A naphthyridinone compound, pharmaceutical composition thereof and use thereof

Abstract

This invention discloses a naphthidone compound, its pharmaceutical composition, and its uses. The compound of this invention can effectively degrade the BRD8 protein in LNCAP cells and U87 cells, and exhibits certain anti-proliferative activity against LNCAP cells. Therefore, the above compound can be used to prepare drugs for the prevention and / or treatment of diseases related to the BRD8 protein, such as drugs for the prevention and / or treatment of glioblastoma, prostate cancer, etc.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a naphthidone compound, its pharmaceutical composition, and its uses. This type of compound can act as a BRD8 protein degrader, and can be used to prepare drugs for the prevention and / or treatment of diseases related to the BRD8 protein. Background Technology

[0002] Bromine-containing domain protein 8 (BRD8), a member of the bromine-containing domain protein family, can recognize and interact with acetylated histones, participating in the regulation of chromatin structure and gene transcription. BRD8 plays an important role in maintaining genome stability, promoting cell proliferation, and resisting apoptosis; in addition, abnormal expression of BRD8 is closely related to various diseases, such as tumors and inflammation.

[0003] Studies have shown (Nature. 2022, 613(7942):195-202) that the BRD8 protein maintains the occupation of histone H2AZ, the target site of the tumor suppressor gene p53, through the histone acetyltransferase complex EP400, thereby inhibiting the expression of p53 protein in glioblastoma and promoting the occurrence and development of glioblastoma. The BRD8 ISO2 protein has been reported as a strong co-activator of the androgen receptor (AR) in prostate cancer cells (LNCAP). MicroRNA-185 can attenuate AR function by inhibiting BRD8 ISO2; AR activation promotes prostate cancer cell growth and inhibits apoptosis in prostate cancer cells. Therefore, BRD8-targeted degradation holds promise for the treatment of tumors such as glioblastoma and prostate cancer.

[0004] Proteolytic targeted chimeras (PROTACs), as a novel drug development strategy, specifically degrade BRD8 by simultaneously binding to BRD8 and E3 ligases, utilizing the ubiquitin-proteasome system. This strategy exhibits high selectivity, specificity, and resistance to drug resistance. Hydrophobic tags (HyTs) are also a protein-targeting degradation technology. After binding to a protein, the hydrophobic tag mimics protein misfolding, causing the target protein to be degraded through the recruitment of chaperone proteins or the proteasome pathway; compared to PROTACs, hydrophobic tags show better drug-forming properties.

[0005] Currently, research on BRD8 mainly focuses on its biological functions, while research on targeting BRD8 is still in its early stages. Therefore, there is an urgent need to find new tools and methods for targeting BRD8. Summary of the Invention

[0006] Objective of the Invention: This invention aims to provide a class of naphthidone compounds, pharmaceutical compositions thereof, and uses. This invention utilizes PROTACs technology and hydrophobic tagging technology to develop a class of naphthidone compounds capable of acting as BRD8 protein degraders.

[0007] This invention involves linking hydrophobic tag fragments of different structures, along with E3 ligases CRBN and VHL ligands, to the BRD8 ligand to obtain hydrophobic tag degraders and PROTACs compounds with different structures. The effect of each compound on the BRD8 protein level in LNCAP cells and glioblastoma U87 cells was then detected by Western blotting. The effect of different compounds on the proliferation of LNCAP and U87 cells was further detected by CellTiter-Lumi luminescence assay.

[0008] One objective of this invention is to provide a naphthidone compound of general formula I or a pharmaceutically acceptable salt or solvate thereof:

[0009]

[0010] in,

[0011] A is selected from:

[0012]

[0013] L is selected from:

[0014]

[0015] In some preferred embodiments, the pharmaceutically acceptable salt includes, but is not limited to, salts formed by compounds of general formula I with the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, carbonic acid, tartaric acid, nitric acid, hydrobromic acid, hydroiodic acid, maleic acid, fumaric acid, citric acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, succinic acid, acetic acid, mandelic acid, isobutyric acid, or malonic acid.

[0016] The compounds of Formula I of the present invention are preferably the following compounds:

[0017]

[0018]

[0019] The compounds of Formula I involved in this invention can also exist in the form of their salts or solvates, which are converted into Formula I compounds in vivo. For example, within the scope of this invention, the compounds of this invention are converted into pharmaceutically acceptable salt forms according to processes known in the art, and used in salt form.

[0020] Another object of the present invention is to provide a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, and a pharmaceutically acceptable carrier thereof.

[0021] The pharmaceutical compositions of the present invention can be administered in various known ways, such as orally, parenterally, by inhalation spray, or via an implanted reservoir. The pharmaceutical compositions of the present invention can be administered alone or in combination with other drugs. Oral compositions can be any orally acceptable dosage form, including, but not limited to, tablets, capsules, emulsions, suspensions, dispersions, and solutions. Commonly used pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers, etc.

[0022] Sterile injectable compositions may be formulated using suitable dispersants or wetting agents and suspending agents in accordance with techniques known in the art. Pharmaceutically acceptable carriers and solvents that may be used include water, mannitol, sodium chloride solution, etc.

[0023] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and route of administration, and is non-toxic to the patient. The selected dosage level depends on a variety of factors, including the activity of the specific compound of the present invention or its salt used, the route of administration, the time of administration, the excretion rate of the specific composition used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the specific composition used, the age, sex, weight, general health condition, and medical history of the patient being treated, and similar factors known in the medical field.

[0024] Another object of the present invention is to provide the use of compounds of formula I or pharmaceutically acceptable salts or solvates thereof in the preparation of BRD8 protein degrading agents.

[0025] Another object of the present invention is to provide the use of compounds of formula I or pharmaceutically acceptable salts or solvates thereof in the preparation of medicaments for the prevention and / or treatment of diseases related to the BRD8 protein.

[0026] The relevant diseases are tumors and inflammation.

[0027] The tumors are colorectal cancer, glioblastoma, and prostate cancer.

[0028] Beneficial effects:

[0029] The compounds of Formula I prepared in this invention, along with their pharmaceutically acceptable salts and solvates, can effectively degrade BRD8 protein in LNCAP and U87 cells and exhibit certain anti-proliferative activity against LNCAP cells. Therefore, these compounds can be used to prepare drugs for the prevention and / or treatment of diseases related to BRD8 protein, such as drugs for the prevention and / or treatment of glioblastoma, prostate cancer, and other diseases. Detailed Implementation

[0030] The technical solution of the present invention will be described in detail below through specific embodiments, but the scope of protection of the present invention is not limited to the embodiments described.

[0031] The preparation method of the compound of general formula I of the present invention is described below with reference to specific embodiments, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art.

[0032] The starting materials and reaction reagents used in the specific embodiments of this invention are all commercially available. This invention can be prepared into a salt form using methods commonly used in the art, such as: dissolving the compound in hydrochloric acid-ethanol at room temperature to generate hydrochloride; or adding benzenesulfonic acid to generate benzenesulfonate.

[0033] Preparation of N-(3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthid-4-yl)benzyl)-N-methylglycine (intermediate 6)

[0034] The synthesis route is as follows:

[0035]

[0036] Reagents and conditions: (a) MeI, Cs2CO3, THF, rt., 3h; (b) Pd(dppf)Cl2·CH2Cl2, pinacol diboronate, potassium acetate, 1,4-dioxane, 90℃, 4h; (c) XPhosPdG2, Cs2CO3, 1,4-dioxane, H2O, 100℃, 12h; (d) tetraisopropyl titanate, sodium triacetoxyborohydride, rt., 3h; (e) TFA, DCM, rt., 24h; (f) HATU, DIPEA, DCM, rt., 3h.

[0037] (1) 4-Bromo-2-methyl-2,7-naphthidium-1(2H)-one (intermediate 2)

[0038]

[0039] Compound 1 (1 g, 4.44 mmol) was added to a round-bottom flask, followed by 30 mL of tetrahydrofuran solution, then cesium carbonate (2.89 g, 8.88 mmol), and iodomethane (1.26 g, 8.88 mmol) was added while stirring. After stirring at room temperature for 3 h, the reaction solution was concentrated and extracted with ethyl acetate and water. The organic phase was concentrated under reduced pressure to give intermediate 2 as a yellow solid (968 mg, yield 92%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 9.26 (s, 1H), 8.88 (s, 1H), 8.22 (s, 1H), 7.48 (s, 1H), 3.51 (s, 3H).

[0040] (2) 2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,7-naphthidium-1(2H)-one (intermediate 3)

[0041]

[0042] Intermediate 2 (900 mg, 3.77 mmol), pinacol diborate ester 2a (1.9 g, 7.53 mmol), potassium acetate (738 mg, 7.53 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (307 mg, 0.377 mmol) were dissolved in 10 mL of 1,4-dioxane in a Shrek tube. The air in the Shrek tube was replaced with dry argon gas. The reaction solution was in an oil bath at 90 °C for 8 h. After cooling to room temperature, the reaction solution was extracted with ethyl acetate and water. The organic phase was concentrated to give residue 3 (754 mg, yield 70%), which was directly added to the next reaction without further processing.

[0043] (3) 3,5-Dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthid-4-yl)benzaldehyde (intermediate 4)

[0044]

[0045] Intermediate 3 (700 mg, 2.45 mmol), 3a (9 mg, 3.67 mmol), cesium carbonate (1.19 g, 3.67 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (200 mg, 0.245 mmol) were dissolved in 20 mL of 1,4-dioxane in a Shrek tube. 5 mL of water was added, and the air in the Shrek tube was replaced with argon. The reaction mixture was incubated in an oil bath at 100 °C for 12 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate and water. The organic phase was concentrated, and the residue was purified by column chromatography (elution system: dichloromethane:methanol = 80:1, v / v) to give intermediate 4 (356 mg, yield 45%) as a white solid. 1 H NMR (300MHz, Chloroform-d) δ (ppm) 10.04 (s, 1H), 9.67 (s, 1H), 8.60 (s, 1H), 7.21 (s, 2H), 7.20 (s, 1H), 6.92-6.79 (m, 1H), 3.80 (s, 6H), 3.67 (s, 3H).

[0046] (4) Tert-butyl N-(3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthid-4-yl)benzyl)-N-methylglycine ester (intermediate 5)

[0047]

[0048] Intermediates 4 (356 mg, 1.09 mmol) and 4a (239 mg, 1.65 mmol) were added to a round-bottom flask containing 5 mL of MeOH. The air in the flask was replaced with dry argon gas. Tetraisopropyl titanate (312 mg, 1.09 mmol) was added, and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (699 mg, 3.27 mmol) was added. The reaction was monitored by TLC until it was complete. The reaction mixture was extracted with ethyl acetate and water. The organic phase was concentrated, and the residue was purified by column chromatography (elution system: dichloromethane:methanol = 50:1, v / v) to give intermediate 5 (423 mg, yield 85%) as a white solid. 1 H NMR(300MHz,Chloroform-d)δ(ppm)9.76(d,J=7.9Hz,1H),8.70(d,J=5.7Hz,1H),7.30(s,1H),7.03(d,J=5.8Hz,1H),6.87( d,J=5.1Hz,2H),3.97(s,2H),3.83(d,J=7.2Hz,6H),3.77(s,3H),3.43(d,J=6.0Hz,2H),2.66(s,3H),1.62(d,J=4.8Hz,9H).

[0049] (5) N-(3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthid-4-yl)benzyl)-N-methylglycine (intermediate 6)

[0050]

[0051] Intermediate 5 (423 mg, 0.93 mmol) was added to a round-bottom flask containing 5 mL of dichloromethane, followed by 5 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 24 h. The reaction was monitored by TLC until it ended. The reaction solution was concentrated to obtain residue 6 (352 mg, 95% yield). No further processing was required before it was added to the next reaction step.

[0052] Example 1: Preparation of (2R,4R)-1-((R)-15-(tert-butyl)-1-(3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyl-4-yl)phenyl)-2-methyl-4,13-dioxo-8,11-dioxa-2,5,14-triazahexadecan-16-acyl)-4-hydroxy-N-(4-(4-methylthiazo-5-yl)benzyl)pyrrolidine-2-carboxamide

[0053] The synthesis route is as follows:

[0054]

[0055] Reagents and conditions: (a) HATU, DIPEA, DCM, rt., 3h; (b) TFA, DCM, rt., 0.5h; (c) HATU, DIPEA, DCM, rt., 3h.

[0056] (1) tert-butyl(2-(2-(2-((R)-1-((2R,4R)-4-hydroxy-2-((4-(4-methylthiazo-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-2-oxoethoxy)ethoxy)amino)ethyl)carbamate (intermediate 8)

[0057]

[0058] Compound 7 (250 mg, 0.58 mmol) and compound 7a (199 mg, 0.76 mmol) were added to a round-bottom flask containing 8 mL of dichloromethane. DIPEA (150 mg, 1.16 mmol) and HATU (266 mg, 0.70 mmol) were added to the round-bottom flask while stirring. The mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC until it was complete. The reaction solution was extracted with ethyl acetate and water. The organic phase was concentrated, and the residue was purified by column chromatography (elution system: dichloromethane:methanol = 50:1, v / v) to give intermediate 8 (321 mg, yield 82%) as a white solid. 1 H NMR (300MHz, MeOD) δ (ppm) 8.87 (s, 1H), 7.89 (d, 3J = 9.2Hz, 1H), 7.47 (d, 3J = 8.3Hz, 2H), 7.44-7.39 (m, 2H), 4.66 (s,1H),4.56(dd,2J=20.9Hz,3J=12.2Hz,2H),4.50(s,1H),4.36(d,3J=15.5Hz,1H),3.89(d,3J=11.0Hz,1H),3. 80(dd,3J=11.0Hz,4J=3.9Hz,1H),3.74(dt,3J=10.9Hz,4J=5.3Hz,2H),3.60(s,4H),3.49(t,3J=5.6Hz,2H),3. 20(m,2H),2.58(m,1H),2.52-2.48(m,1H),2.48(s,3H),2.21(m,1H),2.09(m,1H),1.42(s,9H),1.04(s,9H)ppm.

[0059] (2)(2R,4R)-1-((R)-2-(2-(2-aminoethoxy)ethoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (intermediate 9)

[0060]

[0061] Intermediate 8 (321 mg, 0.48 mmol) was added to a round-bottom flask containing 5 mL of dichloromethane, followed by 5 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 0.5 h. The reaction was monitored by TLC until it was complete. The reaction solution was concentrated to obtain residue 9 (255 mg, 93% yield). No further processing was required before it was added to the next reaction step.

[0062] (3) Preparation of the target compound

[0063] Intermediate 9 (255 mg, 0.44 mmol) and intermediate 6 (175 mg, 0.44 mmol) were added to a round-bottom flask containing 5 mL of dichloromethane. DIPEA (170 mg, 1.32 mmol) and HATU (217 mg, 0.57 mmol) were added to the round-bottom flask while stirring. The mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC until it was complete. The reaction solution was extracted with ethyl acetate and water. The organic phase was concentrated, and the residue was purified by column chromatography (elution system: dichloromethane:methanol = 50:1, v / v) to give the target compound as a white solid (245 mg, yield 58%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 9.39 (s, 1H), 8.98 (s, 1H), 8.62 (s, 1H), 8.58 (d, J = 5.8Hz, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 7.47 -7.41(m,1H),7.39(s,4H),6.90-6.78(m,3H),5.17(d,J=3.4Hz,1H),4.57(d,J=9.5Hz,1H),4.44(t,J=8.2Hz,1H),4.35(d, J=5.6Hz,2H),4.26(dd,J=15.6,5.8Hz,1H),3.96(s,2H),3.66(s,6H),3.64-3.56(m,6H),3.55(s,3H),3.49(d,J=5.9Hz,4H ), 3.31 (s, 2H), 3.07 (s, 2H), 2.44 (d, J = 2.4Hz, 3H), 2.35 (s, 3H), 2.05 (d, J = 8.0Hz, 1H), 1.92 (d, J = 6.4Hz, 1H), 0.94 (s, 9H).

[0064] Example 2 Preparation of 2-((3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthid-4-yl)benzyl)(methyl)amino)-N-(4-((2-(2-6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyl)acetamide)acetamide

[0065] The synthesis route is as follows:

[0066]

[0067] Reagents and conditions: (a) DIPEA, DMSO, 90℃, 3h; (b) TFA, DCM, rt., 0.5h; (c) HATU, DIPEA, DCM, rt., 3h.

[0068] (1) tert-butyl(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyl)carbamate (intermediate 11a)

[0069]

[0070] Compound 10 (500 mg, 1.81 mmol) and compound 10a (442 mg, 2.36 mmol) were added to a Shrek tube containing 3 ml DMSO. DIPEA (701 mg, 5.43 mmol) was added, and the air in the Shrek tube was replaced with nitrogen. The mixture was in an oil bath at 90 °C for 3 h. The reaction was monitored by TLC until it was complete. The reaction mixture was extracted with ethyl acetate and water. The organic phase was concentrated, and the residue was purified by column chromatography (elution system: petroleum ether: ethyl acetate = 2:1, v / v) to give intermediate 11a (603 mg, yield 75%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.09 (s, 1H), 7.57 (t, J = 7.8Hz, 1H), 7.10 (d, J = 8.6Hz, 1 H),7.02(d,J=7.0Hz,1H),6.84(d,J=6.2Hz,1H),6.61-6.51(m,1H),5.05(dd,J=12.9, 5.4Hz,1H),3.30(d,J=6.2Hz,2H),2.95(d,J=6.3Hz,2H),2.90-2.81(m,1H),2.58(d,J =19.9Hz, 2H), 2.01 (t, J = 8.8Hz, 1H), 1.55 (t, J = 7.4Hz, 2H), 1.46 (s, 2H), 1.37 (s, 9H).

[0071] (2) 4-((4-aminobutyl)amino)-2-(2,6-dioxadiazine-3-yl)isoindoline-1,3-dione (12a)

[0072]

[0073] Following the method in step (2) of Example 1, intermediate 11a (603 mg, 1.36 mmol) was used as the raw material to react and obtain intermediate 12a (444 mg, yield 95%) as a yellow solid.

[0074] (3) Preparation of the target compound

[0075]

[0076] Following the method in step (1) of Example 1, using intermediate 12a (100 mg, 0.29 mmol) as a starting material, the target compound (113 mg, yield 54%) was reacted to obtain a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.10 (s, 1H), 9.39 (s, 1H), 8.58 (d, J = 5.6Hz, 1H), 8.01 (s, 1H), 7.60 (s, 1H) ,7.55(t,J=7.8Hz,1H),7.08(d,J=8.6Hz,1H),7.01(d,J=7.0Hz,1H),6.84(s,1H),6.83(s,2H),6.56(t,J =5.9Hz,1H),5.04(dd,J=12.8,5.4Hz,1H),3.65(s,8H),3.55(s,3H),3.30(s,2H),3.17(d,J=6.1Hz,2H), 3.01(s,2H),2.95-2.80(m,1H),2.57(d,J=19.4Hz,2H),2.30(s,3H),2.01(d,J=11.7Hz,1H),1.56(s,4H).

[0077] Example 3 Preparation of 2-((3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyl-4-yl)benzyl)(methyl)amino)-N-(8-((2-(2-6-dioxopiridin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)octyl)acetamide

[0078] (1) tert-butyl(8-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)octyl)carbamate (intermediate 11b)

[0079]

[0080] Following the method in step (1) of Example 2, compound 10 (500 mg, 1.81 mmol) was used as a starting material to react and obtain intermediate 11b (661 mg, yield 73%) as a yellow solid. 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.10 (s, 1H), 7.77 (s, 1H), 7.59 (t, J = 7.8Hz, 1H), 7.09 (d ,J=8.6Hz,1H),7.03(d,J=7.0Hz,1H),6.53(t,J=5.8Hz,1H),5.06(dd,J=12.8,5.3Hz,1 H),3.35-3.23(m,2H),2.89(ddd,J=18.8,14.1,5.4Hz,1H),2.76(p,J=6.4,6.0Hz,2H), 2.65-2.53(m,2H),2.07-2.00(m,1H),1.55(dt,J=16.0,7.6Hz,4H),1.40-1.13(m,17H).

[0081] (2) 4-((8-aminooctyl)amino)-2-(2,6-dioxadiazine-3-yl)isoindoline-1,3-dione (intermediate 12b)

[0082]

[0083] Following the method in step (2) of Example 1, intermediate 11b (661 mg, 1.32 mmol) was used as the raw material to react and obtain intermediate 12b (502 mg, yield 95%) as a yellow solid.

[0084] (3) Preparation of the target compound

[0085]

[0086] Following the method in step (1) of Example 1, using intermediate 12b (100 mg, 0.25 mmol) as a starting material, the target compound (115 mg, yield 59%) was reacted to obtain a yellow solid. 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.10 (s, 1H), 9.38 (s, 1H), 8.58 (d, J = 5.5Hz, 1H), 7.89 (s, 1H), 7.60 (s, 1H) ,7.55(t,J=7.8Hz,1H),7.05(d,J=8.6Hz,1H),7.00(d,J=7.0Hz,1H),6.88-6.79(m,3H),6.50(s,1H),5.13 -4.99(m,1H),3.66(s,6H),3.63(s,2H),3.54(s,3H),3.25(d,J=6.8Hz,2H),3.11(d,J=6.7Hz,2H),2.97(s ,2H),2.86(d,J=14.3Hz,1H),2.61(s,2H),2.30(s,3H),2.04(s,1H),1.48(d,J=31.4Hz,4H),1.26(s,8H).

[0087] Example 4 Preparation of 2-((3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyl-4-yl)benzyl)(methyl)amino)-N-(12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)dodecyl)acetamide)acetamide

[0088] (1) tert-butyl(12-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)dodecyl)carbamate (intermediate 11c)

[0089]

[0090] Following the method in step (1) of Example 2, compound 10 (500 mg, 1.81 mmol) was used as a starting material to react and obtain intermediate 11c (705 mg, 70% yield) as a yellow solid. 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.09 (s, 1H), 7.61-7.49 (m, 1H), 7.08 (dd, J = 8.7, 2.4Hz, 1H), 7.01 (dd, J = 7.2, 2.5Hz, 1H), 6.74 (s, 1H), 6.52 (t, J = 5.7Hz ,1H),5.13-4.97(m,1H),3.28(d,J=7.1Hz,2H),2.87(q,J=7.2Hz,3H),2.58 (d, J=17.9Hz, 2H), 2.02 (d, J=11.5Hz, 1H), 1.56 (s, 4H), 1.37-1.19 (m, 25H).

[0091] (2) 4-((12-aminododecyl)amino)-2-(2,6-dioxadiazine-3-yl)isoindoline-1,3-dione (intermediate 12c)

[0092]

[0093] Following the method in step (2) of Example 1, intermediate 11c (705 mg, 1.27 mmol) was used as the raw material to react and obtain intermediate 12c (548 mg, yield 95%) as a yellow solid.

[0094] (3) Preparation of the target compound

[0095]

[0096] Following the method in step (1) of Example 1, using intermediate 12c (100 mg, 0.22 mmol) as a starting material, the target compound (95 mg, yield 52%) was reacted to obtain a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ(ppm)11.10(s,1H),9.38(s,1H),8.58(s,1H),7.89(s,1H ),7.57(d,J=12.4Hz,2H),7.05(d,J=16.5Hz,2H),6.83(s,3H),6.51(s,1H),5.04 (d,J=12.2Hz,1H),3.65(s,8H),3.54(s,3H),3.10(s,2H),2.97(s,2H),2.89(s,1 H), 2.29 (s, 3H), 2.01 (d, J = 12.2Hz, 1H), 1.54 (s, 2H), 1.40 (s, 2H), 1.20 (s, 16H).

[0097] Example 5 Preparation of 2-((3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyl-4-yl)benzyl)(methyl)amino)-N-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-)dioxopiridine-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)ethoxy)ethyl)acetamide)acetamide

[0098] The synthesis route is as follows:

[0099]

[0100] Reagents and conditions: (a) DIPEA, DMSO, 90℃, 3h; (b) TFA, DCM, rt., 0.5h; (c) HATU, DIPEA, DCM, rt., 3h.

[0101] (1) tert-butyl(2-(2-((2-(2-(2-6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)ethoxy)carbamate (intermediate 13)

[0102] Following the method in step (1) of Example 2, using compound 10 (500 mg, 1.81 mmol) as a starting material, intermediate 13 (638 mg, 70% yield) was reacted to obtain a yellow solid. 1 H NMR (300MHz, Chloroform-d) δ (ppm) 8.45 (s, 1H), 7.50 (dd, J = 8.5, 7.1Hz, 1H), 7.11 (d,J=7.1Hz,1H),6.91(d,J=8.5Hz,1H),6.53(s,1H),5.00(d,J=41.4Hz,1H),3.73 (t,J=5.3Hz,2H),3.65(s,4H),3.57(t,J=5.3Hz,2H),3.48(t,J=5.3Hz,2H),3.32( d, J=5.4Hz, 2H), 2.91-2.73 (m, 3H), 2.13 (td, J=7.5, 6.6, 3.0Hz, 1H), 1.43 (s, 9H).

[0103] (2) 4-((2-(2-(2-)aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 14)

[0104] Following the method in step (2) of Example 1, intermediate 13 (600 mg, 1.19 mmol) was used as the raw material to react and obtain intermediate 14 (457 mg, yield 95%) as a yellow solid.

[0105] (3) Preparation of the target compound

[0106] Following the method in step (1) of Example 1, using intermediate 14 (100 mg, 0.25 mmol) as a starting material, the target compound (118 mg, yield 61%) was reacted to obtain a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.10 (s, 1H), 9.38 (s, 1H), 8.58 (d, J = 5.5Hz, 1H), 7.91 (s, 1H), 7.59 (d, J = 3 .9Hz,1H),7.55(d,J=7.8Hz,1H),7.11(d,J=8.6Hz,1H),7.03(d,J=7.1Hz,1H),6.83(d,J=6.1Hz,3H),6.60 (s,1H),5.14-4.95(m,1H),3.66(s,6H),3.63-3.56(m,4H),3.54(d,J=3.8Hz,5H),3.49-3.41(m,4H),3.29 (s, 4H), 3.00 (s, 2H), 2.86 (d, J = 14.3Hz, 1H), 2.57 (d, J = 17.6Hz, 2H), 2.30 (s, 3H), 2.01 (d, J = 13.4Hz, 1H).

[0107] Example 6 Preparation of 4-(4-((1-(N-(3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthidin-4-yl)benzyl)-N-methylglycyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxoperidin-3-yl)isoindoline-1,3-dione

[0108] The synthesis route is as follows:

[0109]

[0110] Reagents and conditions: (a) DIPEA, DMSO, 90℃, 3h; (b) TFA, DCM, rt., 0.5h; (c) HATU, DIPEA, DCM, rt., 3h.

[0111] (1) tert-butyl 4-((4-(2-(2-6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperazin-1-yl)methyl)piperidin-1-carboxylate (intermediate 15)

[0112] Compound 10 (500 mg, 1.81 mmol) and compound 10e (809 mg, 2.36 mmol) were added to a Shrek tube containing 3 ml DMSO. DIPEA (701 mg, 5.43 mmol) was added, and the air in the Shrek tube was replaced with nitrogen. The mixture was in an oil bath at 90 °C for 3 h. The reaction was monitored by TLC until it was complete. The reaction mixture was extracted with ethyl acetate and water. The organic phase was concentrated, and the residue was purified by column chromatography (elution system: dichloromethane:methanol = 100:1, v / v) to give intermediate 15 (585 mg, yield 60%) as a yellow solid. 1 HNMR (300MHz, DMSO-d6) δ (ppm) 11.08 (s, 1H), 7.69 (dd, J = 8.4, 7.2Hz, 1H), 7.17-7 .44(m,2H),5.08(dd,J=12.8,5.4Hz,1H),3.91(d,J=11.6Hz,2H),3.28(s,4H),2.8 4-2.92(m,1H),2.65-2.76(m,2H),2.60(d,J=2.8Hz,2H),2.50-2.55(m,4H),2.18 (d,J=6.8Hz,2H),1.97-2.07(m,1H),1.67(s,3H),1.38(s,9H),0.86-1.05(m,2H).

[0113] (2) 2-(2,6-dioxadipinidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione (intermediate 16)

[0114] Following the method in step (2) of Example 1, intermediate 15 (500 mg, 0.93 mmol) was used as the raw material to react and obtain intermediate 16 (386 mg, yield 95%) as a yellow solid.

[0115] (3) Preparation of the target compound

[0116] Following the method in step (1) of Example 1, using intermediate 16 (100 mg, 0.23 mmol) as a starting material, the target compound (84 mg, yield 45%) was reacted to obtain a yellow solid. 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.10 (s, 1H), 9.38 (s, 1H), 8.58 (d, J = 5.5Hz, 1H), 7.60 (s, 1H), 7.55 (t, J = 7.8Hz, 1H), 7.05(d,J=8.6Hz,1H),7.00(d,J=7.0Hz,1H),6.88-6.79(m,3H),5.13-4.99(m,1H),3.91(d,J=11.6Hz,2H),3.66(s,6 H),3.63(s,2H),3.54(s,3H),3.28(s,4H),3.11(d,J=6.7Hz,2H),2.84-2.92(m,1H),2.65-2.76(m,2H),2.60(d,J=2 .8Hz,2H),2.50-2.55(m,4H),2.30(s,3H),2.18(d,J=6.8Hz,2H),1.97-2.07(m,1H),1.67(s,3H),0.86-1.05(m,2H). Example 7: Preparation of N-(3-((3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyl-4-yl)benzyl)(methyl)amino)propyl)-2,2,2-triphenylacetamide

[0117] The synthesis route is as follows:

[0118]

[0119] Reagents and conditions: (a) Tetraisopropyl titanate, sodium triacetoxyborohydride, rt., 3h; (b) TFA, DCM, rt., 0.5h; (c) HATU, DIPEA, DCM, rt., 3h.

[0120] (1) tert-butyl(3-((3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyl-4-yl)benzyl)(methyl)amino)propyl)amino)carbamate (intermediate 17)

[0121] Intermediates 4 (356 mg, 1.09 mmol) and 4b (309 mg, 1.65 mmol) were added to a round-bottom flask containing 5 ml of MeOH. The air in the flask was replaced with dry argon gas. Tetraisopropyl titanate (312 mg, 1.09 mmol) was added, and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (699 mg, 3.27 mmol) was added. The reaction was monitored by TLC until it was complete. The reaction mixture was extracted with ethyl acetate and water. The organic phase was concentrated, and the residue was purified by column chromatography (elution system: dichloromethane:methanol = 50:1, v / v) to give intermediate 17 (463 mg, yield 85%) as a white solid. 1 H NMR(300MHz,Chloroform-d)δ(ppm)9.75-9.56(m,1H),8.58(d,J=5.6Hz,1H),7.18(s,1H),7.01-6.85(m,1H),6.67(s,2H),3.71 (s,6H),3.64(s,3H),3.55(s,2H),3.24(q,J=6.3Hz,2H),2.50(t,J=6.7Hz,2H),2.30(s,3H),1.75(q,J=6.6Hz,2H),1.43(s,9H).

[0122] (2) 4-(4-(((3-aminopropyl)(methyl)amino)methyl)-2,6-dimethoxyphenyl)-2-methyl-2,7-naphthyl-1(2H)-one (Intermediate 18)

[0123] Following the method in step (2) of Example 1, intermediate 17 (400 mg, 0.80 mmol) was used as the raw material to react and obtain intermediate 18 (303 mg, yield 95%) as a white solid.

[0124] (3) Preparation of the target compound

[0125]

[0126] Following the method in step (1) of Example 1, using intermediate 18 (100 mg, 0.25 mmol) as a starting material, the target compound (91 mg, yield 54%) was reacted to obtain a white solid. 1H NMR (300MHz, DMSO-d6) δ (ppm) 9.38 (s, 1H), 8.52 (d, J = 5.6Hz, 1H), 7.53 (s, 1H), 7.30-7.23 (m, 9H), 7.22 (s, 1H), 7.20-7.16 (m, 6H), 6.80 ( d,J=5.6Hz,1H),6.72(s,2H),3.61(s,6H),3.51(s,3H),3.47(s,2H),3.24(s,2H),2.30(t,J=7.1Hz,2H),2.12(s,3H),1.69-1.57(m,2H).

[0127] Example 8: Preparation of (3r, 5r, 7r)-N-(3-((3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyl-4-yl)benzyl)(methyl)amino)propyl)adamantane-1-carboxamide

[0128]

[0129] Following the method in step (1) of Example 1, using intermediate 18 (100 mg, 0.25 mmol) as a starting material, the target compound (79 mg, yield 56%) was reacted to obtain a white solid. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 9.39 (s, 1H), 8.59 (s, 1H), 7.58 (s, 1H), 7.44 (s, 1H), 6.84 (d, J = 5.7Hz, 3H), 3.65 (s, 8H),3.55(s,3H),3.15-3.10(m,2H),2.30(s,2H),1.93(s,3H),1.78(s,3H),1.74-1.71(m,6H),1.66-1.62(m,8H).

[0130] Example 9 Preparation of N-(3-((3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyl-4-yl)benzyl)(methyl)amino)propyl)bicyclo[2.2.1]heptane-2-carboxamide

[0131]

[0132] Following the method in step (1) of Example 1, using intermediate 18 (100 mg, 0.25 mmol) as a starting material, the target compound (72 mg, yield 55%) was reacted to obtain a white solid. 1H NMR (300MHz, DMSO-d6) δ (ppm) 9.40 (s, 1H), 8.60 (d, J = 5.6Hz, 1H), 7.83 (s, 1 H),7.61(s,1H),7.08(s,2H),6.86(d,J=5.6Hz,1H),3.69(s,8H),3.56(s,3 H),3.13(s,2H),2.72(s,1H),2.29-2.11(m,4H),1.92(d,J=27.5Hz,3H),1. 70(d,J=11.8Hz,1H), 1.51(d,J=21.1Hz,2H), 1.37(dd,J=34.6,6.3Hz,7H).

[0133] Example 10: Preparation of (S)-N-(3-((3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyl-4-yl)benzyl)(methyl)amino)propyl)-2-(4-isobutylphenyl)propionamide

[0134]

[0135] Following the method in step (1) of Example 1, using intermediate 18 (100 mg, 0.25 mmol) as a starting material, the target compound (78 mg, yield 53%) was reacted to obtain a white solid. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 9.39 (s, 1H), 8.58 (d, J = 5.5Hz, 1H), 7.91 (d, J = 5.6Hz, 1H), 7.60 (s, 1H), 7. 21(d,J=7.7Hz,2H),7.05(d,J=7.8Hz,2H),6.84(d,J=5.6Hz,1H),6.75(s,2H),3.64(d,J=4.0Hz,6H),3. 56(d,J=2.6Hz,3H),3.51(d,J=7.0Hz,2H),3.11(q,J=6.5Hz,2H),2.54(s,1H),2.38(d,J=7.1Hz,5H),2. 16(s,2H),1.77(dt,J=13.4,6.7Hz,1H),1.69-1.54(m,2H),1.29(d,J=7.2Hz,3H),0.83(d,J=6.6Hz,6H).

[0136] Example 11 Preparation of N-(3-((3,5-dimethoxy-4-(2-methyl-1-oxy-1,2-dihydro-2,7-navthioglycoside-4-acyl)phenyl)(methyl)amino)propyl)-2-(9H-fluoroen-9-acyl)acetamide)

[0137]

[0138] Following the method in step (1) of Example 1, using intermediate 18 (100 mg, 0.25 mmol) as a starting material, the target compound (76 mg, yield 50%) was reacted to obtain a white solid. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 9.38 (s, 1H), 8.55 (d, J = 5.6Hz, 1H), 7.98 (s, 1H) ,7.86(d,J=7.5Hz,2H),7.59(s,1H),7.50(d,J=7.5Hz,2H),7.37(t,J=7.4Hz,2 H),7.26(t,J=7.5Hz,2H),6.84(d,J=5.7Hz,1H),6.80(s,2H),4.34(d,J=7.3H z,1H),3.66(s,6H),3.54(s,5H),3.30-3.24(m,2H),2.24(s,3H),1.72(s,2H).

[0139] Example 1: Preparation of 2N-(3-((3,5-dimethoxy-4-(2-methyl-1-oxy-1,2-dihydro-2,7-navthioglycoside-4-acyl)phenyl)(methyl)amino)propyl)-2-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxy)acetamide

[0140]

[0141] Following the method in step (1) of Example 1, using intermediate 18 (100 mg, 0.25 mmol) as a starting material, the target compound (83 mg, yield 56%) was reacted to obtain a white solid. 1H NMR(300MHz,Chloroform-d)δ(ppm)9.77(s,1H),8.71(d,J=5.6Hz,1H),7.34(d,J=6.3Hz,1H),7.30(s,1H),7.03(d,J =5.6Hz,1H),6.84(s,2H),4.21(d,J=14.9Hz,1H),3.98(d,J=15.0Hz,1H),3.83(s,6H),3.76(d,J=6.4Hz,5H),3.58-3 .48(m,2H),3.28(td,J=10.6,4.1Hz,1H),2.69(s,2H),2.50(s,3H),2.29(td,J=7.1,2.7Hz,1H),2.24-2.08(m,2H),1 .97(q,J=8.6,6.7Hz,2H),1.83-1.76(m,2H),1.50(dd,J=15.1,12.7Hz,4H),1.06-1.01(m,6H),0.91(d,J=6.9Hz,3H). Example 13 Preparation of N-(3-((3,5-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthid-4-yl)benzyl)(methyl)amino)propyl)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0142]

[0143] Following the method in step (1) of Example 1, using intermediate 18 (100 mg, 0.25 mmol) as a starting material, the target compound (72 mg, yield 55%) was reacted to obtain a white solid. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 9.41 (s, 1H), 8.60 (d, J = 5.6Hz, 1H), 7.61 (d, J = 1 .3Hz,1H),6.88(s,1H),6.86(s,2H),6.11(dt,J=8.8,2.7Hz,2H),5.78(dd,J=5 .7,2.8Hz,1H),3.68(s,6H),3.57(s,5H),3.13(s,4H),2.81(s,1H),2.76(s,1 H), 2.28-2.19 (m, 2H), 2.07-1.94 (m, 3H), 1.70 (ddd, J = 25.5, 12.0, 7.3Hz, 5H).

[0144] Example 14 Pharmacological Activity Evaluation

[0145] 1. BRD8 protein degradation test

[0146] The antibody anti-BRD8 (AB17969) used in this experiment was purchased from Abcam, and βeta-Actin (66009-1-Ig) was purchased from Proteintech. First, LNCAP cells (Zhejiang Meisen Cell Technology Co., Ltd.) or glioblastoma cells (U87 cells) (Shanghai Cell Bank) were cultured in 96-well plates, and different concentrations of the test compound were added (initial concentration 3 uM, serial dilution 7 times in 3-fold series, dosage: 2 μL of compound added to 2 ml of cells per well).

[0147] After 12 hours of drug treatment, cells were collected by centrifugation and then lysed using medium-efficiency RIPA lysis buffer (Beyotime Biotechnology). The lysed cell solution was centrifuged at 12,000 rpm for 15 min at 4°C, and the supernatant was used to determine protein concentration using the BCA method.

[0148] Next, the protein samples with the determined concentrations were mixed with protein loading buffer (Beyotime Biotechnology) and heated at 100°C for 10 minutes to prepare electrophoresis samples. The samples were then loaded onto a 12% polyacrylamide gel for SDS-PAGE electrophoresis. The initial electrophoresis voltage was 90V until the protein markers left the stacking gel, then the voltage was increased to 150V to continue electrophoresis. After electrophoresis, the samples were transferred to a PVDF membrane containing 10% methanol. After transfer, the PVDF membrane was sheared to separate the target protein bands and blocked in milk solution for 2 hours to reduce non-specific binding. The membrane bands were then incubated overnight at 4°C with anti-BRD8 antibody and β-eta-Actin antibody diluted in milk. The next day, the samples were washed three times with TBST for 10 minutes each time to remove the primary antibody, and then incubated with secondary antibody (Mybioscience, Goat anti-rabbit IgG Antibody / Goat anti-mouse IgG Antibody) at room temperature for 1 hour. The samples were then washed three times with TBST to remove the secondary antibody solution. Finally, the membrane was scanned and analyzed using the Odyssey Infrared Imaging System (LI-COR, Lincoln, Nebraska, USA).

[0149] DC 50 The value refers to the concentration of the degrading agent required to degrade the BRD8 protein by 50%. This is used to calculate DC. 50We started with a 1000 nM degradation agent and serially diluted it 5-fold to nine different concentrations, then used Western blotting to detect the effect of each concentration on BRD8 protein degradation. ImageJ software was used for grayscale analysis of the bands to calculate the remaining amount of BRD8 protein. Then, Graphpad 8.0 software was used to fit the logarithm of the remaining protein amount to the concentration to obtain the DC (degradation concentration). 50 value.

[0150] Experimental results:

[0151] The specific results are shown in Table 1.

[0152] DC 50 <100nM (denoted as: A); DC 50 =100-500nM (denoted as: B); DC 50 >500 nM (denoted as C) Table 1 Degradation of intracellular BRD8 by compounds

[0153]

[0154] 2. Cell anti-proliferation activity test

[0155] First, LNCAP cells (Zhejiang Meisen Cell Technology Co., Ltd.) or glioblastoma cells (U87 cells) (Shanghai Cell Bank) in logarithmic growth phase were seeded into 96-well plates (Corning, 3799) at a density of 5000 cells per well. 100 μL of RPMI 1640 medium (Adamas C8016) containing 20% ​​FBS was added to each well. The cells were incubated overnight at 37°C with 5% CO2.

[0156] The next day, we added 100 μL of an initial concentration of 3 μM, serially diluted 7 times (3-fold) to each well, with three replicate wells for each concentration, labeled RLU. test We also included control wells and blank wells. The control wells contained cells, culture medium, and the same concentration of drug solvent, labeled RLU. control The blank wells contained only culture medium and were labeled RLU. blankAfter 9 days of culture, we aspirated 100 μL of cell suspension from each well and transferred it to a black 96-well plate (Shanghai Wohong Biotechnology Co., Ltd., WHB-96-02), adding 100 μL of CellTiter-Lumi luminescent cell viability assay kit (Beyotime Biotechnology). After mixing the reagent with the cells, we incubated the plate on a shaker in the dark for 10 minutes before assaying. For adherent cells, we aspirated and discarded 100 μL of culture medium from each well and added 100 μL of assay reagent to each 96-well plate. After lysing on a shaker for 2 minutes, we transferred the solution from each well to a 96-well black plate and incubated it on a shaker in the dark for 8 minutes before assaying.

[0157] The chemiluminescence module on a Thermo Scientific Varioflash was used to determine the chemiluminescence values. The formula for calculating cell viability is:

[0158] Cell viability (%) = (RLU) test -RLU blank ) / (RLU control -RLU blank ()×100%, IC calculated using GraphpadPrism 8.0 software. 50 value.

[0159] Experimental results:

[0160] The specific results are shown in Table 2.

[0161] IC 50 <100nM (denoted as: A); IC 50 =100-500nM (denoted as: B); IC 50 >500nM (denoted as: C)

[0162] Table 2. Antiproliferative activity of compounds against cells

[0163]

[0164]

[0165] As described above, although the invention has been shown and described with reference to specific preferred embodiments, it should not be construed as limiting the invention itself. Various changes in form and detail may be made without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. A naphthyridinone compound or a pharmaceutically acceptable salt thereof, characterized by Selected from: ； ； 。 2. The compound of claim 1, wherein The pharmaceutically acceptable salts include salts formed by compounds of general formula I with the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, carbonic acid, tartaric acid, nitric acid, hydrobromic acid, hydroiodic acid, maleic acid, fumaric acid, citric acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, succinic acid, acetic acid, mandelic acid, isobutyric acid, or malonic acid.

3. A pharmaceutical composition, characterized by, It comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

4. Use of the compound of claim 1 in the preparation of a BRD8 protein degrader.

5. Use of a naphthidone compound in the preparation of a medicament for treating prostate cancer, said compound having one of the following structural formulas: ； 。 6. Use of a naphthidinone compound in the preparation of a medicament for treating glioblastoma, said compound having one of the following structural formulas: ； 。

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