Tricyclic BCL6 degradation agent and application thereof

Abstract

The invention discloses a tricyclic BCL6 degradation agent and application of the tricyclic BCL6 degradation agent. The tricyclic compound or the pharmaceutically acceptable salt and solvate thereof provided by the invention are novel in structure, and have a relatively excellent degradation effect on BCL6 protein. Therefore, the compound provided by the invention or the composition containing the compound provided by the invention has a prospect of being developed into drugs for treating diseases which are treated or relieved by degrading the BCL6 protein; cancer such as Hodgkin's lymphoma, B-cell-derived non-Hodgkin's lymphoma, T-cell-derived non-Hodgkin's lymphoma, NK / T-cell-derived non-Hodgkin's lymphoma or diffuse large B-cell lymphoma and the like can be used in the preparation of drugs.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to the synthesis of new compounds and their pharmaceutical uses, specifically to a class of tricyclic BCL6 degrading agents and their uses. Background Technology

[0002] B-cell lymphokine 6 (BCL6) is an important transcriptional repressor in humoral immune responses. The human BCL6 gene is approximately 24 kb, encoding a BCL6 protein of about 95 kDa. The BCL6 protein is a member of the POZ / BTB / Zinc finger protein family and is mainly composed of three parts: 1) The N-terminal POZ / BTB domain—the main functional region for transcriptional repression. For BCL6 to exert its transcriptional repression function, the BTB domain spontaneously forms a dimer. Three major transcriptional co-repressors, SMRT, BCOR, or NCOR, competitively bind to the BTB binding site, jointly exerting transcriptional repression and participating in the early transcriptional regulation of germinal centers (GCs). 2) The middle region (three PEST domains, also known as the RD2 domain), which mainly recruits cofactors such as MTA3 or CTBP1 to stabilize the protein. 3) The C-terminal zinc finger domain, composed of six identical zinc finger structures, mainly functions to bind DNA and is a prerequisite for BCL6 to exert its transcriptional repression function.

[0003] BCL6 is a transcriptional repressor crucial for GC development and maintenance. In the GC response, chromosomal translocations and point mutations of BCL6 lead to persistently high expression of the BCL6 protein, promoting malignant B-cell proliferation and ultimately resulting in B-cell lymphoma. Most non-Hodgkin lymphomas (NHLs) originate from GCs, with diffuse large B-cell lymphoma (DLBCL) being the most common subtype. BCL6 is widely recognized as a carcinogenic driver of DLBCL. Numerous preclinical studies have also demonstrated that blocking the interaction between the BCL6-BTB domain and its transcriptional co-repressors can inhibit GC formation and DLBCL cell proliferation, representing an effective and safe treatment strategy for DLBCL without causing toxic side effects or macrophage-driven inflammatory responses.

[0004] BCL6 is a highly promising target for cancer therapy, including but not limited to Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma, T-cell non-Hodgkin's lymphoma, NK / T-cell non-Hodgkin's lymphoma, or diffuse large B-cell lymphoma. Currently reported BCL6 small molecule inhibitors have several drawbacks, such as poor target binding activity, insufficient in vitro and in vivo cellular activity, unclear mechanisms, and poor drug-like properties. In contrast, reported BCL6 small molecule degraders have clear mechanisms of action; they induce intracellular BCL6 protein aggregation and specifically degrade BCL6. Their unique mechanism of action makes the antiproliferative effect of BI-3802 (a BCL6 small molecule degrader) comparable to that of CRISPR-Cas9 knockout of the BCL6 gene. Currently, there are approximately 18 BCL6 drugs in development, covering small molecule inhibitors (8 classes), PROTACs (5 classes), and molecular gels (5 classes). Only BMS's PROTAC drug (BMS-986458) has entered Phase I clinical trials. Therefore, it remains urgent and necessary to develop small molecule degraders that have novel structures, good drug-like properties and safety, and can rapidly and efficiently degrade BCL6. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a tricyclic BCL6 degrading agent and its uses.

[0006] The above-mentioned objective of this invention is achieved through the following technical solution:

[0007] A compound with a chemical structure as shown in Formula I, or a pharmaceutically acceptable salt or solvate thereof:

[0008]

[0009] in:

[0010] X is -CH2-, -O-, -NH-, or -S-;

[0011] n = 0, 1, or 2;

[0012] R1 is a monosubstituted or polysubstituted heterocyclic group, wherein each substituent of the heterocyclic group is independently selected from -H, -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkoxy, -C1~C6 alkyl-O-C1~C6 alkyl, -C1~C6 alkyl-OH, -C1~C6 alkyl-NH2, -OH, -NH2, -COOH, -F, -Cl, -Br and -I;

[0013] A is in:

[0014] R2 and R3 are -L(CH2) k C = OR4 or Z is -CH= or -N=, where:

[0015] L is -CH2-, -O-, -NH-, or -S-; k = 1, 2, or 3; R4 is -NR5R6, where R5 and R6 are independently selected from -H, -C1~C5 alkyl, -C2~C6 alkenyl, or -C2~C6 alkynyl, and N does not form a ring with the connected R5 or R6 or forms a 4-7 membered heterocycle; h = 1, 2, 3, or 4.

[0016] Preferably, the chemical structure of the above compound is shown in Formula II:

[0017]

[0018] in:

[0019] R1 is a monosubstituted or polysubstituted heterocyclic group, wherein each substituent of the heterocyclic group is independently selected from -H, -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkoxy, -C1~C6 alkyl-O-C1~C6 alkyl, -C1~C6 alkyl-OH, -C1~C6 alkyl-NH2, -OH, -NH2, -COOH, -F, -Cl, -Br and -I;

[0020] A is in:

[0021] R2 and R3 are -L(CH2) k C = OR4 or Z is -CH= or -N=, where:

[0022] L is -CH2-, -O-, -NH- or -S-; k = 1, 2 or 3; R4 is -NR5R6, R5 and R6 are independently selected from -H, -C1~C5 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, N does not form a ring with the connected R5 and R6 or forms a 4-7 membered heterocycle;

[0023] h = 1, 2, 3 or 4.

[0024] Preferably, R1 in the above chemical structure is as shown in Formula III:

[0025]

[0026] in:

[0027] Y is -NH-, -O-, -S- or -C- substituted by R7 and R8, where R7 and R8 are independently selected from -H, -OH and halogen, respectively;

[0028] R 1a R 1b R 1c R 1d R1e R 1f R 1g R 1h The components are independently selected from -H, -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkoxy, -C1~C6 alkyl-O-C1~C6 alkyl, -C1~C6 alkyl-OH, -C1~C6 alkyl-NH2, -OH, -NH2, -COOH, -F, -Cl, -Br and -I.

[0029] More preferably, the chemical structure of the compound is selected from:

[0030]

[0031]

[0032] The use of any of the above compounds or their pharmaceutically acceptable salts or solvates in the preparation of BCL6 protein degrading agents.

[0033] The use of any of the above compounds or their pharmaceutically acceptable salts or solvates in the preparation of medicaments for treating diseases that are treated or alleviated by degrading BCL6 protein.

[0034] Preferably, the disease is cancer.

[0035] More preferably, the cancer is Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, T-cell non-Hodgkin lymphoma, NK / T-cell non-Hodgkin lymphoma, or diffuse large B-cell lymphoma.

[0036] A method of treating a disease, comprising administering to an individual suffering from the disease a therapeutically effective amount of any of the above-mentioned compounds or a pharmaceutically acceptable salt or solvate thereof; wherein the disease is a disease that is treated or alleviated by degradation of BCL6 protein.

[0037] Preferably, the disease is cancer.

[0038] More preferably, the cancer is Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, T-cell non-Hodgkin lymphoma, NK / T-cell non-Hodgkin lymphoma, or diffuse large B-cell lymphoma.

[0039] A pharmaceutical composition comprising any of the compounds described above or a pharmaceutically acceptable salt or solvate thereof.

[0040] The above pharmaceutical composition is used for the preparation of a medicament for treating a disease that is treated or alleviated by degrading BCL6 protein.

[0041] Preferably, the disease is cancer.

[0042] More preferably, the cancer is Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, T-cell non-Hodgkin lymphoma, NK / T-cell non-Hodgkin lymphoma, or diffuse large B-cell lymphoma.

[0043] A method of treating a disease, comprising administering to an individual suffering from the disease a therapeutically effective amount of a pharmaceutical composition containing any of the aforementioned compounds or a pharmaceutically acceptable salt or solvate thereof; wherein the disease is a disease that is treated or alleviated by degrading BCL6 protein.

[0044] Preferably, the disease is cancer.

[0045] More preferably, the cancer is Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, T-cell non-Hodgkin lymphoma, NK / T-cell non-Hodgkin lymphoma, or diffuse large B-cell lymphoma.

[0046] Beneficial effects:

[0047] The tricyclic compounds or their pharmaceutically acceptable salts and solvates provided by this invention have novel structures and exhibit superior degradation activity against BCL6 protein. Therefore, the compounds provided by this invention, or compositions containing the compounds provided by this invention, have the potential to be developed into medicaments for treating or alleviating diseases by degrading BCL6 protein, such as Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, T-cell non-Hodgkin lymphoma, NK / T-cell non-Hodgkin lymphoma, or diffuse large B-cell lymphoma, and other cancers. Detailed Implementation

[0048] The following description of the substantive content of the invention, in conjunction with specific compounds, does not limit the scope of protection of the invention.

[0049] Synthesis Route 1 :

[0050] Compounds 1-9 were synthesized according to synthetic route 1.

[0051]

[0052] Synthetic route 1. Reagents and conditions: (a) 1,2-dibromoethane, K2CO3, DMF, rt, 3h; (b) BBr3, DCM, 0℃, 4h; (c) Cs2CO3, CH3CN, 60℃, 1h; (d) KNO3, H2SO4, 0℃, 4h; (e) (diazomethyl)trimethylsilane, Et3N, EtOH, rt, 12h; (f) 2-bromo-N-methylacetamide, Cs2CO3, DMF, rt, 3h; (g) Fe, NH4Cl, EtOH, H2O, 80℃, 3h; (h) DIPEA, DMSO, 100℃, 3h; (i) DIPEA, DMSO, 100℃, 10h.

[0053] 1-(2-Bromoethyl)-7-methoxyindoline-2,3-dione (SM-1)

[0054] 1-(2-bromoethyl)-7-methoxyindoline-2,3-dione(SM-1)

[0055]

[0056] Synthetic Method 1: A-1a (5.00 g, 28.22 mmol), 1,2-dibromoethane A-1b (10.6 g, 56.45 mmol), and potassium carbonate (7.80 g, 56.45 mmol) were added to a round-bottom flask, followed by 35 mL of DMF solution. The mixture was stirred at room temperature for 3 h, and the reaction was monitored by TLC until complete. 350 mL of water was added and stirred for half an hour. The mixture was then filtered, washed with water, and dried to obtain a red solid SM-1 (6.80 g, yield: 84.8%). 1 HNMR (300MHz, DMSO-d6) δ7.45 (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).

[0057] 1-(2-Bromoethyl)-7-hydroxyindoline-2,3-dione (SM-2)

[0058] 1-(2-bromoethyl)-7-hydroxyindoline-2,3-dione(SM-2)

[0059]

[0060] Synthetic Method 2: SM-1 (0.30 g, 1.06 mmol) was added to a round-bottom flask containing 6 mL of dichloromethane solution. The flask was in an ice bath for 30 min, followed by slow dropwise addition of boron tribromide (0.79 g, 3.17 mmol). After 1 h, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction was then in an ice bath for half an hour, followed by slow dropwise addition of anhydrous methanol. The addition was stopped when no white fumes were produced. The mixture was concentrated under low pressure, and the residue was purified by column chromatography (elution system: petroleum ether: ethyl acetate = 4:1, v / v) to obtain intermediate SM-2 as a red solid (0.16 g, yield: 56.1%). 1 H NMR (300MHz, DMSO-d6) δ10.48(s,1H),7.17(dd,J=8.0,1.3Hz,1H),7.09(dd,J=7 .4,1.3Hz,1H),7.03–6.95(m,1H),4.21(t,J=6.9Hz,2H),3.70(t,J=6.9Hz,2H).

[0061] 2,3-Dihydro-[1,4]oxazindo[2,3,4-hi]indole-5,6-dione (SM-3)

[0062] 2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-5,6-dione(SM-3)

[0063]

[0064] Synthetic Method 3: SM-2 (1.00 g, 3.70 mmol) was added to a round-bottom flask, followed by 30 mL of acetonitrile solution, and then cesium carbonate (2.41 g, 7.41 mmol). The mixture was heated at 60 °C for 1 h, and the reaction was monitored by TLC until completion. Heating was removed, and the reaction mixture was allowed to cool to room temperature. The mixture was then filtered, washed with ethyl acetate, concentrated, and the residue was purified by column chromatography (elution system: petroleum ether: ethyl acetate = 4:1, v / v) to obtain intermediate SM-3 as a red solid (0.57 g, yield: 81.8%). 1 H NMR (300MHz, DMSO-d6) δ7.24–7.11(m,2H),6.99(t,J=7.8Hz,1H),4.32(t,J=4.7Hz,2H),3.79(t,J=4.9Hz,2H).

[0065] 2,3-Dihydro-[1,4]oxazindo[2,3,4-hi]indole-5,6-dione (SM-4)

[0066] 2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-5,6-dione(SM-4)

[0067]

[0068] Following synthetic route 1, SM-3 (2.40 g, 12.69 mmol) was added to a round-bottom flask and stirred in an ice bath for 15 min. Then, 20 mL of concentrated sulfuric acid solution was slowly added, and the mixture was stirred in an ice bath for 0.5 h. Subsequently, potassium nitrate (1.28 g, 12.69 mmol) was slowly added, and the reaction was carried out at room temperature for 6 h. The reaction was monitored by TLC until it was complete. The reaction solution was slowly poured into a stirred ice-water bath, and ethyl acetate was added. The mixture was extracted three times, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (elution system: petroleum ether: ethyl acetate = 4:1, v / v) to give intermediate SM-4 as an orange-yellow solid (1.80 g, yield: 60.6%). 1 H NMR (300MHz, 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).

[0069] 6-Hydroxy-9-nitro-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-5-one (SM-5)

[0070] 6-hydroxy-9-nitro-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-5-one(SM-5)

[0071]

[0072] Following synthetic route 1, SM-4 (0.33 g, 1.41 mmol) was added to a round-bottom flask, followed by triethylamine (0.28 g, 2.82 mmol) and then anhydrous ethanol (10 mL). Subsequently, TMS-CHN2 (0.70 mL, 1.40 mmol, 2 M in hexane) was slowly added dropwise with stirring. The mixture was purged with argon and stirred overnight at room temperature. The reaction was monitored by TLC until complete. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (elution system: dichloromethane:methanol = 80:1, v / v) to obtain intermediate SM-5 as a yellow solid (0.07 g, yield: 19.4%). 1HNMR (300MHz, 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] + 249.05.

[0073] N-Methyl-2-(9-nitro-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)acetamide (SM-6a)

[0074] N-methyl-2-((9-nitro-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)acetam ide(SM-6a)

[0075]

[0076] Synthetic Method 4: SM-5 (1.00 g, 4.03 mmol) was added to a round-bottom flask, followed by SM-5a (0.74 g, 4.83 mmol) and cesium carbonate (2.63 g, 8.06 mmol), then DMF (15 mL). The mixture was stirred at room temperature for 1 h, and the reaction was monitored by TLC until completion. Equal volumes of ethyl acetate and water were added for three hydration extractions. The organic layers were combined and concentrated under low pressure to remove the solvent. The residue was purified by column chromatography (elution system: dichloromethane:methanol = 60:1, v / v) to obtain intermediate SM-6a as a yellow solid (0.84 g, yield: 65.5%). 1 HNMR(300MHz,DMSO-d6)δ8.27(d,J=2.5Hz,1H),7.96(s,1H),7.75(d,J=2.5Hz,1H),7.54 (s, 1H), 4.62 (s, 2H), 4.48 (t, J = 4.8Hz, 2H), 4.25 (t, J = 4.8Hz, 2H), 2.69 (d, J = 4.6Hz, 3H).

[0077] N,N-Dimethyl-2-((9-nitro-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)acetamide (SM-6b)

[0078] N,N-dimethyl-2-((9-nitro-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)ac etamide(SM-6b)

[0079]

[0080] Following general synthesis method 4, using SM-5 (1.00 g, 4.03 mmol) as the reactant, the target product, a yellow solid (0.84 g, yield: 65.5%), was obtained. 1 H 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).

[0081] 2-(9-amino-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)-N-methylacetamide (SM-7a)

[0082] 2-((9-amino-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylaceta mide(SM-7a)

[0083]

[0084] Synthetic Method 5: SM-6a (0.40 g, 1.25 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 to 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 to greater than 7. The mixture was filtered through diatomaceous earth, washed with dichloromethane:methanol = 20:1 (600 mL), and the filtrate was collected. The filtrate was concentrated under low pressure, extracted with ethyl acetate, and concentrated under reduced pressure to obtain a pale yellow solid SM-7a (0.24 g, yield: 67.0%). ESI-MS: m / z: [M+H] + 290.11.

[0085] 2-((9-amino-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)-N,N-dimethylacetamide (SM-7b)

[0086] 2-((9-amino-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N,N-dimethyla cetamide(SM-7b)

[0087]

[0088] Following general synthesis method 5, using SM-6b (0.40 g, 1.20 mmol) as the starting material, the target product, pale yellow solid SM-7b (0.23 g, yield: 63.5%), was obtained. ESI-MS: m / z: [M+H] + 304.12.

[0089] 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 (SM-9a)

[0090] 2-((9-((2,5-dichloropyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]qui nolin-6-yl)oxy)-N-methylacetamide(SM-9a)

[0091]

[0092] Synthetic Method 6: SM-7a (0.40 g, 1.38 mmol) and SM-8 (0.51 g, 2.77 mmol) were added to a round-bottom flask containing 20 mL of DMSO solution. DIPEA (0.54 g, 4.15 mmol) was added, and the mixture was heated at 100 °C for 3 h. The reaction was monitored by TLC until completion. After the reaction solution cooled to room temperature, 80 mL of water was added and the mixture was stirred for 30 min. The mixture was filtered, washed with water, and dried to obtain a yellow solid SM-9a (0.43 g, yield: 71.6%). ESI-MS: m / z: [M+H] + 436.04.

[0093] 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 (SM-9b)

[0094] 2-((9-((2,5-dichloropyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]qui nolin-6-yl)oxy)-N,N-dimethylacetamide(SM-9b)

[0095]

[0096] Following general synthetic method 6, using SM-7b (0.40 g, 1.38 mmol) and SM-8 (0.51 g, 2.77 mmol) as starting materials, the target product, yellow solid SM-9b (0.43 g, yield: 76.0%), was obtained. ESI-MS: m / z: [M+H] + 450.06.

[0097] Example 1

[0098] 2-(9-(5-chloro-2-(3R,5S)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)-N-methylacetamide (1)

[0099] 2-(((9-((5-chloro-2-((3R,5S)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-di hydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(1)

[0100]

[0101] Synthetic Method 7: SM-9a (0.05 mg, 0.12 mmol) and SM-10a (0.03 g, 0.23 mmol) were added to a round-bottom flask containing 4 mL DMSO, followed by DIPEA (0.05 g, 0.34 mmol). The mixture was heated at 100 °C for 10 h, and the reaction was monitored by TLC until completion. After the reaction solution cooled to room temperature, equal volumes of ethyl acetate and water were added for three extractions. The organic layers were combined and concentrated under low pressure to remove the solvent. The residue was subjected to column chromatography (elution system: dichloromethane:methanol = 60:1, v / v) to give product 1, a brown solid (0.02 g, yield: 35.7%). 1 H NMR (300MHz, DMSO-d6) δ8.74(s,1H),8.04(s,1H),7.94(s,1H),7.52(d,J=2.2Hz,1H),7. 47(d,J=2.2Hz,1H),7.15(s,1H),4.57(s,2H),4.51(d,J=12.9Hz,2H),4.40(t,J=4.7Hz, 2H), 4.19 (t, J = 4.8Hz, 2H), 2.68 (d, J = 4.7Hz, 3H), 2.31 (t, J = 12.1Hz, 2H), 1.79 (d, J = 12. 7Hz,1H),1.55(ddt,2H),0.89(d,J=6.6Hz,6H),0.81(q,J=12.0Hz,1H).HRMS(ESI):calcd for C 25 H 29 ClN6O4[M+H] + 513.00, found 513.2040 Purity: 94.99% by HPLC (MeOH / H2O = 80:20, t R =5.932min).

[0102] Example 2

[0103] 2-(9-(5-chloro-2-(2S,6R)-2,6-dimethylmorpholin-4-yl)pyrimidin-4-amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide (2)

[0104] 2-((9-((5-chloro-2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)amino)-5-oxo-2,3-dih ydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(2)

[0105]

[0106] Following general synthesis method 7, using SM-9a (0.05 mg, 0.12 mmol) as the reactant, the target product, brown solid 2 (18 mg, yield: 30.5%), was obtained. 1 H NMR (300MHz, DMSO-d6) δ8.89(s,1H),8.09(s,1H),7.99(s,1H),7.57(d,J=2.3Hz,1H),7.40(d,J=2.1Hz,1H),7.19(s,1H),4.58(s,2H),4.40(s,2 H),4.34(d,J=12.4Hz,2H),4.19(t,J=4.8Hz,2H),3.60–3.52(m,2H),2.68(d,J=4.6Hz,3H),2.48(s,2H),1.13(d,J=6.1Hz,6H).HRMS(ESI):calcd for C 24 H 27 ClN6O5[M+H] + 515.1731, found 515.1804.

[0107] Example 3

[0108] (S)-2-((9-((5-chloro-2-(3-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)-N-methylacetamide (3)

[0109] (S)-2-((9-((5-chloro-2-(3-methylpiperidin-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(3)

[0110]

[0111] Following general synthesis method 7, using SM-9a (0.05 mg, 0.12 mmol) as the reactant, the target product, brown solid 3 (23 mg, yield: 40.2%), was obtained. 1HNMR(300MHz,DMSO-d6)δ8.75(s,1H),8.01(d,J=11.5Hz,2H),7.56(s,1H),7.43(s,1H),7.12(s,1H),4.59(s,2H),4.40(s,4H),4.19(s,2H) ,3.48(s,1H),2.92–2.78(m,1H),2.76–2.62(m,3H),1.65(d,J=9.0Hz,1H),1.26(t,J=26.5Hz,4H),0.89(d,J=6.4Hz,3H).HRMS(ESI):calcd for C 24 H 27 ClN6O4[M+H] + 499.1782, found 499.1848.

[0112] Example 4

[0113] 2-((9-((5-chloro-2-(4-fluoropiperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)-N-methylacetamide(4)

[0114] 2-((9-((5-chloro-2-(4-fluoropiperidin-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(4)

[0115]

[0116] Following general synthesis method 7, using SM-9a (0.05 mg, 0.12 mmol) as the reactant, the target product, brown solid 4 (19 mg, yield: 33.0%), was obtained. 1H NMR (300MHz, DMSO-d6) δ8.97(s,1H),8.22(s,1H),8.16(t,J=6.0Hz,1H),7.73(d,J=2.2Hz,1H),7.49(d,J=2.2Hz,1H),7.24(s,1H),5.05(d,J=48 .6Hz,1H),4.75(s,2H),4.54(t,J=4.7Hz,2H),4.32(t,J=4.6Hz,2H),3. 96(s,2H),3.80(s,2H),2.81(d,J=4.6Hz,3H),2.06(s,2H),1.84(s,2H). HRMS(ESI):calcd forC 23 H 24 ClFN6O4[M+H] + 503.1532, found 503.1603.

[0117] Example 5

[0118] 2-((9-((5-chloro-2-(4-chloropiperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)-N-methylacetamide(5)

[0119] 2-((9-((5-chloro-2-(4-chloropiperidin-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(5)

[0120]

[0121] Following general synthesis method 7, using SM-9a (0.05 mg, 0.12 mmol) as the reactant, the target product, brown solid 5 (19 mg, yield: 31.9%), was obtained. 1HNMR(300MHz,DMSO-d6)δ8.82(s,1H),8.06(s,1H),8.00(d,J=4.8Hz,1H),7.56 (d,J=2.2Hz,1H),7.34(d,J=2.2Hz,1H),7.09(s,1H),4.59(s,2H),4.46(s,1H), 4.38(t,J=4.8Hz,2H),4.17(d,J=5.5Hz,2H),4.00(d,J=13.3Hz,2H),3.50(d,J =10.3Hz,2H),2.66(d,J=4.6Hz,3H),2.07(d,J=11.2Hz,2H),1.77–1.67(m,2H). HRMS(ESI):calcd for C 23 H 24 Cl2N6O4[M+H] + 519.1236, found 519.1289.

[0122] Example 6

[0123] 2-((9-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)-N-methylacetamide(6)

[0124] 2-((9-((5-chloro-2-(4,4-difluoropiperidin-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(6)

[0125]

[0126] Following general synthesis method 7, using SM-9a (0.05 mg, 0.12 mmol) as the reactant, the target product, a brown solid 6 (14 mg, yield: 23.4%), was obtained. 1HNMR(300MHz,DMSO-d6)δ8.89(s,1H),8.11(s,1H),8.00(d,J=5.0Hz,1H),7.59(d,J=2.2Hz,1H),7.31(d,J=2.1Hz,1H),7.11(s,1H ), 4.61 (s, 2H), 4.39 (t, J = 5.3Hz, 2H), 4.19 (t, J = 4.7Hz, 2H), 3.79 (d, J = 5.9Hz, 4H), 2.67 (d, J = 4.6Hz, 3H), 2.02 (d, J = 15.3Hz, 4H). HRMS(ESI):calcd for C 23 H 23 ClF2N6O4[M+H] + 521.1437, found 521.1509.

[0127] Example 7

[0128] (R)-2-((9-((5-chloro-2-(3-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)-N-methylacetamide(7)

[0129] (R)-2-((9-((5-chloro-2-(3-methylpiperidin-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(7)

[0130]

[0131] Following general synthesis method 7, using SM-9a (0.05 mg, 0.12 mmol) as the reactant, the target product, brown solid 7 (15 mg, yield: 26.2%), was obtained. 1HNMR(300MHz,DMSO-d6)δ8.75(s,1H),8.04(s,1H),7.98(d,J=5.3Hz,1H),7.5 6(d,J=2.1Hz,1H),7.44(d,J=2.0Hz,1H),7.12(s,1H),4.59(s,2H),4.39(d,J= 5.9Hz,4H),4.19(d,J=5.0Hz,2H),2.84(t,J=12.2Hz,1H),2.68(d,J=4.6Hz,3H ),2.57(s,1H),1.26(d,J=7.5Hz,4H),0.90(d,J=6.5Hz,3H).HRMS(ESI):calcd forC 24 H 27 ClN6O4[M+H] + 499.1782, found 499.1845.

[0132] Example 8

[0133] 2-((9-((5-chloro-2-(3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)-N-methylacetamide(8)

[0134] 2-(((9-((5-chloro-2-(3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dih ydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N-methylacetamide(8)

[0135]

[0136] Following general synthesis method 7, using SM-9a (0.05 mg, 0.12 mmol) as the reactant, the target product, a brown solid 8 (22 mg, yield: 37.3%), was obtained. 1HNMR(300MHz,Chloroform-d)δ8.13(s,1H),7.80(s,1H),7.15(m,2H),6.69(m,2H), 6.25(d,J=12.3Hz,1H),5.01(m,2H),4.76–4.67(d,2H),4.51(m,2H),3.64(m,J=12.5 ,1H),3.59(m,2H),3.32(m,J=14.1Hz,1H),3.07(m,J=7.0Hz,1H),2.83(d,3H),1.82 (m,1H),1.55(m,3H),1.48(m,J=13.2,1H),1.05(m,J=11.7Hz,1H).HRMS(ESI):calcd for C 24 H 27 ClN6O5[M+H] + 515.1731, found 515.1795.

[0137] Example 9

[0138] 2-((9-((5-chloro-2-((3R,5S)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-dihydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-6-yl)oxy)-N,N-dimethylacetamide(9)

[0139] 2-((9-((5-chloro-2-((3R,5S)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-5-oxo-2,3-di hydro-5H-[1,4]oxazino[2,3,4-ij]quinolin-6-yl)oxy)-N,N-dimethylacetamide(9)

[0140]

[0141] Following general synthesis method 7, using SM-9b (0.05 g, 0.11 mmol) as the reactant, the target product, brown solid 9 (25 mg, yield: 42.7%), was obtained. 1H NMR(300MHz,Chloroform-d)δ7.99(s,1H),7.49(d,J=2.1Hz,1H),7.30(d,J=1.8Hz,1 H),7.10(s,1H),4.85(s,2H),4.62(d,J=12.8Hz,2H),4.39(d,J=5.6Hz,2H),4.32(d,J =5.0Hz,2H),3.14(s,3H),2.96(s,3H),2.35(t,J=12.1Hz,2H),1.85(d,J=13.0Hz,1H ),1.69–1.64(m,2H),1.35(d,J=11.7Hz,1H),0.96(d,J=6.5Hz,6H).HRMS(ESI):calcd for C 26 H 31 ClN6O4[M+H] + 527.2095, found 527.2170.

[0142] Synthesis Route 2 :

[0143] Compound 10 was synthesized according to synthetic route 2.

[0144]

[0145] Synthetic Route 2. Reagents and Conditions: (a) 1,2-Dibromoethane, K2CO3, DMF, rt, 3h; (b) Pd / C, H2, MeOH, rt, 4h; (c) CDI, DMF, rt, 2h; (d) BBr3, DCM, 0℃, 4h; (e) Cs2CO3, CH3CN, 60℃, 1h; (f) BnNH2, LiHMDS, BrettPhos Pd G3, N2, THF, 80℃, 2h; (g) Pd / C, H2, MeOH, rt, 4h; (h) DIPEA, DMSO, 20℃, 3h; (i) DIPEA, DMSO, 100℃, 10h; (f) KI, Cs2CO3, DMSO, 80℃, 12h.

[0146] 4-Bromo-N-(2-Bromoethyl)-2-methoxy-6-nitroaniline (SM-11)

[0147] 4-bromo-N-(2-bromoethyl)-2-methoxy-6-nitroaniline(SM-11)

[0148]

[0149] Following general synthesis method 1, using B-1 (5.00 g, 20.24 mmol) and 1,2-dibromoethane A-1b (4.90 g, 26.31 mmol) as starting materials, the target product, yellow solid SM-11 (4.2 g, yield: 59.0%), was obtained. 1 H NMR (300MHz, Chloroform-d) δ6.85 (d, J = 2.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 3.94 (s, 3H), 3.60–3.49 (m, 4H).

[0150] 4-Bromo-N 1 2-Bromoethyl)-6-methoxyphenyl-1,2-diamine (SM-12)

[0151] 4-bromo-N 1 -(2-bromoethyl)-6-methoxybenzene-1,2-diamine(SM-12)

[0152]

[0153] Following synthetic route 2, SM-11 (4.20 g, 11.86 mmol) was added to a round-bottom flask containing 30 mL of methanol solution. Pd / C (10%, 0.30 g) was added, and the mixture was purged with hydrogen. The mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until completion. The mixture was filtered through diatomaceous earth, washed with methanol, and the organic phases were combined and concentrated under reduced pressure to give intermediate SM-12 as a pale yellow solid (3.62 g, yield: 94.2%). ESI-MS: m / z: [M+H] + 322.95.

[0154] 5-Bromo-1-(2-Bromoethyl)-7-methoxy-1,3-dihydro-2H-benzo[d]imidazol-2-one (SM-13)

[0155] 5-bromo-1-(2-bromoethyl)-7-methoxy-1,3-dihydro-2H-benzo[d]imidazol-2-one(SM-13)

[0156]

[0157] Following synthetic route 2, SM-12 (3.00 g, 9.26 mmol) was added to a round-bottom flask containing 30 mL of LDM solution, followed by CDI (2.61 g, 18.52 mmol). The mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC until completion. Equal volumes of ethyl acetate and water were added for three hydration extractions. The organic layers were combined and concentrated under low pressure to remove the solvent. The residue was purified by column chromatography (elution system: dichloromethane:methanol = 60:1, v / v) to obtain intermediate SM-13 as a yellow solid (1.81 g, yield: 55.8%). 1 H NMR (300MHz, Chloroform-d) δ7.05 (d, J = 1.5 Hz, 1H), 6.79 (d, J = 1.5 Hz, 1H), 3.94 (s, 3H), 3.60–3.53 (m, 2H), 3.46–3.39 (m, 2H).

[0158] 5-Bromo-1-(2-Bromoethyl)-7-hydroxy-1,3-dihydro-2H-benzo[d]imidazol-2-one (SM-14)

[0159] 5-bromo-1-(2-bromoethyl)-7-hydroxy-1,3-dihydro-2H-benzo[d]imidazol-2-one(SM-14)

[0160]

[0161] Following general synthesis method 2, using SM-13 (1.50 g, 4.29 mmol) as the starting material, the target product, yellow solid SM-14 (1.02 g, yield: 70.8%), was obtained. 1 HNMR (300MHz, Chloroform-d) δ6.97 (d, J = 1.5 Hz, 1H), 6.74 (d, J = 1.6 Hz, 1H), 3.61–3.53 (m, 2H), 3.48–3.40 (m, 2H).

[0162] 7-Bromo-3,4-dihydro-5-oxa-1,2a-diazathane-2(1H)-one (SM-15)

[0163] 7-bromo-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2(1H)-one(SM-15)

[0164]

[0165] Following general synthesis method 3, using SM-14 (1.50 g, 4.29 mmol) as the starting material, the target product, yellow solid SM-15 (0.51 g, yield: 67.6%), was obtained. 1 HNMR (300MHz, Chloroform-d) δ 7.14 (d, J = 1.5 Hz, 1H), 6.92 ( d, J = 1.4 Hz, 1H), 4.20 ( t, J = 4.9 Hz, 2H), 3.35 ( t, J = 4.8 Hz, 2H).

[0166] 7-(benzylamino)-3,4-dihydro-5-oxa-1,2a-diazathane-2(1H)-one (SM-16)

[0167] 7-(benzylamino)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2(1H)-one(SM-16)

[0168]

[0169] Following synthetic route 2, SM-15 (0.50 g, 1.96 mmol) was added to a sealed tube containing 10 mL of LDM solution. LiHMDS (1 M in THF, 4.70 mL, 4.70 mmol) was slowly added dropwise at room temperature, followed by argon purging. Then, BrettPhos (0.04 g, 0.08 mmol) and BrettPhos Pd G3 (0.04 g, 0.04 mmol) were added sequentially, followed by argon purging. The mixture was stirred at 80 °C for 2 h, and the reaction was monitored by TLC until completion. Equal volumes of ethyl acetate and water were added for three hydration extractions. The organic layers were combined and concentrated under low pressure to remove the solvent. The residue was purified by column chromatography (elution system: dichloromethane:methanol = 100:1, v / v) to obtain intermediate SM-16 as a yellow solid (0.36 g, yield: 65.5%). 1 HNMR (300MHz, Chloroform-d) δ7.41–7.29(m,5H),6.74(d,J=1.5Hz,1H),5.58(d,J=1.7Hz,1H),4.32(d,2H),4.20(t,J=4.9Hz,2H),3.35(t,J=4.9Hz,2H).

[0170] 7-Amino-3,4-dihydro-5-oxa-1,2a-diazathane-2(1H)-one (SM-17)

[0171] 7-amino-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2(1H)-one(SM-17)

[0172]

[0173] Following synthetic route 2, SM-16 (0.80 g, 2.84 mmol) was added to a round-bottom flask containing 10 mL of methanol solution. Pd / C (10%, 0.12 g) was added, and the mixture was purged with hydrogen. The mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until completion. The mixture was filtered through diatomaceous earth, washed with methanol, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (elution system: dichloromethane:methanol = 70:1, v / v) to give intermediate SM-17 as a yellow solid (0.49 g, yield: 90.1%). ESI-MS: m / z: [M+H] + 192.10.

[0174] 7-((2,5-dichloropyrimidin-4-yl)amino)-3,4-dihydro-5-oxa-1,2a-diazathane-2(1H)-one (SM-18)

[0175] 7-((2,5-dichloropyrimidin-4-yl)amino)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2(1H)-one(SM-18)

[0176]

[0177] Following general synthetic method 6, using SM-17 (1.00 g, 5.23 mmol) as the reactant, the target product, brown solid SM-18 (1.26 g, yield: 71.2%), was obtained. ESI-MS: m / z: [M+H] + 338.05.

[0178] 7-((5-chloro-2-((3R,5S)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3,4-dihydro-5-oxa-1,2a-diazathane-2(1H)-one (SM-19a)

[0179] 7-((5-chloro-2-((3R,5S)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3,4-dihydro-5-o xa-1,2a-diazaacenaphthylen-2(1H)-one(SM-19a)

[0180]

[0181] Following general synthesis method 7, using SM-18 (0.20 g, 0.59 mmol) as the reactant, the target product, brown solid SM-19a (0.13 g, yield: 53.0%), was obtained. 1 H NMR(300MHz,Chloroform-d)δ8.17(s,1H),6.81(d,J=1.5Hz,1H),6.54(d,J=1.5Hz,1H),4.39(m,J=6.0Hz,4H ), 4.19 (t, J = 5.0Hz, 2H), 3.67 (m, J = 12.4, 7.0Hz, 2H), 1.81–1.68 (m, J = 6.9Hz, 2H), 1.66 (m, 1H), 0.98 (m, 7H).

[0182] Example 10

[0183] 7-((5-chloro-2-((3R,5S)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-(3-hydroxy-3-methylbutyl)-3,4-dihydro-5-oxa-1,2a-diazathane-2(1H)-one (10)

[0184] 7-((5-chloro-2-((3R,5S)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-(3-hydroxy-3-methylbutyl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2(1H)-one(10)

[0185]

[0186] Following synthetic route 2, SM-19a (0.10 g, 0.24 mmol) and SM-19b (0.12 g, 0.48 mmol) were added to a round-bottom flask containing 5 mL DMSO. Potassium iodide (0.02 g, 0.12 mmol) and cesium carbonate (0.16 g, 0.48 mmol) were added, and the mixture was heated at 80 °C for 12 h. The reaction was monitored by TLC until completion. After the reaction solution cooled to room temperature, equal volumes of ethyl acetate and water were added for three-stage extraction. The organic layers were combined and concentrated under low pressure to remove the solvent. The residue was subjected to column chromatography (elution system: dichloromethane:methanol = 40:1, v / v) to give product 10 (0.03 g, yield: 24.8%), a brown solid. 1H NMR(300MHz,Chloroform-d)δ8.19(s,1H),6.81(d,J=2.0Hz,1H),6.54(d,J=2.0Hz,1H),4.28(m,4H),4.15(t,J=5.0 Hz, 2H), 3.68 (m, 4H), 1.86 (m, J = 13.4, 2H), 1.74 (m, J = 13.7, 2H), 1.66–1.57 (m, 1H), 1.29 (s, 6H), 0.98–0.86 (m, 7H). HRMS(ESI):calcd for C 25 H 29 ClN6O4[M+H] + 501.23, found 501.2324 Purity: 96.91% by HPLC (MeOH / H2O = 80:20, t R =4.671 min).

[0187] Pharmacological activity evaluation :

[0188] OCI-LY1 cells (Zhejiang Meisen Cell Technology Co., Ltd.) were seeded in 6-well plates, and then different concentrations of the compound were added. Twelve hours after drug administration, cells were collected by centrifugation, mixed with medium-efficiency RIPA lysis buffer (Beyotime Biotechnology), and lysed. The supernatant was collected by centrifugation, and protein concentration was determined by the BCA method. Protein samples were mixed with protein loading buffer (Beyotime Biotechnology) and heated dry at 100°C for 10 min for sample preparation. The samples were then added to a 12% polyacrylamide gel SDS-PAGE gel and electrophoresed at 60V until the marker left the stacking gel. Electrophoresis was continued at 120V, and the membrane was transferred to a wet transfer buffer containing 10% methanol for 90 min. The PVDF membrane was then cut into the desired bands, blocked with milk for 2 hours, and anti-BCL6 antibody (abcam) and β-Actin antibody (Proteintech) diluted with milk were added to the corresponding bands, respectively, and incubated overnight at 4°C. The next day, the primary antibody was washed away with TBST, and the secondary antibody was added and incubated at room temperature for 45 min. TBST was used to wash away the secondary antibody solution, and the membrane was scanned using the Odyssey Infrared Imaging System (LI-COR, Lincoln, Nebraska, USA). DC 50This refers to the concentration of the BCL6 degrading agent required to degrade 50% of the BCL6 protein. The calculation process is as follows: Starting from 1000 nM, the degrading agent was serially diluted 5-fold to nine concentrations. Western blotting was used to detect the degradation of BCL6 protein at each concentration. Grayscale analysis was performed using ImageJ software to calculate the remaining amount of BCL6. The DC was obtained by fitting the logarithm (Log(C)) of the remaining protein amount and concentration using Graphpad 8.0 software. 50 value.

[0189] Table 1. Degradation of BCL6 in OCI-LY1 cells by the compounds.

[0190]

Claims

1. A compound with a chemical structure as shown in Formula I, or a pharmaceutically acceptable salt or solvate thereof: in: X is -CH2-, -O-, -NH-, or -S-; n = 0, 1, or 2; R1 is a monosubstituted or polysubstituted heterocyclic group, wherein each substituent of the heterocyclic group is independently selected from -H, -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkoxy, -C1~C6 alkyl-O-C1~C6 alkyl, -C1~C6 alkyl-OH, -C1~C6 alkyl-NH2, -OH, -NH2, -COOH, -F, -Cl, -Br and -I; A is in: R2 and R3 are -L(CH2) k C = OR4 or Z is -CH= or -N=, where: L is -CH2-, -O-, -NH-, or -S-; k = 1, 2, or 3; R4 is -NR5R6, where R5 and R6 are independently selected from -H, -C1~C5 alkyl, -C2~C6 alkenyl, or -C2~C6 alkynyl, and N does not form a ring with the connected R5 or R6 or forms a 4-7 membered heterocycle; h = 1, 2, 3, or 4.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, characterized in that, The chemical structure is shown in Formula II: in: R1 is a monosubstituted or polysubstituted heterocyclic group, wherein each substituent of the heterocyclic group is independently selected from -H, -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkoxy, -C1~C6 alkyl-O-C1~C6 alkyl, -C1~C6 alkyl-OH, -C1~C6 alkyl-NH2, -OH, -NH2, -COOH, -F, -Cl, -Br and -I; A is in: R2 and R3 are -L(CH2) k C = OR4 or Z is -CH= or -N=, where: L is -CH2-, -O-, -NH- or -S-; k = 1, 2 or 3; R4 is -NR5R6, R5 and R6 are independently selected from -H, -C1~C5 alkyl, -C2~C6 alkenyl, -C2~C6 alkynyl, N does not form a ring with the connected R5 and R6 or forms a 4-7 membered heterocycle; h = 1, 2, 3 or 4.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, characterized in that, R1 is shown in Equation III: in: Y is -NH-, -O-, -S- or -C- substituted by R7 and R8, where R7 and R8 are independently selected from -H, -OH and halogen, respectively; R 1a R 1b R 1c R 1d R 1e R 1f R 1g R 1h The components are independently selected from -H, -C1~C6 alkyl, -C1~C6 haloalkyl, -C1~C6 alkoxy, -C1~C6 alkyl-O-C1~C6 alkyl, -C1~C6 alkyl-OH, -C1~C6 alkyl-NH2, -OH, -NH2, -COOH, -F, -Cl, -Br and -I.

4. The compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, characterized in that, The chemical structure of the compound is selected from:

5. Use of the compound of any one of claims 1 to 4 or its pharmaceutically acceptable salt or solvate for the preparation of a BCL6 protein degrading agent.

6. Use of the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating a disease, wherein the disease is a disease that is treated or alleviated by degrading BCL6 protein.

7. The use according to claim 6, characterized in that: The disease in question is cancer.

8. The use according to claim 7, characterized in that: The cancer is Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma, T-cell non-Hodgkin's lymphoma, NK / T-cell non-Hodgkin's lymphoma, or diffuse large B-cell lymphoma.

9. A pharmaceutical composition, characterized in that: It contains any of the compounds described in claims 1 to 4 or their pharmaceutically acceptable salts or solvates.

10. Use of the pharmaceutical composition of claim 9 for the preparation of a medicament for treating a disease, wherein the disease is a disease that is treated or alleviated by degrading BCL6 protein.

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