOH / H2O = 80:20, t R = 3.782 min).

[0355] Example 18

[0356] 2-((9-((5-chloro-2-(4-(4-((2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-2- fluorophenyl)-2,8-diazaspiro[4.5]dec-8-yl)methyl)piperidine-l-carbonyl)piperidin-l- yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[l,4]oxazepino[2,3,4-ij]quinolin-6- yl)oxy)-N-methylacetamide (Example 18)

[0357] 2-((9-((5-chloro-2-(4-(4-((2-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 18)

[0358] Following General Synthesis 9, 54b (60 mg, 0.11 mmol) was used as the starting material to give the target product Example 18 (7 mg, yield: 6.5%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.79 (s, 1H), 8.06 (s, 1H), 7.99 (d, J = 5.3 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.12 (s, 1H), 6.94 (dd, J = 15.0, 2.0 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.66 (t, J = 9.1 Hz, 1H), 4.60 (s, 2H), 4.50 (d, J = 12.2 Hz, 2H), 4.42 - 4.38 (m, 2H), 4.36 (s, 1H), 4.21 - 4.16 (m, 2H), 4.02 (d, J = 13.0 Hz, 1H), 3.74 (dd, J = 11.4, 4.8 Hz, 1H), 3.46 (s, 4H), 3.16 (s, 2H), 2.98 (q, J = 11.7 Hz, 4H), 2.67 (d, J = 4.6 Hz, 4H), 2.60 (d, J = 4.7 Hz, 1H), 2.35 (d, J = 20.4 Hz, 3H), 2.17 (d, J = 12.2 Hz, 3H), 2.04 - 1.97 (m, 1H), 1.82 - 1.72 (m, 5H), 1.65 (d, J = 14.0 Hz, 3H), 1.53 (d, J = 19.7 Hz, 6H), 1.25 (s, 1H). HRMS (ESI): calcd for C 49 H 58 ClFN 10 O7[M+H] + 953.4163, found 953.4231.

[0359] Synthesis route 9:

[0360] Example 19 was synthesized according to synthesis route 9.

[0361] Synthesis route 9: Reagents and conditions: (a) K2CO3, DMF, 60 °C, 4 h; (b) H2, Pd / C, EtOH, rt, 6 h; (c) NaHCO3, DMF, 80 °C, 16 h; (d) TFA, DCM, rt, 3 h; (e) NaBH(OAc)3, DCE, rt, 5 h; (f) TFA, DCM, rt, 2 h; (g) DIPEA, EDCI, HOBt, rt, 12 h.

[0362] 2-(2-fluoro-4-nitrophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (56)

[0363] 2-(2-fluoro-4-nitrophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (56)

[0364] Synthetic general method 13: 55 (400 mg, 2.51 mmol), 47b (604 mg, 2.51 mmol), potassium carbonate (695 mg, 5.03 mmol) were added to a round bottom flask, 10 mL of DMF solution was added, after stirring at 60 °C for 4 h, TLC monitoring reaction was completed. After the reaction was cooled to room temperature, extracted with ethyl acetate, the organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was purified by column chromatography (elution system was petroleum ether: ethyl acetate = 4: 1, v / v) to give intermediate 56 as a white solid (874 mg, yield: 91.6%). ESI-MS: m / z: [M+H] + 380.19.

[0365] 2-(4-amino-2-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (57)

[0366] 2-(4-amino-2-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (57)

[0367] Following General Synthesis Procedure 2, using intermediate 56 (800 mg, 2.11 mmol) as the starting material, the target product 57 was obtained as a white oil (719 mg, yield: 97.6%). ESI-MS: m / z: [M+H] + 350.22.

[0368] tert-butyl-2-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate (58)

[0369] tert-butyl-2-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate (58)

[0370] Following General Synthesis Procedure 14, 57 (800 mg, 2.29 mmol), 57a (1.10 g, 5.72 mmol), sodium bicarbonate (1.92 g, 22.90 mmol) were added to a round bottom flask, 15 mL of DMF solution was added, and the reaction was stirred at 85 °C for 16 h. TLC monitoring showed that the reaction was completed. After the reaction was cooled to room temperature, ethyl acetate was used for extraction, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent system: dichloromethane:methanol = 50:1, v / v) to obtain intermediate 58 as a white solid (632 mg, yield: 59.9%). ESI-MS: m / z: [M+H] + 461.25.

[0371] tert-butyl-2-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate (58)

[0372] tert-butyl-2-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate (58)

[0373] Following General Synthesis Procedure 4, using 58 (600 mg, 1.30 mmol) as the starting material, the target product 59 was obtained as a white oil (431 mg, yield: 91.8%). ESI-MS: m / z: [M+H] + 361.20.

[0374] 4-((2-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)piperidine-1-carboxylate (60)

[0375] 4-((2-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)piperidine-1-carboxylate (60)

[0376] Following General Synthesis 1, using intermediate 59 (400 mg, 1.11 mmol) as the reactant, the target product 60 (301 mg, yield: 48.6%) was obtained as a white solid. ESI-MS: m / z: [M+H] + 558.34.

[0377] 3-((3-Fluoro-4-(8-(piperidin-4-ylmethyl)-2,8-diazaspiro[4.5]decan-2-yl)phenyl)amino)piperidine-2,6-dione (61)

[0378] 3-((3-Fluoro-4-(8-(piperidin-4-ylmethyl)-2,8-diazaspiro[4.5]decan-2-yl)phenyl)amino)piperidine-2,6-dione (61)

[0379] Following General Synthesis 4, using 60 (300 mg, 0.54 mmol) as the reactant, the target product 61 (208 mg, yield: 84.5%) was obtained as a white oil. ESI-MS: m / z: [M+H] + 458.28.

[0380] Example 19

[0381] 2-((9-((5-Chloro-2-(4-(4-((2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 19)

[0382] 2-((9-((5-chloro-2-(4-(4-((2-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 19)

[0383] Following General Synthesis 9, 61 (60 mg, 0.11 mmol) was used as the starting material to obtain the target product 19 as a brown solid (9 mg, yield: 8.2%). 1 H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.79 (s, 1H), 8.07 (s, 1H), 7.99 (d, J = 4.4 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 7.12 (s, 1H), 6.66 - 6.48 (m, 2H), 6.41 (d, J = 8.7 Hz, 1H), 5.58 (d, J = 7.6 Hz, 1H), 4.60 (s, 2H), 4.50 (d, J = 12.2 Hz, 2H), 4.39 (d, J = 4.9 Hz, 2H), 4.36 (s, 1H), 4.28 - 4.21 (m, 1H), 4.19 (d, J = 4.8 Hz, 2H), 4.03 (d, J = 12.3 Hz, 1H), 3.19 (t, J = 6.0 Hz, 2H), 2.98 (t, J = 16.9 Hz, 8H), 2.76 (d, J = 12.2 Hz, 1H), 2.67 (d, J = 4.6 Hz, 4H), 2.60 (d, J = 4.6 Hz, 1H), 2.34 (s, 3H), 2.11 (dd, J = 8.8, 4.7 Hz, 3H), 1.73 (s, 4H), 1.57 (s, 4H), 1.35 (s, 2H), 1.31 (s, 1H), 1.27 (s, 4H). HRMS (ESI): calcd for C 49 H 59 ClFN 11 O7[M+H] + 968.4271, found 968.4332. Purity: 95.87% by HPLC (MeOH / H2O = 80:20, tR = 3.697 min).

[0384] Synthesis route 10:

[0385] Example 20 was synthesized according to synthesis route 10.

[0386] Synthesis route 10: Reagents and conditions: (a) K2CO3, DMF, 60 °C, 4 h; (b) H2, Pd / C, EtOH, rt, 6 h; (c) NaHCO3, DMF, 80 °C, 16 h; (d) TFA, DCM, rt, 3 h; (e) DIPEA, EDCI, HOBt, rt, 12 h.

[0387] tert-butyl 4-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (56b)

[0388] tert-butyl 4-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (56b)

[0389] Following general synthesis procedure 13, 55 (500 mg, 3.14 mmol) was used as the starting material to afford the target product 56b (1.13 g, yield: 85.1%) as a white solid. ESI-MS: m / z: [M+H] + 423.23.

[0390] tert-butyl 4-((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (57b)

[0391] tert-butyl 4-((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (57b)

[0392] Following general synthesis procedure 2, 56b (700 mg, 1.66 mmol) was used as the starting material to afford the target product 57b (626 mg, yield: 96.3%) as a white oil. ESI-MS: m / z: [M+H] + 393.26.

[0393] tert-butyl 4-((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (57b)

[0394] tert-butyl-4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate(58b)

[0395] Following General Synthesis 14, using 57b (700 mg, 1.27 mmol) as the starting material, the target product 58b was obtained as dark purple solid (301 mg, yield: 46.9%). ESI-MS: m / z: [M+H] + 504.29.

[0396] 3-((3-Fluoro-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (59b)

[0397] 3-((3-Fluoro-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione (59b)

[0398] Following General Synthesis 4, using 58b (283 mg, 0.56 mmol) as the starting material, the target product 59b was obtained as dark purple oil (199 mg, yield: 87.8%). ESI-MS: m / z: [M+H] + 404.24.

[0399] Example 20

[0400] 2-((9-((5-Chloro-2-(4-(4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperazine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazepino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 20)

[0401] 2-((9-((5-chloro-2-(4-(4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperazine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (Example 20)

[0402] Following General Synthesis 9, 35 (60 mg, 0.11 mmol) was used as the starting material to give the target product Example 20 (11 mg, yield: 10.2%) as a brown solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.79 (s, 1H), 8.06 (q, J = 3.7 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.12 (s, 1H), 6.84 (t, J = 9.3 Hz, 1H), 6.51 (dd, J = 15.0, 2.4 Hz, 1H), 6.42 (d, J = 8.9 Hz, 1H), 5.81 (d, J = 7.6 Hz, 1H), 4.60 (s, 2H), 4.50 (d, J = 12.6 Hz, 2H), 4.40 (t, J = 4.7 Hz, 2H), 4.28 (dd, J = 10.4, 6.2 Hz, 1H), 4.19 (d, J = 4.8 Hz, 2H), 3.56 (s, 2H), 3.46 (s, 2H), 3.12 (d, J = 10.8 Hz, 2H), 2.96 (t, J = 12.1 Hz, 3H), 2.67 (d, J = 4.6 Hz, 3H), 2.60 (d, J = 4.7 Hz, 1H), 2.55 (s, 4H), 2.38 (s, 2H), 2.30 (s, 2H), 2.20 (d, J = 6.8 Hz, 2H), 2.14 - 2.05 (m, 1H), 1.78 (d, J = 12.1 Hz, 2H), 1.66 (d, J = 12.6 Hz, 2H), 1.51 (t, J = 12.5 Hz, 2H), 1.36 - 1.20 (m, 3H). HRMS (ESI): calcd for C 45 H 53 ClFN 11 O7[M+H] +914.3802, found 914.3814.

[0403] Synthesis route 11:

[0404] Example 21 was synthesized according to synthesis route 11.

[0405] Synthesis route 11: Reagents and conditions: (a) Cs2CO3, Xantphos, Pd(OAc)2, dioxane, 110 °C, 10 h; (b) LiOH, MeOH, H2O, rt, 12 h; (c) EDCI, HOBt, TEA, DMF, 12 h; (d) TFA, DCM, 3 h; (e) NaBH(OAc)3, DCE, 6 h; (f) TFA, DCM, 3 h; (g) EDCI, HOBt, DIPEA, DMF, 12 h.

[0406] tert-butyl-2-(3-fluoro-4-(methoxycarbonyl)phenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate (63)

[0407] tert-butyl-2-(3-fluoro-4-(methoxycarbonyl)phenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate (63)

[0408] According to general synthesis 6, intermediate 62 (360 mg, 1.54 mmol) and 47b (482 mg, 1.70 mmol) were added to a sealed tube containing 10 mL of dry dioxane, followed by the addition of cesium carbonate (1.01 g, 3.09 mmol), palladium acetate (17 mg, 0.08 mmol), XantPhos (89 mg, 0.15 mmol), and argon was purged. The reaction was heated at 110 °C for 16 h, and TLC was used to monitor the completion of the reaction. After the reaction was cooled to room temperature, ethyl acetate was used to extract the reaction mixture, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative chromatography (eluent: dichloromethane:methanol = 100:1, v / v) to give intermediate 63 as a white solid (390 mg, yield: 58.0%). ESI-MS: m / z: [M+H] + 393.21.

[0409] 4-(8-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]dec-2-yl)-2-fluorobenzoic acid (64)

[0410] 4-(8-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-fluorobenzoic acid(64)

[0411] According to the general synthesis method 7, intermediate 63 (200 mg, 0.46 mmol) was added to a round-bottom flask containing a mixture of methanol: water = 8 mL: 2 mL, then lithium hydroxide (55 mg, 2.30 mmol) was added, and the reaction was carried out at 40 °C for 10 hours, and TLC was used to monitor the completion of the reaction. After the reaction was cooled to room temperature, dilute hydrochloric acid was added to adjust the pH of the solution to 5-6, and extraction was performed using ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent system: dichloromethane:methanol = 100:1, v / v) to obtain intermediate 64 as a white solid (180 mg, yield: 93.0%). ESI-MS: m / z: [M+H] + 379.20.

[0412] 2-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester(65)

[0413] tert-butyl-2-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate(65)

[0414] According to the general synthesis method 8, intermediate 64 (180 mg, 0.43 mmol) was added to a round-bottom flask containing 5 mL of DMF solution, then DIPEA (276 mg, 2.14 mmol), EDCI (123 mg, 0.64 mmol), and HOBt (87 mg, 0.64 mmol) were sequentially added, and the mixture was stirred at room temperature for half an hour. Then 27a (83 mg, 0.51 mmol) was added, and the reaction was carried out at room temperature overnight, and TLC was used to monitor the completion of the reaction. Extraction was performed using ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent system: dichloromethane:methanol = 50:1, v / v) to obtain intermediate 65 as a white solid (160 mg, yield: 70.5%). ESI-MS: m / z: [M+H] + 489.24

[0415] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(2,8-diazaspiro[4.5]decan-2-yl)benzamide (66)

[0416] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(2,8-diazaspiro[4.5]decan-2-yl)benzamide (66)

[0417] Following the general synthesis protocol 4, using 65 (320 mg, 0.65 mmol) as the starting material, the target product 66 (237 mg, yield: 93.2%) was obtained as a white oil. ESI-MS: m / z: [M+H] + 389.19.

[0418] 4-((2-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)piperidine-1-carboxylate (67)

[0419] 4-((2-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)piperidine-1-carboxylate (67)

[0420] Following the general synthesis protocol 1, using intermediate 66 (230 mg, 0.59 mmol) as the starting material, the target product 67 (195 mg, yield: 56.2%) was obtained as a white solid. ESI-MS: m / z: [M+H] + 586.33.

[0421] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(8-(piperidin-4-ylmethyl)-2,8-diazaspiro[4.5]decan-2-yl)benzamide (68)

[0422] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(8-(piperidin-4-ylmethyl)-2,8-diazaspiro[4.5]decan-2-yl)benzamide (68)

[0423] Following the general synthesis procedure 4, 67 (190 mg, 0.32 mmol) as the reactant gave the target product 68 (143 mg, yield: 90.8%) as a white oil. ESI-MS: m / z: [M+H] + 486.28.

[0424] Example 21

[0425] 4-(8-((1-(1-(5-chloro-4-((6-(2-(methylamino)-2-oxoethoxy)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-9-yl)amino)pyrimidin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)-2,8-diazaspiro[4.5]decan-2-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide(Example 21)

[0426] 4-(8-((1-(1-(5-chloro-4-((6-(2-(methylamino)-2-oxoethoxy)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-9-yl)amino)pyrimidin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)-2,8-diazaspiro[4.5]decan-2-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide(Example 21)

[0427] Following the general synthesis procedure 9, 35 (60 mg, 0.11 mmol) as the reactant gave the target product Example 21 (17 mg, yield: 15.0%) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.79 (s, 1H), 8.07 (s, 1H), 8.00 (q, J = 4.1, 3.7 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.66 (t, J = 8.9 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.12 (s, 1H), 6.43 (dd, J = 9.1, 2.2 Hz, 1H), 6.35 (d, J = 15.1 Hz, 1H), 4.74 (dt, J = 12.4, 6.4 Hz, 1H), 4.60 (s, 2H), 4.51 (d, J = 12.0 Hz, 2H), 4.41 (d, J = 4.4 Hz, 2H), 4.33 (s, 1H), 4.21 - 4.16 (m, 2H), 4.03 (d, J = 12.9 Hz, 1H), 3.68 - 3.39 (m, 3H), 3.17 (s, 2H), 2.99 (dd, J = 24.0, 11.5 Hz, 4H), 2.83 - 2.72 (m, 1H), 2.67 (d, J = 4.6 Hz, 3H), 2.42 - 2.29 (m, 2H), 2.15 (d, J = 11.7 Hz, 2H), 2.08 - 1.97 (m, 2H), 1.86 (s, 3H), 1.76 (s, 2H), 1.68 - 1.49 (m, 8H), 1.32 (s, 1H), 1.26 (d, J = 7.7 Hz, 4H). HRMS (ESI): calcd for C 50 H 59 ClFN 11 O8[M+H] + 996.4221, found 996.4289. Purity: 96.27% by HPLC (MeOH / H2O = 80:20, t R = 3.891 min).

[0428] Synthesis Route 12:

[0429] Example 22 was synthesized according to Synthesis Route 12.

[0430] Synthesis Route 12: Reagents and conditions: (a) DIPEA, DMSO, 100 °C, 10 h; (b) Dess-Martin periodinane, DMF, 100 °C, 2 h; (c) NaBH(OAc)3, DCE, 6 h.

[0431] 2-((9-((5-chloro-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(12b)

[0432] 2-((9-((5-chloro-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(12b)

[0433] Intermediate 11 (300 mg, 0.69 mmol), starting material 11c (158 mg, 1.38 mmol), DIPEA (151 mg, 1.17 mmol) were added to a round bottom flask, 6 mL of DMSO solution was added, stirred at 100 °C overnight after TLC monitoring reaction was completed. Slowly add 40 mL of water and stir for ten minutes, suction filtration, water washing, dry to get yellow solid 12b (212 mg, yield: 59.9%). ESI-MS: m / z: [M+H] + 515.17.

[0434] 2-((9-((5-chloro-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(12b)

[0435] 2-((9-((5-chloro-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(12b)

[0436] Intermediate 12b (200 mg, 0.39 mmol), Dess-Martin Oxidizing reagent (496 mg, 1.17 mmol) were added to a round bottom flask, 5 mL of dry DMF solution was added, stirred at room temperature for 2 h, TLC monitoring reaction was completed. Extracted twice with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a yellow solid crude 13b (141 mg, yield: 70.8%). ESI-MS: m / z: [M+H] + 513.16.

[0437] Example 22

[0438] 2-((9-((5-chloro-2-(4-((4-((7-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 22)

[0439] 2-((9-((5-chloro-2-(4-((4-((7-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 22)

[0440] Intermediate 13b (80 mg, 0.16 mmol) and 54a (100 mg, 0.23 mmol) were added to a round bottom flask containing 5 mL of dry DMF solution, stirred at room temperature for 15 min, then NaBH(OAc)3 (99 mg, 0.47 mmol) was added, stirred at room temperature overnight, TLC monitoring reaction was completed. Extracted three times with ethyl acetate, the organic phase was combined, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was purified by preparative chromatography (mobile phase system dichloromethane:methanol = 15:1, v / v) to give the target compound Example 22 as a brown solid (10 mg, yield: 6.93%). 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.03 (s, 1H), 7.79 (s, 1H), 7.18 (s, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.61 (d, J = 2.9 Hz, 2H), 6.59 (d, J = 7.5 Hz, 1H), 4.77 (s, 2H), 4.41 (dt, J = 12.5, 7.1 Hz, 2H), 4.39 (s, 2H), 4.05 (s, 2H), 3.82 (s, 1H), 3.71 (dt, J = 9.5, 7.1 Hz, 1H), 3.66 - 3.51 (m, 3H), 3.32 (d, J = 9.5 Hz, 1H), 3.17 - 3.10 (m, 2H), 2.81 (s, 3H), 2.63 - 2.54 (m, 2H), 2.59 - 2.46 (m, 4H), 2.33 - 2.19 (m, 2H), 2.22 - 2.13 (m, 2H), 2.00 (d, J = 9.5 Hz, 1H), 1.97 - 1.86 (m, 2H), 1.91 - 1.77 (m, 2H), 1.82 - 1.69 (m, 2H), 1.72 - 1.55 (m, 2H), 1.42 - 1.32 (m, 4H), 1.39 - 1.30 (m, 2H), 1.33 - 1.20 (m, 2H). HRMS (ESI): calcd for C 48 H 58 ClFN 10 O6[M+H] + 925.4213, found 925.4217. Purity: 96.02% by HPLC (MeOH / H2O = 80:20, t R = 3.797 min).

[0441] Synthesis Route 13:

[0442] Example 23 was synthesized according to Synthesis Route 13.

[0443] Synthesis route 13: Reagents and conditions: (a) Na2CO3, Pd(PPh)3Cl2, dioxane, 110 °C, 4 h; (b) Pd / C, EtOH, rt, 16 h; (c) LiOH, MeOH, H2O, rt, 16 h; (d) BuLi, THF, DMF, -78 °C, 6 h; (e) K2CO3, DMF, rt, 5 h; (f) NaBH3CN, DIPEA, DCE; (g) TFA, DCM, 3 h; (h) dimethylchlorosilane, ACN, 6 h; (i) Pd / C, H2, rt, 12 h; Boc2O, EtOH, THF, rt, 3 h; (j) Tf2O, TEA, DCM, rt, 3 h; (k) K2CO3, DMF, 70 °C, 4 h; (l) TFA, DCM, 3 h; (m) DIPEA, NMP, 170 °C, 3 h.

[0444] 4-(2-Fluoro-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (70)

[0445] tert-butyl-4-(2-fluoro-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(70)

[0446] Intermediate 69a (5.00 g, 21.46 mmol) and 69b (8.62 g, 27.89 mmol) were added to a sealed tube containing a solution of dioxane: water = 60:20 mL, followed by sodium carbonate (4.29 g, 42.92 mmol), Pd(PPh)3Cl2(1.51 g, 2.15 mmol) sequentially, argon was replaced, 100 °C for 4 hours, TLC monitoring reaction was completed. After the reaction was cooled to room temperature, extracted with ethyl acetate, the organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent system: petroleum ether: ethyl acetate = 5:1, v / v) to give intermediate 70 as a white solid (4.6 g, yield: 63.9%). ESI-MS: m / z: [M+H] + 336.15.

[0447] 4-(2-Fluoro-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (71)

[0448] tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate(71)

[0449] Following General Synthesis Procedure 2, 70 (4.50 g, 13.42 mmol) was used as the starting material to obtain the target product 71 (4.32 g, yield: 95.4%) as colorless oil. ESI-MS: m / z: [M+H] + 338.17.

[0450] 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-fluorobenzoic acid (72)

[0451] 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-fluorobenzoic acid (72)

[0452] Following General Synthesis Procedure 7, 71 (4.40 g, 13.04 mmol) was used as the starting material to obtain the target product 72 (4.06 g, yield: 96.3%) as white solid. ESI-MS: m / z: [M+H] + 324.15.

[0453] tert-butyl-4-(4-fluoro-3-hydroxy-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate (73)

[0454] tert-butyl-4-(4-fluoro-3-hydroxy-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate (73)

[0455] Intermediate 72 (5.00 g, 15.46 mmol) was added to a two-necked flask containing a mixture of dry THF: dry DMF = 40 mL: 20 mL solution, purged with argon, stirred at -78 °C for 30 min, then BuLi (23.19 mL, 23.19 mmol, 1 M in THF) was added slowly, the reaction was allowed to proceed at room temperature for 6 h, TLC was used to monitor the completion of the reaction. After the reaction was allowed to return to room temperature, it was quenched by the slow addition of saturated ammonium chloride, then extracted with ethyl acetate, the organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and intermediate 73 was obtained as a white solid without further purification (2.40 g, yield: 44.2%). ESI-MS: m / z: [M+H] + 352.15.

[0456] tert-butyl-4-(4-fluoro-3-hydroxy-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate (73)

[0457] tert-butyl 4-(2-fluoro-3-formyl-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate(74)

[0458] Intermediate 73 (4.00 g, 11.38 mmol) was added to a round-bottom flask containing 40 mL of DMF solution, followed by potassium carbonate (3.15 g, 22.77 mmol). The reaction was carried out at room temperature for 4 hours, and TLC was used to monitor the completeness of the reaction. Extraction was performed using ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (elution system: petroleum ether:ethyl acetate = 5:1, v / v) to give intermediate 74 as a white solid (1.93 g, yield: 46.4%). ESI-MS: m / z: [M+H] + 366.16.

[0459] 4-(2-fluoro-3-formyl-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (75)

[0460] tert-butyl 4-(2-fluoro-3-formyl-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate(75)

[0461] Intermediate 74 (5.00 g, 13.68 mmol) was added to a round-bottom flask containing 60 mL of DCE solution, followed by DIPEA (3.54 g, 27.37 mmol) and 74a (2.10 g, 16.42 mmol). The mixture was stirred at room temperature for 30 minutes, then NaBH3CN (1.72 g, 27.37 mmol) was added, and the reaction was carried out at room temperature for 6 hours. The reaction was monitored by TLC until complete. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (elution system: dichloromethane:methanol = 100:1, v / v) to give intermediate 75 as a white solid (2.17 g, yield: 35.6%). ESI-MS: m / z: [M+H] + 446.20.

[0462] 3-(4-fluoro-1-oxo-5-(piperidin-4-yl)isoindoline-2-yl)piperidin-2,6-dione (76)

[0463] 3-(4-fluoro-1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione(76)

[0464] Following the general synthesis procedure 4, 75 (3.00 g, 6.73 mmol) was used as the starting material to give the target product 76 as colorless oil (2.19 g, yield: 94.16%). ESI-MS: m / z: [M+H] + 336.15.

[0465] 4-((1s,3s)-3-(BENZYLOXY)CYCLOBUTOXY)PIPERIDINE-1-CARBOXYLIC ACID BENZYL ESTER (78)

[0466] benzyl 4-((1s,3s)-3-(benzyloxy)cyclobutoxy)piperidine-1-carboxylate(78)

[0467] Intermediate 77 (17.67 g, 75.74 mmol) was added to a round bottom flask containing 100 mL of anhydrous acetonitrile solution, ice bath for half an hour, then dimethylchlorosilane (9.56 g, 100.99 mmol), 77 (9.00 g, 50.50 mmol) were added in turn, and the reaction was carried out at room temperature for 6 hours, and TLC was used to monitor the completion of the reaction. Concentration under reduced pressure, extraction with ethyl acetate, the organic layer was washed with saturated brine, then anhydrous sodium sulfate was added for drying, and concentrated under reduced pressure. The residue was purified by column chromatography (elution system: dichloromethane:methanol = 100:1, v / v) to give intermediate 78 as a white solid (8.20 g, yield: 41.1%). ESI-MS: m / z: [M+H] + 396.21.

[0468] 4-((1s,3s)-3-HYDROXYCYCLOBUTOXY)PIPERIDINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER (79)

[0469] tert-butyl 4-((1s,3s)-3-hydroxycyclobutoxy)piperidine-1-carboxylate(79)

[0470] Intermediate 78 (8.00 g, 20.23 mmol) was added to a round bottom flask containing 100 mL of methanol solution, palladium on carbon (1.60 g, 20% m / m) was added, hydrogen gas was replaced, and the reaction was allowed to proceed at room temperature overnight, with TLC monitoring until the reaction was complete. Silica gel was suction filtered, washed with methanol, and concentrated under reduced pressure to obtain a colorless oil. Ethanol: tetrahydrofuran = 40 mL: 40 mL mixed solution was added, Boc2O (6.62 g, 30.34 mmol) was added, and the reaction was allowed to proceed at room temperature for 4 h, with TLC monitoring until the reaction was complete. Extraction was performed using ethyl acetate, the organic layer was washed with saturated brine, dried by adding anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane:methanol = 40:1, v / v) to obtain intermediate 79 as a colorless oil (5.01 g, yield: 91.28%). ESI-MS: m / z: [M+H] + 272.18.

[0471] tert-butyl 4-((1s,3s)-3-(((trifluoromethyl)sulfonyl)oxy)cyclobutoxy)piperidine-1-carboxylate (80)

[0472] tert-butyl 4-((1s,3s)-3-(((trifluoromethyl)sulfonyl)oxy)cyclobutoxy)piperidine-1-carboxylate (80)

[0473] Intermediate 79 (5.00 g, 18.43 mmol) was added to a round bottom flask containing 50 mL of anhydrous DCM solution, and then TEA (3.72 g, 36.86 mmol) and Tf2O (7.80 g, 27.64 mmol) were sequentially added, and the reaction was allowed to proceed at room temperature for 3 h, with TLC monitoring until the reaction was complete. Concentration was performed under reduced pressure, extraction was performed using ethyl acetate, the organic layer was washed with saturated brine, dried by adding anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane:methanol = 50:1, v / v) to obtain intermediate 80 as a colorless oil (6.28 g, yield: 84.5%). ESI-MS: m / z: [M+H] + 404.13.

[0474] tert-butyl 4-((1r,3r)-3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate (81)

[0475] tert-butyl-4-((1r,3r)-3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate(81)

[0476] Intermediate 76 (1.00 g, 2.90 mmol) was added to a round bottom flask containing 20 mL of anhydrous DMF solution, then potassium carbonate (0.80 g, 5.79 mmol), 80 (1.28 g, 3.18 mmol) were added successively, and the reaction was carried out at 70 °C for 4 h, and TLC was used to monitor the completion of the reaction. Extraction was performed using ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent system: dichloromethane:methanol = 50:1, v / v) to obtain intermediate 81 as a colorless oil (1.29 g, yield: 74.4%). ESI-MS: m / z: [M+H] + 599.32.

[0477] 3-(4-Fluoro-1-oxo-5-(1-((1r,3r)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione(82)

[0478] 3-(4-Fluoro-1-oxo-5-(1-((1r,3r)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione(82)

[0479] According to General Synthesis 4, using 81 (1.10 g, 1.84 mmol) as the reaction material, the target product 82 was obtained as a colorless oil (0.85 g, yield: 92.8%). ESI-MS: m / z: [M+H] + 499.26.

[0480] Example 23

[0481] 2-((9-((5-chloro-2-(4-((1r,3r)-3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 23)

[0482] 2-((9-((5-chloro-2-(4-((1r,3r)-3-(4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(Example 23)

[0483] Following General Synthesis 5, using 82 (171 mg, 0.34 mmol) as the starting material, the target product, Example 23 (85 mg, yield: 41.3%) was obtained as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.12 (s, 1H), 7.83 (s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 6.62 - 6.62 (m, 2H), 5.11 (dt, J = 8.6, 7.0 Hz, 2H), 4.91 (s, 2H), 4.81 (d, J = 19.4 Hz, 1H), 4.50 (m, J = 19.4 Hz, 1H), 4.31 (t, J = 4.6 Hz, 2H), 4.22 (m, J = 12.5, 7.1, 3.8 Hz, 2H), 4.07 (t, J = 4.7 Hz, 2H), 3.62 (d, J = 12.6, 7.1, 3.9 Hz, 2H), 3.32 - 3.21 (m, 3H), 2.97 (m, J = 14.3, 7.1 Hz, 1H), 2.92 - 2.81 (m, 2H), 2.80 (s, 3H), 2.62 - 2.51 (m, 2H), 2.51 - 2.36 (m, 2H), 2.19 - 2.01 (m, 7H), 1.91 - 1.72 (m, 4H), 1.57 (m, J = 13.7, 7.1 Hz, 2H). HRMS (ESI): calcd for C 45 H49 ClFN9O8[M+H] + 898.3377, found 898.3366. Purity: 96.33% by HPLC (MeOH / H20 = 80:20, t R = 4.147 min).

[0484] Synthesis route 14:

[0485] Example 24 was synthesized according to synthesis route 14.

[0486] Synthesis route 14: Reagents and conditions: (a) N,N-dimethyl-bromoacetamide, Cs2C03, DMF, rt, 3 h; (b) Fe, NH4CI, EtOH, H20, 80 °C, 3 h; (c) DIPEA, DMSO, 100 °C, 3 h; (d) DIPEA, DMSO, 100 °C, 10 h; (e) DIPEA, EDCI, HOBt, rt, 12 h.

[0487] N,N-dimethyl-2-((9-nitro-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)acetamide (8b)

[0488] N,N-dimethyl-2-((9-nitro-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)acetamide (8b)

[0489] Intermediate 7 (1.00 g, 4.03 mmol) was added to a round bottom flask, followed by 7b (0.83 g, 4.83 mmol), and cesium carbonate (2.63 g, 8.06 mmol), then DMF (15 mL) was added, stirred at room temperature for 4 h, TLC monitored the reaction was completed. First add 50 mL of water, suction filtration, water washing, filter cake drying, add an equal volume of ethyl acetate and water to the filtrate liquid-liquid extraction 3 times, combined organic layer and low pressure concentration to remove the solvent, the residue combined with the filter, column chromatography (elution system dichloromethane: methanol = 60: 1, v / v) purification of intermediate 8b as a yellow solid (0.53 g, yield: 37.3%). 1H NMR(300MHz,DMSO-d6)δ8.23(d,J=2.5Hz,1H),7.73(d,J=2.5Hz,1H),7.45(s,1H),4 .97(s,2H),4.49(t,J=4.7Hz,2H),4.24(t,J=4.8Hz,2H),3.05(s,3H),2.90(s,3H). ESI-MS:m / z:[M+H] + 334.10.

[0490] 2-((9-amino-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)-N,N-dimethylacetamide (9b)

[0491] 2-((9-amino-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N,N-dimethylacetamide(9b)

[0492] 8b (0.40 g, 1.20 mmol) was added to a round-bottom flask containing anhydrous ethanol:water = 20 mL:4 mL. Ammonium chloride (0.35 g, 6.26 mmol) was added, followed by reduced iron powder (0.34 g, 6.26 mmol) while stirring. The mixture was heated at 80 °C for 3 h, and the reaction was monitored by TLC until completion. Heating was removed, and the reaction solution was allowed to cool to room temperature. 2 mL of ammonia-methanol solution was added to adjust the pH of the solution to be greater than 7. The mixture was filtered through diatomaceous earth, washed with dichloromethane:methanol = 20:1 (1000 mL), and the filtrate was collected and concentrated under low pressure to obtain a pale yellow solid 9b (0.23 g, yield: 63.5%). ESI-MS: m / z: [M+H] + 304.12.

[0493] 2-((9-((2,5-dichloropyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)-N,N-dimethylacetamide (11b)

[0494] 2-((9-((2,5-dichloropyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N,N-dimethylacetamide(11b)

[0495] Intermediate 9b (0.40 g, 1.38 mmol), 10 (0.51 g, 2.77 mmol), DIPEA (0.54 g, 4.02 mmol) were added to a round bottom flask, 8 mL of DMSO solution was added, stirred at 100 °C for 3 h, TLC monitoring reaction was completed. 35 mL of water was added and stirred for half an hour, suction filtration, water washing, drying to get light yellow solid intermediate 11b (0.43 g, yield: 76.0%). ESI-MS: m / z: [M+H] + 450.06.

[0496] 1-(5-chloro-4-((6-(2-(dimethylamino)-2-oxoethoxy)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-9-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid(35b)

[0497] 1-(5-chloro-4-((6-(2-(dimethylamino)-2-oxoethoxy)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-9-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid(35b)

[0498] Intermediate 11b (300 mg, 0.69 mmol), raw material 12i (178 mg, 1.39 mmol), DIPEA (151 mg, 1.17 mmol) were added to a round bottom flask, 8 mL of DMSO solution was added, stirred at 100 °C for 10 h, TLC monitoring reaction was completed. Slowly add dilute hydrochloric acid to adjust the pH of the solution to 2-5, then add 50 mL of water and stir for ten minutes, suction filtration, water washing, drying to get yellow solid 35b (310 mg, yield: 85.2%). ESI-MS: m / z: [M+H] + 543.17.

[0499] Example 24

[0500] 2-((9-((5-chloro-2-(4-(4-((2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,8-diazaspiro[4.5]dec-8-yl)methyl)piperidin-1- carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4- ij]quinolin-6-yl)oxy)-N,N-dimethylacetamide (Example 24)

[0501] 2-((9-((5-chloro-2-(4-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N,N-dimethylacetamide (Example 24)

[0502] Following General Synthesis 13, 35b (60 mg, 0.10 mmol) was used as the starting material to give the target product Example 24 (13 mg, yield: 12.2%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.79 (s, 1H), 8.10 - 8.05 (m, 1H), 8.00 (d, J = 4.8 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.12 (s, 1H), 6.94 (d, J = 2.1 Hz, 1H), 6.83 (dd, J = 8.7, 2.1 Hz, 1H), 5.08 (dd, J = 12.6, 5.4 Hz, 1H), 4.60 (s, 2H), 4.51 (d, J = 12.5 Hz, 2H), 4.41 (d, J = 4.5 Hz, 2H), 4.37 (s, 1H), 4.19 (t, J = 4.7 Hz, 2H), 4.03 (d, J = 12.7 Hz, 1H), 3.49 (s, 3H), 3.40 (s, 3H), 3.31 (s, 1H), 3.10 - 2.85 (m, 6H), 2.67 (d, J = 4.6 Hz, 3H), 2.62 (s, 1H), 2.57 (s, 6H), 2.40 - 2.12 (m, 2H), 2.06 - 1.98 (m, 1H), 1.94 - 1.87 (m, 2H), 1.79 (d, J = 13.8 Hz, 3H), 1.65 (d, J = 12.0 Hz, 6H), 1.51 (d, J = 6.6 Hz, 2H), 1.26 (s, 1H). HRMS (ESI): calcd for C 52 H 60 ClN 11 O9[M+H]+ 1018.4264, found 1018.4270. Purity: 95.49% by HPLC (MeOH / H2O = 80:20, t R = 4.203 min).

[0503] Pharmacological activity evaluation

[0504] BCL6 protein degradation test: OCI-LY1 cells (Zhejiang Meisen Cell Technology Co., Ltd.) were seeded in 6-well plates, and then different concentrations of compounds were added. After 12 hours of administration, the cells were collected by centrifugation, mixed and lysed with medium-strength RIPA lysis buffer (Bi Yun Tian Biotechnology), the supernatant was aspirated by centrifugation, and the protein concentration was determined by BCA method. The protein sample was mixed with protein loading buffer (Bi Yun Tian Biotechnology) and heated at 100°C for 10 min to prepare the sample, then the sample was added to 12% polyacrylamide gel SDS-PAGE, electrophoresis at 60V constant voltage until the marker left the concentrated gel, then continue electrophoresis at 120V constant voltage, transfer the membrane in wet transfer buffer containing 10% methanol for 90 min, then cut the required band from the transferred PVDF membrane, block with milk for 2 hours, add anti-BCL6 antibody (abcam) and β-Actin (Proteintech) antibody diluted with milk to the corresponding bands, and incubate at 4°C overnight. The next day, wash the primary antibody with TBST, add the secondary antibody and incubate at room temperature for 45 min. Continue to wash the secondary antibody solution with TBST, and scan the membrane under the Odyssey Infrared Imaging System (LI-COR, Lincoln, Nebraska, USA). DC 50 BCL6 degrader to degrade 50% of BCL6 protein, the calculation process is as follows: the degrader is diluted by 5 times gradient from 1000 nM to 9 concentrations, and the degradation of BCL6 protein at each concentration is detected by WB method. Image J software is used for gray scale analysis to calculate the remaining amount of BCL6. Through Graphpad 8.0 software, the protein remaining amount and the concentration logarithm (Log(C)) are fitted to obtain DC 50 value.

[0505] Table 1 degradation of BCL6 in OCI-LY1 cells by compounds

[0506] Cell anti-proliferation activity test: Cells in logarithmic growth phase were seeded in 96-well plates (Coring, 3799) at a density of 5000 per well with 100 μL of RPMI 1640 medium (Adamas) containing 20% FBS, and cultured overnight at 37°C in a 5% CO2 incubator. The next day, 100 μL of drug solution at different concentrations prepared in culture medium was added, with three replicate wells for each concentration (denoted as RLU test ), and control and blank wells were set. The control wells were cells, culture medium and drug dissolution medium at the same concentration (denoted as RLU control ), and the blank wells were culture medium (denoted as RLU blank ). After 9 days, 100 μL of suspended cells was aspirated per well into a 96-well black plate (Shanghai Wohong Biotechnology Co., Ltd., WHB-96-02), and 100 μL of CellTiter-Lumi Luminescent Cell Viability Assay Kit (Bi Yun Tian Biotechnology) was added to each well. After incubation on a shaker for 10 min in the dark, detection was performed. For adherent cells, 100 μL of medium was discarded per well, and 100 μL of detection reagent was added to each well in a 96-well plate. After 2 min of lysis on a shaker, the solution in the wells was aspirated into a 96-well black plate, and incubated on a shaker for 8 min in the dark before detection. Chemiluminescence values were detected by a chemiluminescence module on a Thermo scientific varioskan flash. The percentage of cell survival was calculated by the following formula: cell survival rate (%) = (RLU test -RLU blank ) / (RLU control -RLU blank ) x 100%, and the IC 50 value was calculated using Graphpad Prism 8.0 software.

[0507] Table 2 Anti-proliferation activity of compounds on OCI-LY1 cells

Claims

A compound having a chemical structure as shown in Formula I or a pharmaceutically acceptable salt, solvate thereof: POI-L-E3L Ⅰ wherein: L is a Linker connecting POI and E3L; E3L is independently selected from: wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 are independently selected from -H, halogen, -Ci-C3alkyl, -Ci-C3haloalkyl, -Ci-C3alkoxy; R 22 independently selected from -H, -C1-C3alkyl; POI is independently selected from: wherein: R 23 independently selected from -H, halogen; R 24 , R 25 is independently selected from -H, -C1-C3alkyl; L is independently selected from: wherein: n = 1, 2, or 3. A compound of one of the following chemical structures or a pharmaceutically acceptable salt, solvate thereof: A pharmaceutical composition, characterized by: A compound of claim 1 or 2 or a pharmaceutically acceptable salt, solvate thereof. Use of a compound of claim 1 or 2 or a pharmaceutically acceptable salt, solvate thereof for the manufacture of a BCL6 protein degrader. Use of a compound of claim 1 or 2 or a pharmaceutically acceptable salt, solvate thereof for the manufacture of a medicament for treating a disease that is treated or ameliorated by degrading BCL6 protein. Use according to claim 5, characterized in that: The disease is cancer. Use according to claim 6, characterized in that: The cancer is Hodgkin lymphoma, B-cell derived non-Hodgkin lymphoma, T-cell derived non-Hodgkin lymphoma, NK / T-cell derived non-Hodgkin lymphoma, or diffuse large B-cell lymphoma. Use of a pharmaceutical composition of claim 3 for the manufacture of a medicament for treating a disease that is treated or ameliorated by degrading BCL6 protein. Use according to claim 8, characterized in that: The disease is cancer. Use according to claim 9, characterized in that: The cancer is Hodgkin lymphoma, B-cell derived non-Hodgkin lymphoma, T-cell derived non-Hodgkin lymphoma, NK / T-cell derived non-Hodgkin lymphoma, or diffuse large B-cell lymphoma.

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