Glutarimide derivatives and their use

Abstract

The application discloses a series of glutarimide derivatives and application thereof, and specifically discloses a compound shown in formula (VI-1), a stereoisomer or a pharmaceutically acceptable salt thereof.

Description

[0001] This application claims priority to Chinese patent application 2024110486039, filed on 2024 / 07 / 31. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to a series of glutarimide derivatives and their applications, particularly to compounds of formula (VI-1), their stereoisomers, or pharmaceutically acceptable salts thereof. Background Technology

[0003] G1 to S phase transition 1 (GSPT1) is a GTPase that forms a complex with eRF1, regulating protein translation termination. GTP hydrolysis of GSPT1 promotes a conformational change in eRF1, releasing the protein from the ribosome; therefore, GSPT1 is a crucial regulatory protein for protein translation. GSPT1 is widely distributed in various tissues and plays an important role in both normal cellular physiological functions and tumorigenesis. Downregulation of GSPT1 can lead to abnormal expression of key proteins in various tumor cells, inhibiting cell proliferation or inducing apoptosis. Studies have shown that GSPT1 is overexpressed in various tumors, such as colon cancer, acute myeloid leukemia, gastric cancer, liver cancer, breast cancer, ovarian cancer, glioma, and prostate cancer. Other studies have shown that GSPT1 expression levels are correlated with the survival of cancer patients. In recent years, GSPT1 has attracted much attention as a target for anti-cancer therapy. Many companies have begun to study GSPT1 degrading agents (such as MRT-2359, CC-90009, CC-885, etc.). Among them, ORUM has developed several products that link GSPT1 degrading agents with antibodies, such as ORM-5029 linked with Her2 antibody and ORM-6151 linked with CD33 antibody. These products are currently in the early stages of clinical development and are intended to treat hematologic malignancies or solid tumors. Clinical proof of concept has not yet been completed.

[0004] Therefore, the development of novel small molecule GSPT1 degrading agents still has significant clinical application potential and broad development prospects. Summary of the Invention

[0005] This invention discloses a series of small molecule GSPT1 degrading agents, which are glutarimide derivatives substituted with 1,2,5-thiadiazole groups. They have novel structures and excellent in vitro and in vivo pharmaceutical properties.

[0006] This invention provides compounds of formula (VI-1), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0007]

[0008] in,

[0009] Each R2 is independently selected from H, F, Cl, or C substituted with 1, 2, or 3 F atoms. 1-3 Alkyl groups and C atoms optionally substituted with 1, 2 or 3 F atoms 1-3 Alkoxy;

[0010] R a1 Selected from H and F;

[0011] n is selected from 1, 2, and 3.

[0012] In some technical solutions of the present invention, the above-mentioned structural units Selected from Other variables are as defined in this invention.

[0013] In some technical solutions of the present invention, the above-mentioned structural units Selected from Other variables are as defined in this invention.

[0014] In some technical solutions of the present invention, each of the above R2 is independently selected from H, F, Cl, CH3, CF3, OCH3 and OCF3, and other variables are as defined in the present invention.

[0015] In some technical solutions of the present invention, each of the above-mentioned R2 is independently selected from F, Cl, CH3 and OCH3, and other variables are as defined in the present invention.

[0016] Some technical solutions of this invention are derived from arbitrary combinations of the above-mentioned variables.

[0017] The present invention also provides the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0018]

[0019] The present invention also provides a pharmaceutical composition comprising the compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0020] The present invention also provides the use of the above-mentioned compounds, their stereoisomers, their pharmaceutically acceptable salts, or combinations thereof in the preparation of medicaments for treating GSPT1-related cancers, inflammations, autoimmune diseases, or immune disorders.

[0021] Technical effect

[0022] The compounds of this invention exhibit significant degradation activity against GSPT-1 protein in both 22RV-1 and BT-474 cells, and significant inhibitory activity against BT-474 cell proliferation. They demonstrate good metabolic stability in mouse and human liver microsomes, and show no significant inhibitory effect on the five major cytochrome P450 enzymes in human liver microsomes. They exhibit low clearance rate in mouse pharmacokinetics, high oral exposure, and high oral bioavailability, demonstrating excellent pharmacokinetic properties and great potential for oral drug development. In the human lung cancer NCI-H1155 pharmacodynamic model, they showed good tumor-suppressing effects, good tolerability in mice, and high safety.

[0023] In summary, the compounds of this invention possess excellent in vitro activity, good pharmacokinetic properties, and significant in vivo efficacy, and represent a novel, orally administered GSPT1 degrader.

[0024] Definitions and Explanations

[0025] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0026] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0027] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention, prepared by reacting a compound having specific substituents, as discovered in the present invention, with a relatively non-toxic acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in their free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both.

[0028] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0029] The compounds of this invention can exist in specific tautomers. Unless otherwise stated, the term "tautomer" or "tautomer form" refers to a functional group isomer resulting from the rapid movement of one or more atoms in a molecule between two positions. A tautomer is a special type of functional group isomer. A pair of tautomers can interconvert, but usually the more stable isomer is the dominant form. Different functional group isomers are in dynamic equilibrium and can rapidly interconvert. If tautomers are possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the rearrangement of some bonding electrons. For example, a specific instance of keto-enol tautomerization is the tautomerization between two tautomers: pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0030] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0031] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0032] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0033] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0034] Unless otherwise stated, the terms "rich in one isomer," "isomer enrichment," "rich in one enantiomer," or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0035] Unless otherwise stated, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0036] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0037] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0038] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0039] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0040] The solvents used in this invention are commercially available. Compounds are named according to conventional naming principles in the art or using… Software naming conventions are used; commercially available compounds use supplier catalog names. Attached Figure Description

[0041] Figure 1 : Changes in tumor volume in mice after administration of compound 7 in the NCI-H1155 pharmacodynamic model. Detailed Implementation

[0042] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

[0043] Intermediate 1

[0044]

[0045] Step 1: Under a nitrogen atmosphere at room temperature, compound M2-1 (sodium cyanide, 9.44 g, 192.62 mmol) was dissolved in ethanol (62.5 mL) and water (87.5 mL). The solution was cooled to -15 °C, and chlorine gas was slowly introduced while potassium hydroxide (354 mg, 6.31 mmol) in water (25 mL) was slowly added dropwise until the addition was complete. The chlorine gas was then stopped, and the reaction solution was slowly heated to 25 °C and stirred for 12 hours. The reaction solution was purged with nitrogen gas until the chlorine gas was completely expelled. Then, ethyl acetate was added for extraction (50 mL × 2). The organic phases were combined and washed with water (100 mL). The solution was dried over anhydrous potassium carbonate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M2-2. 1 H NMR (400MHz, DMSO-d6) δ = 8.73 (br s, 2H), 4.15 (q, J = 6.8Hz, 4H), 1.26 (t, J = 7.2Hz, 6H).

[0046] Step 2: Under a nitrogen atmosphere at room temperature, compound M2-2 (2 g, 13.87 mmol) and pyridine (3.53 mL, 43.70 mmol) were dissolved in dichloromethane (20 mL). The reaction solution was cooled to 10 °C, and thionyl chloride (1.73 g, 14.57 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to 25 °C and stirred for 1 hour. Dilute the reaction solution with dichloromethane (100 mL), wash with water (100 mL × 2), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound M2. 1 HNMR (400MHz, CDCl3) δ = 4.59-4.51 (m, 4H), 1.49 (t, J = 7.2Hz, 6H).

[0047] Intermediate 2

[0048]

[0049] Step 1: Under a nitrogen atmosphere, bromosuccinimide (1.87 g, 10.52 mmol) and azobisisobutyronitrile (133 mg, 809 μmol) were added to a dichloromethane (50 mL) solution of compound M6-1 (2 g, 8.10 mmol), and the reaction was carried out at 80 °C for 17 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 0 / 1 to 20 / 1) to obtain compound M6-2. 1 H NMR (400MHz, CDCl3) δ = 7.71-7.66 (m, 1H), 7.63-7.56 (m, 1H), 5.01 (d, J = 2.1Hz, 2H), 3.96 (s, 3H).

[0050] Step 2: Under a nitrogen atmosphere, compound M6-3 (1.34 g, 10.43 mmol, HCl) and diisopropylethylamine (3.63 mL, 20.86 mmol) were added to dimethylformamide (68 mL), and stirred at 120 °C for 5 minutes. Then, a solution of compound M6-2 (1.7 g, 5.22 mmol) in dimethylformamide (5 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at 120 °C for 1 hour. The reaction solution was cooled to room temperature, and water (150 mL) was added. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 - 0 / 1) to obtain compound M6-4. LCMS (m / z): 341.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ=11.02(br s,1H),7.95-7.80(m,1H),7.54(d,J=8.1Hz,1H),5.12(dd,J=5.0,13.3Hz,1H),4.72-4.32(m,2H),2.97-2.82(m,1H),2.60(br d,J=17.4Hz,1H),2.46-2.33(m,1H),2.05-1.94(m,1H).

[0051] Step 3: Solution 1: Under a nitrogen atmosphere, compound M6-4 (2.55 g, 7.48 mmol), 2-{[(tert-butoxy)carbonyl]amino}acetic acid (2.62 g, 14.95 mmol), 4,4-di-tert-butyl-2,2-bipyridine nickel chloride (II) (149 mg, 373.7 μmol), [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine N1,N1']bis [3,5-Difluoro-2-[5-(trifluoromethyl)-2-pyridylN]phenylC]iridium hexafluorophosphate(III) (CAS: 870987-63-6, 167.73 mg, 149.50 μmol), phthalimide (1.10 g, 7.48 mmol) and 2-tert-butyl-1,1,3,3-tetramethylguanidine (1.28 g, 7.48 mmol) were dissolved in dimethyl sulfoxide (51 mL). The reaction was performed at 40°C for 2 hours using photofluid chemistry: Solution 1 was pumped into flow reactor 1 [FLR1, FEP, coil reactor, 3.175 (1 / 8”) mm, 20.096 mL, 40°C] at a flow rate of 20.096 mL / min using pump 1 (P1). The residence time in flow reactor 1 was FLR1, 1 min. A 450 nm, 600 W lamp was turned on. The reaction solution was collected in a bottle. Samples were taken for analysis after 120 minutes.

[0052] After the reaction was complete, water (60 mL) was added, and the mixture was extracted with ethyl acetate (300 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by reversed-phase column chromatography (column: Phenomenex luna C18 (250 × 70 mm, 10 μm); mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 40%-70%) to give compound M6-5. LCMS (m / z): 392.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 11.00 (s, 1H), 7.62-7.45 (m, 3H), 5.11 (dd, J = 5.1, 13.3Hz, 1H), 4.58-4.35 (m, 2H), 4.27 (br d,J=5.9Hz,2H),2.97-2.84(m,1H),2.63-2.57(m,1H),2.46-2.33(m,1H),2.04-1.96(m,1H),1.45-1.21(m,9H).

[0053] Step 4: Under a nitrogen atmosphere at room temperature, add compound M6-5 (200 mg, 511.00 μmol), acetonitrile (0.5 mL), and dioxane hydrochloride (2 M, 2.00 mL) to a dry reaction flask. React the mixture at room temperature for half an hour. Filter the reaction mixture, add acetonitrile (2 mL) to the filter cake, stir at room temperature for 10 min, filter again, and dry the filter cake to obtain crude hydrochloride of compound M6.

[0054] Example 1

[0055]

[0056] Step 1: Under a nitrogen atmosphere and at room temperature, compound M2 (500 mg, 2.63 mmol) and compound 1-1 (372.20 mg, 2.63 mmol) were added to 10 mL of anhydrous ethanol, followed by zinc trifluoromethanesulfonate (95.55 mg, 262.85 μmol). The reaction mixture was heated to 40 °C and reacted for 12 hours. The mixture was filtered, and the filter cake was washed with ethanol (5 mL) and dried to obtain compound 5-2. LCMS (m / z): 286.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.46 (s, 1H), 8.06 (d, J = 2.4Hz, 1H), 7.77 (dd, J = 2.4, 8.4H z, 1H), 7.39 (d, J = 8.8Hz, 1H), 4.63-4.49 (m, 2H), 2.31 (s, 3H), 1.45 (t, J = 7.2Hz, 3H).

[0057] Step 2: Under a nitrogen atmosphere and at room temperature, compound 5-2 (150 mg, 524.94 μmol) and compound 2-1 (325.19 mg, 1.05 mmol, hydrochloride) were added to 2 mL of N,N-dimethylacetamide, followed by 4-dimethylaminopyridine (320.66 mg, 2.62 mmol). The reaction mixture was reacted at 25 °C for 12 hours. After filtration, the filter cake was washed with acetonitrile (2 mL), and then water (1 mL) was added to the filter cake. The mixture was stirred at room temperature for 10 min, filtered again, and then acetonitrile (1 mL) was added to the filter cake. The mixture was stirred at room temperature for 10 min, filtered again, and the filter cake was dried to obtain compound 5'. LCMS (m / z): 513.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6)δ=10.98(br s,1H),10.18(br s,1H),9.11-8.80(m,1H),8.01(br s,1H),7.75(br d,J=6.8Hz,1H),7.67(brs,1H),7.62-7.49(m,2H),7.40(br d,J=6.4Hz,1H),5.19-5.05(m,1H),4.75(br s,2H),4.47(br d,J=17.2Hz,1H),4.40-4.29(m,1H),2.97-2.85(m,1H),2.62(br d,J=1.6Hz,1H),2.43-2.36(m,1H),2.31(br s,3H),2.01(br d,J=2.8Hz,1H).

[0058] Step 3: Under a nitrogen atmosphere and at room temperature, compound 5' (150 mg, 292.42 μmol) was added to 2 mL of dimethyl sulfoxide, followed by the slow addition of zinc powder (140 mg, 2.14 mmol) solution and simultaneously, the slow addition of hydrochloric acid (12 M, 20 μL). The reaction mixture was reacted at 25 °C for 12 hours. The mixture was filtered, and the filtrate was preparatively separated by reversed-phase column chromatography (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: water (0.1% formic acid)-acetonitrile; gradient (acetonitrile%): 40%-60%) to obtain compound 5. LCMS (m / z): 497.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 10.98 (s, 1H), 9.26 (s, 1H), 7.94 (d, J = 2.0Hz, 1H), 7.72 (d, J = 8.0Hz, 1H), 7.63 (s, 1H), 7.55 (d, J = 8.0Hz, 1H), 7.50 (br t,J=5.2Hz,1H),7.44(dd,J=2.0,8.4Hz,1H),7.29(d,J=8.4Hz,1H),5.11(dd,J=5.2,13.6Hz,1H),4.70(br d,J=5.2Hz,2H),4.50-4.39(m,1H),4.37-4.26(m,1H),2.96-2.86(m,1H),2.62-2.57(m,1H),2.38(br dd,J=4.4,13.2Hz,1H),2.27(s,3H),2.04-1.95(m,1H).

[0059] Example 2

[0060]

[0061] Step 1: Under a nitrogen atmosphere, compound M2 (400 mg, 2.10 mmol) and compound 3-1 (615.44 mg, 3.15 mmol) were added to anhydrous ethanol (4 mL), followed by zinc trifluoromethanesulfonate (76.44 mg, 210.28 μmol). The mixture was heated to 80 °C and reacted for 14 hours. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1-2:1) to obtain compound 6-1. LCMS (m / z): 340.0 [M+1] + .

[0062] Step 2: Under a nitrogen atmosphere, compound 6-1 (110 mg, 324.23 μmol) and N,N-diisopropylethylamine (419.04 mg, 3.24 mmol) were added to anhydrous N,N-dimethylacetamide (1 mL), followed by compound 2-1 (502.15 mg, 1.62 mmol, hydrochloride). The mixture was heated to 40 °C and reacted for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18150*40 mm*15 μm; mobile phase: water (0.1% formic acid)-acetonitrile; gradient (acetonitrile%): 30%-50%) to obtain compound 6'. LCMS (m / z): 567.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 10.98 (br s, 1H), 10.77-9.84 (m, 1H), 9.48-8.69 (m, 1H), 8.41-8.20 (m, 1H), 7.74 (d, J = 8.0Hz, 1H), 7.64 (s, 1H), 7.55 (br d,J=8.0Hz,1H),7.42(br dd,J=8.8,9.6Hz,1H),7.26-7.08(m,1H),5.11(dd,J=5.2,13.2Hz,1H),4.72(br s,2H),4.55-4.26(m,2H),2.98-2.84(m,1H),2.68-2.57(m,1H),2.43-2.31(m,1H),2.07-1.93(m,1H).

[0063] Step 3: Under a nitrogen atmosphere, compound 6' (150 mg, 264.79 μmol) and glacial acetic acid (159.01 mg, 2.65 mmol) were added to anhydrous N,N-dimethylacetamide (1 mL), followed by zinc powder (110 mg, 1.68 mmol). The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 6 was preparatively separated by high-performance liquid chromatography (HPLC) (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: water (0.1% formic acid)-acetonitrile; gradient (acetonitrile%): 40%-70%). LCMS (m / z): 551.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.98 (s, 1H), 9.07 (s, 1H), 8.42 (dd, J = 2.4, 6.8Hz, 1H), 8.09 (br t,J=5.2Hz,1H),7.72(d,J=7.6Hz,1H),7.63(s,1H),7.55(d,J=7.6Hz,1H), 7.48-7.34(m,1H),7.10-6.95(m,1H),5.10(dd,J=5.2,13.6Hz,1H),4.68(br d,J=5.2Hz,2H),4.48-4.28(m,2H),2.96-2.85(m,1H),2.68-2.60(m,1H),2.42-2.32(m,1H),2.05-1.95(m,1H).

[0064] Example 3

[0065]

[0066] Step 1: Under a nitrogen atmosphere at room temperature, 4-dimethylaminopyridine (320 mg, 2.62 mmol) was added to an anhydrous N,N-dimethylacetamide (2.5 mL) solution of compound 6-1 (148 mg, 436 μmol) and M6 (174 mg, 531 μmol, hydrochloride). The reaction solution was reacted at 25 °C for 4 hours. The pH of the reaction solution was adjusted to 7 with formic acid, filtered, and the filtrate was preparatively separated by reversed-phase column chromatography (column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: water (0.225% FA)-acetonitrile; gradient (acetonitrile %): 40%-70%) to obtain compound 7-1. LCMS (m / z): 585.1 [M+H] + .

[0067] Step 2: Under a nitrogen atmosphere, zinc powder (39.1 mg, 599 μmol) was added to an anhydrous N,N-dimethylacetamide (1 mL) solution of compound 7-1 (35 mg, 59.9 μmol) and glacial acetic acid (34.3 μL, 599 μmol). The reaction solution was reacted at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was preparatively separated by reversed-phase column chromatography (column: Unisil 3-100C18 Ultra 150×50 mm×3 μm; mobile phase: water (0.225% formic acid)-acetonitrile; gradient (acetonitrile %): 46%-76%) to obtain compound 7. LCMS (m / z): 569.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 11.02 (s, 1H), 9.09 (s, 1H), 8.42 (dd, J = 2.8, 7.2Hz, 1H), 8.10 (t, J = 5.2Hz, 1H), 7.69-7.63 (m,1H),7.61-7.57(m,1H),7.43(dd,J=8.8,11.2Hz,1H),7.08-7.00(m,1H),5.13(dd,J=5.2,13.2Hz,1H),4.73(br d,J=5.2Hz,2H),4.65-4.35(m,2H),3.00-2.85(m,1H),2.69-2.57(m,1H),2.47-2.39(m,1H),2.09-1.95(m,1H); 19 F NMR (376MHz, DMSO-d6) δ = -57.09, -125.43, -128.49.

[0068] Example 4

[0069]

[0070] Step 1: Under a nitrogen atmosphere at room temperature, zinc trifluoromethanesulfonate (128.37 mg, 353.11 μmol) was added to an anhydrous ethanol (10 mL) solution of compound M2 (671.69 mg, 3.53 mmol) and compound 12-1 (0.5 g, 3.53 mmol). The reaction solution was heated to 80 °C and reacted for 2 hours. The reaction solution was filtered, and the filter cake was dried to obtain compound 12-2. LCMS (m / z): 285.9 [M+H] + .

[0071] Step 2: Under a nitrogen atmosphere at room temperature, compound 12-2 (60 mg, 209.97 μmol), N,N-diisopropylethylamine (103.71 μL, 629.92 μmol), and dimethyl sulfoxide (1 mL) were added to a dry reaction flask. Then, compound M6 (82.58 mg, 251.97 μmol, hydrochloride) was added, and the mixture was stirred at room temperature for 12 hours. Water (3 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was concentrated under reduced pressure to obtain compound 12-3. LCMS (m / z): 531.0 [M+H] + .

[0072] Step 3: Under a nitrogen atmosphere at room temperature, compound 12-3 (100 mg, 188.34 μmol), dimethyl sulfoxide (1 mL), and acetic acid (0.1 mL) were added to a dry reaction flask, followed by zinc powder (220 mg, 3.36 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was preparatively purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: water (0.05% HCl)-acetonitrile; gradient (acetonitrile%): 45%-75%), yielding compound 12. LCMS (m / z): 515.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ=11.02(s,1H),9.32(s,1H),7.94(d,J=2.1Hz,1H),7.67-7.62(m,1H),7.61-7.55(m,2H),7.47-7.42(m,1H) ,7.29(d,J=8.6Hz,1H),5.17-5.09(m,1H),4.78-4.70(m,2H),4.59(d,J=17.9Hz,1H),4.46-4.38(m,1H),2.98-2.85(m,1H),2.62(br d,J=1.8Hz,1H),2.42(br d,J=4.2Hz,1H),2.27(s,3H),2.08-1.94(m,1H).

[0073] Reference compound

[0074]

[0075] Biological test data

[0076] Test Example 1: Anti-cell proliferation activity test

[0077] Human breast cancer cells (BT-474 cells) were seeded in white 96-well plates, with 80 μL of cell suspension per well, containing 5000 BT-474 cells. The cell culture plates were incubated overnight in a CO2 incubator. A 5-fold diluted test compound was added to the culture medium, and after mixing, the medium containing the compound was added to the cell culture plates. The final compound concentration range was 3 μM serially diluted downwards. The cell culture plates were incubated in a CO2 incubator for 3–7 days. Cell viability was detected using CellTiter-Glo reagent (purchased from Promega). 25 μL of chemiluminescent cell viability assay reagent was added to each well of the cell culture plate, and the plates were incubated at room temperature for 10 minutes. The signal value of each well was read using an EnVision multilabel analyzer (PerkinElmer). A separate cell culture plate was prepared, and the signal value (Max) was read on the day of drug addition as the initial cell count. Min represents the signal value of the blank plate, and Sample represents the signal value of the test sample plate.

[0078] The cell proliferation inhibition rate of the compound was calculated based on the signal value of each well. Inhibition rate = (Sample-Min) / (Max-Min)*100%. The IC50 was obtained by curve fitting using four parameters (obtained in the "log(inhibitor) vs. response--Variable slope" mode of GraphPad Prism).

[0079] The experimental results are shown in Table 1. Among them, compounds 5, 6, and 12 showed high anti-proliferative activity against BT-474 cells, approximately 7 times that of the reference compound CC-90009, which was significantly superior to CC-90009.

[0080] Table 1. Results of antiproliferative activity tests of the compounds of the present invention against BT-474 cells.

[0081] 5 15 6 17 12 17 CC-90009 114

[0082] Conclusion: The compound of the present invention has a significant inhibitory effect on the proliferation of BT-474 cells, and is significantly superior to the reference compound CC-90009.

[0083] Test Example 2: Protein Degradation Activity Test

[0084] Experimental objective: To detect the degradation activity of the compounds of this invention on GSPT1 protein using Western blot.

[0085] Experimental methods:

[0086] Main experimental materials:

[0087] Human prostate cancer cells (22RV-1 cells), supplier ATCC, catalog number CRL-2505, culture medium 10% fetal bovine serum + 90% RRMI-1640; Human breast cancer cells (BT-474 cells), supplier ATCC, catalog number HTB-20, culture medium 10% fetal bovine serum + 90% DMEM / F12 + 1% AA; Pierce TM BCA reagent kit, supplier Thermo Scientific, catalog number 23225;

[0088] Novex 4-12% Bis-Tris adhesive, supplied by Thermo Scientific, catalog number WG1403BOX;

[0089] NuPAGE TM MESSDS buffer solution, supplied by Thermo Scientific, catalog number NP0002.

[0090] 1. Cell Culture: Cancer cell lines of human breast cancer (BT-474 cells) and human prostate cancer (22RV-1 cells) were maintained and cultured at 37°C in 5% CO2 atmosphere. Tumor cells were passaged periodically. Cells in the exponential growth phase were collected and counted for plating experiments.

[0091] 2. Preparation of compound masterbatch (1000x concentrated masterbatch): The mother liquor is serially diluted in DMSO from the highest concentration to the lowest concentration. All masterbatches should be prepared immediately before use.

[0092] 3. Cell plating and compound treatment

[0093] (1) Use trypan blue staining and count cells using a hemocytometer.

[0094] (2) Adjust the cell concentration to 800,000 cells / well, add culture medium to make a cell suspension, and add 1.8 mL of suspension to each well of a 6-well plate.

[0095] (3) Preparation of 10-fold concentrated compounds: Add 297 μL of detection medium to each well, and transfer 3 μL of stock solution of each concentration of compound from the master plate (1000-fold concentrated master plate); add 3 μL of DMSO to the control group. Mix thoroughly by pipetting.

[0096] (4) Aspirate a 10-fold concentrated compound into the cells of a 6-well plate;

[0097] (5) Incubate the culture plate at 37°C, 5% CO2 and 100% relative humidity for 48 hours.

[0098] 4. Cell collection

[0099] (1) Discard the culture medium and wash twice with pre-cooled 1×DPBS.

[0100] (2) Add EDTA-trypsin and digest for 3-5 minutes, then stop digestion with culture medium.

[0101] (3) Centrifuge at 4℃ and 1300rpm for 3 minutes, and wash twice with pre-cooled 1×DPBS.

[0102] (4) Centrifuge at 4℃ and 1300rpm for 3 minutes, and discard the supernatant.

[0103] (5) The cell pellet was stored at -80°C for Western blotting.

[0104] 5. Western Blotting (immunoblotting)

[0105] 5.1 Protein Extraction and Quantification

[0106] (1) Remove the cell pellet from the -80℃ freezer.

[0107] (2) Add 40-80 μL of RIPA lysis buffer (containing 1% protease inhibitor + 1% phosphatase inhibitor 2).

[0108] (3) On ice, break up for 30 minutes, and vortex oscillate once every 5 minutes.

[0109] (4) Centrifuge at 4℃ and 15000rpm for 10 minutes; gently transfer the clear supernatant to a pre-cooled new centrifuge tube.

[0110] (5) Using Pierce TM BCA protein quantification kit is used to determine the concentration.

[0111] (6) Based on the BCA results, dilute the sample to the same final concentration using RIPA lysis buffer + 4×LDS loading buffer + 10× reducing agent (cell pellet at 2μg / μL); heat at 100℃ for 10 minutes to denature.

[0112] (7) Perform Western blotting immediately or store the denatured sample at -80°C.

[0113] 5.2 Western Blot Procedure

[0114] (1) Take a protein sample and add Novex 4-12% Bis-Tris gel (20 wells), 10 μL sample per well.

[0115] (2) Use MESSDS electrophoresis buffer, electrophoresis at 80V for 30 minutes, then switch to 120V for 70 minutes.

[0116] (3) Through 2. Transfer the protein to a nitrocellulose membrane using a transfer apparatus (20V, 7 minutes).

[0117] (4) Cut the membrane of the target strip area, wash it 3 times with 10mL 1×TBS, 5 minutes each time.

[0118] (5) Block nonspecific proteins for 2 hours at room temperature with 10 mL of Odyssey blocking buffer.

[0119] (6) Wash the membrane 5 times with 1×TBST buffer, 5 minutes each time.

[0120] (7) Incubate overnight at 4℃ with gentle shaking: Prepare primary antibody in 10 mL of Odyssey blocking buffer containing 0.1% Tween20 (except for the Newin antibody, all are diluted 1:1000, and the internal control antibody is diluted 1:5000).

[0121] (8) Wash the membrane 5 times with a 1×TBST medium-speed shaker, each time for 5 minutes.

[0122] (9) Subsequent steps: Incubate gently at room temperature for 1 hour: Prepare a secondary antibody mixture (anti-mouse IgG 1:10000 + anti-rabbit IgG 1:10000) in 10 mL of blocking solution containing 0.1% Tween20.

[0123] (10) Wash the membrane 3 times with 10mL 1×TBST, 5 minutes each time.

[0124] (11) Wash the membrane 3 times with 10mL of 1×TBS, 5 minutes each time.

[0125] (12) Near-infrared fluorescence signals were detected using Odyssey Clx.

[0126] 5.3 Quantitative analysis of band intensity: The intensity of each band was quantified using Imagelab software.

[0127] 6. Data Analysis: The intensity values ​​of each band were obtained and analyzed. Protein expression levels were quantified using a reference protein as a baseline, and the normalized fold increase of each sample relative to the solvent control group was calculated. Statistical analysis was performed using GraphPad Prism. The experimental results are shown in Table 2. Where A represents DC... 50 or DC 90 ≤10nM, B represents 10nM <DC 50 or DC 90≤50nM, where C represents 50nM <DC 50 or DC 90 ≤200nM, D represents DC 50 or DC 90 >200nM.

[0128] Table 2. Degradation activity of the compounds of the present invention against GSPT-1 protein.

[0129] 7 22RV-1 A B 99 12 BT-474 B B 97

[0130] Conclusion: The compounds of this invention exhibit significant degradation activity against GSPT-1 protein in both 22RV-1 and BT-474 cells.

[0131] Test Example 3: Hepatic Microsomal Metabolic Stability

[0132] The test substance was prepared into a 10mM MDMSO solution with DMSO, and then diluted to 100μM with 100% acetonitrile to obtain the working solution (organic phase content: 99% acetonitrile, 1% DMSO).

[0133] Prepare two 96-well incubation plates, and name them T60 incubation plate and NCF60 incubation plate respectively.

[0134] Add 445 μL of microsomal working solution (liver microsomal protein concentration of 0.56 mg / mL) to both T60 and NCF60 incubation plates, and then place the incubation plates in a 37°C water bath for pre-incubation for about 10 minutes.

[0135] After the pre-incubation is completed, add 5 μL of the working solution of the test sample or control compound to the T60 incubation plate and the NCF60 incubation plate respectively, and mix well.

[0136] To initiate the reaction, add 50 μL of potassium phosphate buffer to each well of the NCF60 incubation plate. In the T0 stop plate, add 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labenoyl in acetonitrile) and 6 μL of NADPH regeneration working solution. Transfer 54 μL of sample from the T60 incubation plate to the T0 stop plate (T0 sample generation). In the blank plate, add only 54 μL of microsomal working solution, 6 μL of NADPH regeneration working solution, and 180 μL of stop solution. To initiate the reaction, add 44 μL of NADPH regeneration working solution to each well of the T60 incubation plate. Therefore, in the sample of the test or control compound, the final reaction concentrations of the compound, testosterone, diclofenac, and propafenone are 1 μM, the concentration of liver microsomes is 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system are 0.01% (v / v) and 0.99% (v / v), respectively.

[0137] After incubation for appropriate times (e.g., 5, 15, 30, 45, and 60 minutes), add 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labenoyl in acetonitrile) to each well of the stop plate. Then, remove 60 μL of sample from the T60 or NCF60 incubation plate to terminate the reaction.

[0138] All sample plates were shaken well and centrifuged at 3220×g for 20 minutes. Then, 80 μL of the supernatant from each well was diluted to 240 μL of pure water for liquid chromatography-tandem mass spectrometry analysis. The in vitro elimination rate constant ke for the test and control compounds was calculated by converting the ratio of the compound's peak area to the internal standard peak area into a residual percentage using the formula below. The in vitro intrinsic clearance rate of liver microsomes (CL) was calculated using ke. int (mic)), the calculation formula is: CL int (mic) = 0.693 / T 1 / 2 / Microsomal protein content (microsomal concentration during incubation, mg / mL).

[0139] Experimental results showed that compound 7 had a CL content in mouse and human liver microsomes. int (mic) is less than 9.6 μL / min / mg.

[0140] In conclusion, the compounds of this invention exhibit very good stability in mouse and human liver microsomes.

[0141] Test Example 4: Study on Inhibition of Cytochrome P450 Enzyme (CYP)

[0142] Test objective:

[0143] The inhibitory effects of the test compounds on the activity of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) were determined.

[0144] Experimental methods:

[0145] The test compound (10.0 mM) was serially diluted to prepare working solutions (100 × final concentration), with working solution concentrations of 5.00, 1.50, 0.500, 0.150, 0.0500, 0.0150 and 0.00500 mM. Simultaneously, working solutions were prepared for mixtures of positive inhibitors and specific substrates of P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A (using midazolam as a probe substrate)). Human liver microsomes stored at below -60°C were thawed on ice until completely dissolved, then diluted with potassium phosphate buffer (PB) to prepare a working solution of a specific concentration (0.253 mg / mL).

[0146] Add 20.0 μL of substrate mixture to the reaction plate (add 20.0 μL of PB to the blank well), then add 158 μL of human liver microsome working solution to the reaction plate. Place the reaction plate on ice and set aside. At this time, add 2.00 μL of each concentration of the test compound (N=1) and specific inhibitor (N=2) to the corresponding well. For the inhibitor-free group (no test compound or positive inhibitor), add the corresponding organic solvent as the control sample (the test compound control sample is DMSO:MeOH = 1:1, and the positive control samples are all DMSO:MeOH = 1:9). Preheat the reaction plate in a 37°C water bath. After incubation for 10 min, 20.0 μL of coenzyme factor (NADPH) solution was added to the reaction plate and incubated in a 37°C water bath for 10 min. The reaction was terminated by adding 400 μL of pre-cooled acetonitrile solution (containing internal standard). The reaction plate was placed on a shaker and shaken for 10 min to mix. Then, it was centrifuged at 4°C and 4000 rpm for 20 min. 200 μL of the supernatant was added to 100 μL of water to dilute the sample. Finally, the plate was sealed, shaken for 10 min to mix, and then detected by LC-MS / MS.

[0147] Experimental results showed that compound 7 had an IC50 inhibitory effect on cytochrome P450 enzymes (CYP1A2, CYP2D6, CYP3A4) in human liver microsomes. 50 >50μM, the IC50 of inhibition against cytochrome P450 enzymes (CYP2C9, CYP2C19) is greater than 15μM.

[0148] Conclusion: The compounds of this invention do not have a significant inhibitory effect on the five major cytochrome P450 enzymes in human liver microsomes.

[0149] Test Example 5: Mouse PK Test

[0150] Six male CD1 mice were used (divided into two groups of three). The intravenous (iv) group received the drug via intravenous injection, with the solvent being 5% DMA / 50% PEG400 / 5% glucose aqueous solution. The oral (po) group received the drug via gavage, with the solvent being 5% DMSO / 95% 30% hydroxypropyl-β-cyclodextrin aqueous solution. Whole blood was collected at 5 min (IV group only), 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after drug administration, and plasma was prepared by centrifugation. The concentration of the test substance in the plasma was determined by LC-MS / MS, and pharmacokinetic parameters were calculated.

[0151] The experimental results are shown in Table 3. Where: CL represents the clearance rate, Vdss represents the distribution volume, and T... 1 / 2 The half-life, AUC 0-last The area under the whole blood concentration-time curve from 0 to the last quantifiable time point is represented by F, which represents bioavailability.

[0152] Table 3 Results of mouse PK test of the compounds of the present invention.

[0153]

[0154] Experimental results showed that the oral exposure of the reference compound CC-885 was low (AUC). 0-last It has a low oral bioavailability (only 46 ng·h / mL) and very low oral bioavailability (F% only 2.1%), with almost no oral absorption.

[0155] Compound 5 has a high oral exposure (approximately 3.1 times that of CC-885 at the same dose) and high oral bioavailability (9.9 times that of CC-885).

[0156] Compound 6 has a high oral exposure (2.9 times that of CC-885 at the same dose) and high oral bioavailability (4.8 times that of CC-885 at the same dose).

[0157] Compound 7 has a high oral exposure (48 times that of CC-885 at the same dose) and high oral bioavailability (26 times that of CC-885 at the same dose).

[0158] Compound 12 has a high oral exposure (12 times that of CC-885 at the same dose) and high oral bioavailability (11.7 times that of CC-885 at the same dose).

[0159] Conclusion: The compounds of this invention exhibit low clearance in mouse pharmacokinetic studies, high oral exposure, and high oral bioavailability, demonstrating favorable pharmacokinetic properties. Compared to CC-885, the compounds of this invention possess significantly superior oral absorption properties and hold greater potential for oral drug development.

[0160] Test Example 6: In vivo drug efficacy

[0161] Experimental objective: To test the in vivo efficacy of the compound of this invention in the NCI-H1155 model.

[0162] Experimental methods:

[0163] (1) Animals: BALB / c Nude mice, female, 6-8 weeks old. Provided by Vital River Laboratory Animal Co., Ltd. After arrival, the animals were housed in SPF-grade animal rooms with IVC (independent ventilation system) cages (3-5 mice per cage) for 3-7 days before the start of the experiment.

[0164] (2) Cell Culture: Human lung cancer NCI-H1155 cells, derived from ATCC, were maintained and passaged by Shanghai Alamo Pharmaceutical Technology Co., Ltd. The culture medium was RPMI medium containing 10% fetal bovine serum, and the culture conditions were 37℃ and 5% carbon dioxide. The passage ratio was 1:2 to 1:3, with passages performed 2 to 3 times per week. When the cell saturation reached 80%-90% and the required number was achieved, the cells were harvested, counted, and seeded.

[0165] (3) Tumor inoculation: 2×10 6 One NCI-H1155 cell was resuspended in 0.2 mL of PBS and subcutaneously seeded into the right posterior back of each mouse.

[0166] (4) Animal grouping and administration: Weigh the animals and measure the tumor volume. The average tumor volume reached approximately 80 mm. 3 Animals were randomly grouped according to tumor volume, with 6 animals in each group.

[0167] Solvent control group (Vehicle): The solvent (5% dimethyl sulfoxide + 30% w / v hydroxypropyl-β-cyclodextrin + water) was administered orally by gavage at a volume of 10 μL / g (calculated based on mouse body weight) once daily.

[0168] In the treatment group, compound 7 was dissolved in a solvent (5% dimethyl sulfoxide + 30% w / v hydroxypropyl-β-cyclodextrin + water) and administered orally by gavage at a dose of 45 mg / kg once daily.

[0169] If weight loss exceeds 15%, discontinue medication and resume medication only after weight has recovered to 10% of the previous decrease.

[0170] Data Analysis:

[0171] After administration, tumor diameter was measured every three days to calculate tumor volume (V), and then the tumor growth inhibition rate (TGI, used to evaluate the antitumor efficacy of the compound) was calculated. The calculation formula is as follows:

[0172] V = 0.5L × W 2 L and W represent the long and short diameters of the tumor, respectively;

[0173] TGI(%) = [(1 - (mean tumor volume at the end of treatment in a certain treatment group - mean tumor volume at the beginning of treatment in that treatment group)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the beginning of treatment in the solvent control group)] × 100.

[0174] Experimental results:

[0175] After administration of compound 7, the tumor volume changed as follows: Figure 1As shown in the figure. Experimental results showed that compound 7 had a TGI of 86% at a dose of 45 mg / kg, exhibiting a significant antitumor effect. Furthermore, the mice tolerated the medication well during administration.

[0176] Conclusion: The compounds of this invention showed good antitumor effects in the NCI-H1155 pharmacodynamic model, and were well tolerated and safe in mice.

Claims

1. The compound represented by formula (VI-1) or a pharmaceutically acceptable salt thereof, ， in, each R2is independently selected from H, F, Cl, C 1-3 alkyl and C 1-3 alkoxy; R a1 selected from H and F; n is selected from 1, 2, and 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Structural unit selected from and .

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Structural unit selected from and .

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Each R2 is independently selected from H, F, Cl, CH3, CF3, OCH3, and OCF3.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, Each R2 is independently selected from F, Cl, CH3 and OCH3.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, , , and .

7. A pharmaceutical composition comprising the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or the composition according to claim 7, in the preparation of a GSPT1 degrading agent.

9. The use according to claim 8, characterized in that, The GSPT1 degrading agent is used to treat cancer.

Images