Naphthyridinone compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a naphthyridinone compound as well as a pharmaceutical composition and application thereof. The compound provided by the invention can effectively degrade BRD8 protein in LNCAP cells and U87 cells, and has certain anti-proliferative activity on the LNCAP cells. Therefore, the compound can be used for preparing medicines for preventing and / or treating diseases related to the BRD8 protein, such as medicines for preventing and / or treating diseases such as glioblastoma and prostatic cancer.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a naphthyridone compound, a pharmaceutical composition and use thereof. The compound can be used as a BRD8 protein degrader for preparing a drug for preventing and / or treating diseases related to the BRD8 protein. Background Art

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

[0003] Studies have shown (Nature.2022, 613(7942):195-202) that BRD8 protein maintains the occupancy of histone H2AZ at the target site of the tumor suppressor gene p53 through the histone acetyltransferase complex EP400, inhibits the expression of glioblastoma p53 protein, and promotes the occurrence and development of glioblastoma. BRD8 ISO2 protein is reported to be a strong co-activator of androgen receptor (AR) in prostate cancer cells (LNCAP). MicroRNA-185 can weaken AR function by inhibiting BRD8 ISO2, and AR activation promotes prostate cancer cell growth and inhibits prostate cancer cell apoptosis. Therefore, BRD8 targeted degradation is expected to be applied to the treatment of tumors such as glioblastoma, prostate cancer, etc.

[0004] As a new drug development strategy, proteolysis targeting chimeras (PROTACs) use the ubiquitin-proteasome system to specifically degrade BRD8 by simultaneously binding to BRD8 and E3 ligase. This strategy is highly selective, specific, and resistant to drug resistance. Hydrophobic tags (HyT) are also a protein-targeted degradation technology. After the hydrophobic tag binds to the protein, it simulates misfolded proteins, causing the target protein to be degraded by recruiting chaperone proteins or the proteasome pathway; compared with PROTACs, hydrophobic tags have better drugability.

[0005] Currently, the research on BRD8 mainly focuses on its biological function, and the research on targeting BRD8 is still in its early stages. Therefore, it is urgent to find new tools and methods to target BRD8. Summary of the invention

[0006] Purpose of the invention: The present invention aims to provide a naphthyridinone compound, a pharmaceutical composition and use thereof. The present invention utilizes PROTACs technology and hydrophobic tag technology to develop a class of naphthyridinone compounds that can be used as BRD8 protein degraders.

[0007] The present invention connects hydrophobic tag fragments of different structures and E3 ligase CRBN ligand and VHL ligand to BRD8 ligand to obtain hydrophobic tag degraders and PROTACs compounds of different structures. Then, the effect of each compound on the BRD8 protein level in LNCAP cells and glioblastoma U87 cells was detected by Western Blot method. And the effect of different compounds on the proliferation of LNCAP cells and U87 cells was detected by CellTiter-Lumi luminescence method.

[0008] One of the purposes of the present invention is to provide a naphthyridinone 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 salts include, but are not limited to, salts formed by the compound of formula I and 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 above-mentioned compounds of formula I of the present invention may also exist in the form of their salts and solvates, which are converted into compounds of formula I in vivo. For example, within the scope of the present invention, the compounds of the present invention are converted into pharmaceutically acceptable salt forms according to processes known in the art, and they are used in the form of salts.

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

[0021] The pharmaceutical composition 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 composition of the present invention can be administered alone or in combination with other drugs. Oral compositions can be in 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, adhesives, colorants, fillers, emulsifiers, etc.

[0022] Sterile injectable compositions can be formulated using suitable dispersing agents or wetting agents and suspending agents according to techniques known in the art. Pharmaceutically acceptable carriers and solvents that can be used include water, mannitol, sodium chloride solution, and the like.

[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 the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The dosage level selected 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 and previous medical history of the patient being treated, and similar factors well known in the medical field.

[0024] Another object of the present invention is to provide a use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in the preparation of a BRD8 protein degrader.

[0025] Another object of the present invention is to provide use of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof in the preparation of a drug for preventing and / or treating diseases associated with the BRD8 protein.

[0026] The related diseases are tumor and inflammation.

[0027] The tumor is colorectal cancer, glioblastoma, or prostate cancer.

[0028] Beneficial effects:

[0029] The compound of formula I prepared by the present invention and its pharmaceutically acceptable salt and solvate can effectively degrade BRD8 protein in LNCAP cells and U87 cells, and has certain anti-proliferation activity on LNCAP cells. Therefore, the above compound can be used to prepare drugs for preventing and / or treating diseases related to BRD8 protein, such as preparing drugs for preventing and / or treating diseases such as glioblastoma and prostate cancer. DETAILED DESCRIPTION

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

[0031] The preparation method of the compound of general formula I of the present invention is described below in conjunction with specific examples, but these specific methods do not constitute any limitation to the present invention. The compound 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 a combination can be easily carried out by a technician in the field to which the present invention belongs.

[0032] The starting materials, reaction reagents, etc. used in the specific embodiments of the present invention are all commercially available. The present invention can be prepared in the form of salt by using a salt-forming method commonly used in the art, for example, dissolving the compound in hydrochloric acid ethanol at room temperature to react to generate a hydrochloride; or adding benzenesulfonic acid to react to generate a benzenesulfonate.

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

[0034] The synthetic route is as follows:

[0035]

[0036] Reagents and conditions: (a) MeI, Cs2CO3, THF, rt., 3h; (b) Pd(dppf)Cl2·CH2Cl2, diboronic acid pinacol ester, 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-naphthyridin-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, and then cesium carbonate (2.89 g, 8.88 mmol) was added, 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 obtain 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-dioxaborolan-2-yl)-2,7-naphthyridin-1(2H)-one (Intermediate 3)

[0041]

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

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

[0044]

[0045] In a Shrek tube, intermediate 3 (700 mg, 2.45 mmol), 3a (9 mg, 3.67 mmol), cesium carbonate (1.19 g, 3.67 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (200 mg, 0.245 mmol) were dissolved in 20 mL 1,4-dioxane, and 5 mL water was added. The air in the Shrek tube was replaced with argon. The reaction solution was in an oil bath at 100°C for 12 h. The reaction solution was cooled to room temperature and 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 obtain 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-naphthyridin-4-yl)benzyl)-N-methylglycinate (Intermediate 5)

[0047]

[0048] Intermediate 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, and the air in the flask was replaced with dry argon. 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, and the reaction was monitored by TLC. The reaction solution was extracted with ethyl acetate and water, and the organic phase was concentrated. The residue was purified by column chromatography (elution system: dichloromethane: methanol = 50: 1, v / v) to obtain 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-naphthyridin-4-yl)benzyl)-N-methylglycine (Intermediate 6)

[0050]

[0051] The intermediate 5 (423 mg, 0.93 mmol) was added to a round-bottom flask containing 5 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 24 h. The reaction was completed after monitoring by TLC. The reaction solution was concentrated to obtain the residue 6 (352 mg, yield 95%), which was directly used for the next step without further treatment.

[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-triazahexadecane-16-yl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0053] The synthetic route is as follows:

[0054]

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

[0056] (1) tert-Butyl (2-(2-(2-((R)-1-((2R,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-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 completed after monitoring by TLC. 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 obtain 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)acetylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Intermediate 9)

[0060]

[0061] The intermediate 8 (321 mg, 0.48 mmol) was added to a round-bottom flask containing 5 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 0.5 h. The reaction was completed after monitoring by TLC. The reaction solution was concentrated to obtain the residue 9 (255 mg, yield 93%), which was directly used for the next step without further treatment.

[0062] (3) Preparation of 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 completed after monitoring by TLC. 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 obtain 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-naphthyridin-4-yl)benzyl)(methyl)amino)-N-(4-((2-(2-6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)acetamide)acetamide

[0065] The synthetic route is as follows:

[0066]

[0067] Reagents and conditions: (a) DIPEA, DMSO, 90°C, 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-dioxoisoindolin-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 of DMSO, and DIPEA (701 mg, 5.43 mmol) was added. The air in the Shrek tube was replaced with nitrogen, and the mixture was placed in an oil bath at 90°C for 3 h. The reaction was completed after monitoring by TLC. The reaction solution was extracted with ethyl acetate and water, and the organic phase was concentrated. The residue was purified by column chromatography (elution system: petroleum ether: ethyl acetate = 2:1, v / v) to obtain 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-dioxopiperidin-3-yl)isoindoline-1,3-dione (12a)

[0072]

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

[0074] (3) Preparation of target compound

[0075]

[0076] According to the method of step (1) of Example 1, intermediate 12a (100 mg, 0.29 mmol) was used as the starting material to obtain the target compound (113 mg, yield 54%) as 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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)acetamide

[0078] (1) tert-Butyl (8-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamate (Intermediate 11b)

[0079]

[0080] According to the method of step (1) of Example 2, compound 10 (500 mg, 1.81 mmol) was used as starting material to 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-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 12b)

[0082]

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

[0084] (3) Preparation of target compound

[0085]

[0086] According to the method of step (1) of Example 1, intermediate 12b (100 mg, 0.25 mmol) was used as starting material to obtain the target compound (115 mg, yield 59%) as 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-dioxoisoindolin-4-yl)amino)dodecyl)acetamide)acetamide

[0088] (1) tert-Butyl (12-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecyl)carbamate (Intermediate 11c)

[0089]

[0090] According to the method of step (1) of Example 2, compound 10 (500 mg, 1.81 mmol) was used as the starting material to give intermediate 11c (705 mg, yield 70%) 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-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 12c)

[0092]

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

[0094] (3) Preparation of target compound

[0095]

[0096] According to the method of step (1) of Example 1, intermediate 12c (100 mg, 0.22 mmol) was used as the starting material to obtain the target compound (95 mg, yield 52%) as 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-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)acetamide)acetamide

[0098] The synthetic route is as follows:

[0099]

[0100] Reagents and conditions: (a) DIPEA, DMSO, 90°C, 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-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)carbamate (Intermediate 13)

[0102] According to the method of step (1) of Example 2, compound 10 (500 mg, 1.81 mmol) was used as starting material to give intermediate 13 (638 mg, yield 70%) as 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] According to the method of step (2) of Example 1, intermediate 13 (600 mg, 1.19 mmol) was used as a raw material to obtain intermediate 14 (457 mg, yield 95%) as a yellow solid.

[0105] (3) Preparation of target compound

[0106] According to the method of step (1) of Example 1, intermediate 14 (100 mg, 0.25 mmol) was used as the starting material to obtain the target compound (118 mg, yield 61%) as 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-naphthyridin-4-yl)benzyl)-N-methylglycol)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0108] The synthetic route is as follows:

[0109]

[0110] Reagents and conditions: (a) DIPEA, DMSO, 90°C, 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-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidine-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 of DMSO, and DIPEA (701 mg, 5.43 mmol) was added. The air in the Shrek tube was replaced with nitrogen, and the mixture was placed in an oil bath at 90°C for 3 h. The reaction was completed after monitoring by TLC. The reaction solution was extracted with ethyl acetate and water, and the organic phase was concentrated. The residue was purified by column chromatography (elution system: dichloromethane: methanol = 100: 1, v / v) to obtain 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-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione (Intermediate 16)

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

[0115] (3) Preparation of target compound

[0116] According to the method of step (1) of Example 1, intermediate 16 (100 mg, 0.23 mmol) was used as the starting material to obtain the target compound (84 mg, yield 45%) as 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 synthetic 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] Intermediate 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, and the air in the flask was replaced with dry argon. 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, and the reaction was monitored by TLC. The reaction solution was extracted with ethyl acetate and water, and the organic phase was concentrated. The residue was purified by column chromatography (elution system: dichloromethane: methanol = 50: 1, v / v) to obtain 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] According to the method of step (2) of Example 1, intermediate 17 (400 mg, 0.80 mmol) was used as a starting material to obtain intermediate 18 (303 mg, yield 95%) as a white solid.

[0124] (3) Preparation of target compound

[0125]

[0126] According to the method of step (1) of Example 1, intermediate 18 (100 mg, 0.25 mmol) was used as the starting material to obtain the target compound (91 mg, yield 54%) as 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] According to the method of step (1) of Example 1, intermediate 18 (100 mg, 0.25 mmol) was used as the starting material to obtain the target compound (79 mg, yield 56%) as 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] According to the method of step (1) of Example 1, intermediate 18 (100 mg, 0.25 mmol) was used as the starting material to obtain the target compound (72 mg, yield 55%) as 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] According to the method of step (1) of Example 1, intermediate 18 (100 mg, 0.25 mmol) was used as the starting material to obtain the target compound (78 mg, yield 53%) as 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-nafurfuryl-4-yl)phenyl)(methyl)amino)propyl)-2-(9H-fluoroen-9-yl)acetamide

[0137]

[0138] According to the method of step (1) of Example 1, intermediate 18 (100 mg, 0.25 mmol) was used as the starting material to obtain the target compound (76 mg, yield 50%) as 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 12 Preparation of N-(3-((3,5-dimethoxy-4-(2-methyl-1-oxy-1,2-dihydro-2,7-nafurfuryl-4-yl)phenyl)(methyl)amino)propyl)-2-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxy)acetamide

[0140]

[0141] According to the method of step (1) of Example 1, intermediate 18 (100 mg, 0.25 mmol) was used as the starting material to obtain the target compound (83 mg, yield 56%) as 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-naphthyridin-4-yl)benzyl)(methyl)amino)propyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0142]

[0143] According to the method of step (1) of Example 1, intermediate 18 (100 mg, 0.25 mmol) was used as the starting material to obtain the target compound (72 mg, yield 55%) as 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 Evaluation of Pharmacological Activity

[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 test compounds of different concentrations (initial concentration 3uM, 3-fold gradient dilution 7 times, dosage: 2ul compound added to 2ml cells per well) were added.

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

[0148] Next, the protein samples with the determined concentration were mixed with protein loading buffer (Biyuntian Biotechnology) and heated at 100°C for 10 minutes to prepare the electrophoresis samples. The samples were then loaded into a 12% polyacrylamide gel for SDS-PAGE electrophoresis, with an initial electrophoresis voltage of 90V until the protein markers left the concentrated gel of the gel, and then the voltage was increased to 150V to continue electrophoresis. After the electrophoresis was completed, the membrane was transferred (PVDF) in an electrophoresis buffer containing 10% methanol. After the transfer was completed, the PVDF membrane was cut to separate the target protein bands and blocked in a milk solution for 2 hours to reduce nonspecific binding. After that, the membrane bands were incubated with anti-BRD8 antibodies and βeta-Actin antibodies diluted in milk at 4°C overnight. The next day, the primary antibody was washed off with TBST three times for 10 minutes each time, and the secondary antibody (Mybioscience, Goat anti-rabbitIgG Antibody / Goat anti-mouse IgG Antibody) was added and incubated at room temperature for 1 hour. Wash three times with TBST to wash off the secondary antibody solution. Finally, the membranes were scanned and analyzed using the Odyssey Infrared Imaging System (LI-COR, Lincoln, Nebraska, USA).

[0149] DC 50 The values ​​refer to the concentration of degradant required to degrade BRD8 protein by 50%. 50We started with 1000 nM of the degradant and diluted it 5-fold to 9 different concentrations. We then used Western Blot to detect the effect of each concentration on BRD8 protein degradation. We used Image J software to perform grayscale analysis on the bands to calculate the remaining amount of BRD8 protein. Then, we used Graphpad 8.0 software to fit the logarithm of the protein remaining amount and the concentration to obtain DC. 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 >500nM (denoted as: C) Table 1 Degradation effect of compounds on intracellular BRD8

[0153]

[0154] 2. Cell antiproliferative activity test

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

[0156] On the second day, we added 100uL of the drug solution with an initial concentration of 3uM and 3-fold gradient dilution 7 times to each well. Three replicate wells were set for each concentration and marked as RLU. test At the same time, we also set up control wells and blank wells. The control wells contain cells, culture medium, and the same concentration of drug solvent, marked as RLU control ; while blank wells contain only culture medium and are labeled as RLU blank. After 9 days of culture, we aspirated 100uL of cell suspension from each well, transferred it to a black 96-well plate (Shanghai Wohong Biotechnology Co., Ltd., WHB-96-02), and added 100uL of CellTiter-Lumi Luminescent Cell Viability Detection Kit (Biyuntian Biotechnology). After the reagent was mixed with the cells, it was incubated on a shaker in the dark for 10 minutes before detection. For adherent cells, we aspirated 100uL of culture medium from each well and discarded it, and then added 100uL of detection reagent to the 96-well plate. After lysis on a shaker for 2 minutes, the solution in the well was transferred to a 96-well black plate and incubated on a shaker in the dark for 8 minutes before detection.

[0157] The chemiluminescence value was determined using the chemiluminescence module on the Thermo Scientific Varioflash. The cell viability was calculated as follows:

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

[0159] Experimental results:

[0160] See Table 2 for specific results.

[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 on cells

[0163]

[0164]

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

Claims

1. A naphthyridinone compound of general formula I or a pharmaceutically acceptable salt or solvate thereof: in, A is selected from: L is selected from:

2. The compound according to claim 1, characterized in that Selected from:

3. The compound according to claim 1, characterized in that The pharmaceutically acceptable salts include salts of the compound of formula I formed 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.

4. A pharmaceutical composition, characterized in that It comprises the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

5. Use of the compound according to any one of claims 1 to 3 in the preparation of a BRD8 protein degrader.

6. Use of the compound according to any one of claims 1 to 3 in the preparation of a medicament for preventing and / or treating a disease associated with the BRD8 protein.

7. The use according to claim 6, characterized in that The related diseases are tumor and inflammation.

8. The use according to claim 7, characterized in that The tumor is colorectal cancer, glioblastoma, or prostate cancer.

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