A nitrogen-containing ring derivative as a STING degrading agent for linkers, its synthesis method and uses

Abstract

This invention discloses a nitrogen-containing ring derivative as a linker STING degrading agent, its synthesis method, and its uses. This STING degrading agent comprises compounds described in general formulas I and II, and inhibits the expression of inflammatory factors by downregulating the STING / NF-κB signaling axis. It can serve as a renal protective agent for the treatment / prevention of acute kidney injury and has potential drug development prospects.

Description

Technical Field

[0001] This invention belongs to the field of STING targeted inhibition technology, and relates to a nitrogen-containing ring derivative as a STING degrading agent for Linker, its synthesis method and uses. Background Technology

[0002] Acute kidney injury (AKI) is a disease characterized by acute inflammation and a rapid deterioration of kidney function caused by congenital immune overactivation. Epidemiological statistics show that 13.3 million people worldwide are diagnosed with AKI each year, and 1.7 million die from it. Furthermore, 19%–31% of patients with a benign course will develop chronic kidney disease, eventually progressing to end-stage renal disease, placing a heavy burden on families and society.

[0003] Interferon gene-stimulating factor (STING) is an innate immune molecule primarily discovered as a mediator of type I interferon (IFN-I) immune signal transduction. Over the past decade, STING has garnered significant attention from the scientific community and pharmaceutical companies due to its target function and important physiological roles. Increasing evidence suggests that activation of the innate immune pathway cGAS-STING is closely related to mitochondrial damage and the subsequent induced inflammatory response. Therefore, aberrant STING activation is closely associated with the development of acute kidney injury (AKI) and represents an important potential therapeutic target for AKI.

[0004] In recent years, research on STING targeted inhibition has deepened, giving rise to a series of STING inhibitors with different scaffold types. Although a series of small molecule STING inhibitors have been reported, most of them suffer from insufficient activity, significant side effects, and poor drug-likeness. Therefore, a novel strategy of developing STING-PROTAC degraders will successfully compensate for the shortcomings of existing small molecule STING inhibitors and can serve as a nephroprotective agent for the treatment / prevention of acute kidney injury, showing potential for drug development. Summary of the Invention

[0005] This invention provides a nitrogen-containing ring derivative as a STING degrading agent for linkers, its synthesis method, and its uses. It also provides a series of nitrogen-containing ring derivatives that, by regulating the STING / NF-κB signaling pathway, use protein degradation technology to treat inflammation-related diseases as STING-PROTAC degrading agents for linkers, their preparation methods, and their effects of downregulating the STING / NF-κB signaling axis to inhibit the expression of inflammatory factors. These derivatives can be used as renal protective agents for the treatment / prevention of acute kidney injury.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] This invention provides a nitrogen-containing ring derivative as a STING degrading agent for linkers, comprising compounds of general formulas I and II:

[0008]

[0009] Linker can be selected from

[0010] X can be selected from -(CH2)2-, -(CH2)3-, or -CH2OCH2-.

[0011] Preferably, the compound comprises any one of the following compounds:

[0012]

[0013]

[0014] This invention also provides a method for synthesizing nitrogen-containing ring derivatives as linker STING degrading agents, comprising:

[0015]

[0016] (a) The compound undergoes intermolecular ring-opening and cyclization reactions;

[0017] (b) The compound undergoes a nucleophilic substitution reaction;

[0018] (c) The compound undergoes deprotection of its Boc protecting group;

[0019] (d) The compound undergoes a reductive amination reaction with the corresponding aldehyde or ketone;

[0020] (e) The compound undergoes Dess-Martin oxidation.

[0021] Preferably, the solvent used in step (a) for the intermolecular ring-opening and cyclization reaction includes, but is not limited to, glacial acetic acid, water, ethyl acetate, or a mixture of these solvents; the reaction temperature is from 0°C to 140°C.

[0022] Preferably, the solvent used in step (b) for the nucleophilic substitution reaction includes, but is not limited to, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, or a mixture of these solvents; the basic catalyst used is N,N-diisopropylethylamine; the reagents used include, but are not limited to, N,N-diisopropylethylamine and triethylamine; and the reaction temperature is 75°C to 85°C.

[0023] Preferably, the reagents used in step (c) include, but are not limited to, dioxane hydrochloride, methanol hydrochloride, and ethyl acetate hydrochloride solution; the reaction temperature is 25°C to 35°C.

[0024] Preferably, the solvent used in step (d) for the sodium cyanoborohydride-mediated reductive amination reaction is dichloromethane, methanol, or a mixture of these solvents; the acid used is glacial acetic acid; the reagent used is the corresponding amine; and the reaction temperature is 25°C to 35°C.

[0025] Preferably, the solvent used in the Dess-Martin oxidation reaction in step (e) includes, but is not limited to, dichloromethane, methanol, tetrahydrofuran, N,N-dimethylformyl solution, or a mixture of these solvents; the reagent used is the Dess-Martin oxidant; and the reaction temperature is -5°C to 5°C.

[0026] This invention also provides another method for synthesizing nitrogen-containing ring derivatives as STING degrading agents for linkers, comprising:

[0027]

[0028] The Linker can be selected from

[0029] (a) The compound undergoes an amide condensation reaction.

[0030] Preferably, the solvent used in step (a) amide condensation reaction includes, but is not limited to, N,N-dimethylformamide, tetrahydrofuran, or a mixture of these solvents; the condensing agent includes, but is not limited to, HATU, EDCI, HOBT, T3P; the alkaline catalyst includes, but is not limited to, N,N-diisopropylethylamine, triethylamine; and the reaction temperature is 25°C to 35°C.

[0031] This application also provides the use of the above-mentioned STING degrading agent, or its pharmaceutically acceptable salt, racemate, optical isomer or solvent compound, in the preparation of a degrading agent with STING / NF-κB signal axis inhibitory activity.

[0032] This application also provides the use of the aforementioned STING degrading agent, or a pharmaceutically acceptable salt, racemate, optical isomer, or solvent compound thereof, in the preparation of a nephroprotective medicament for the treatment / prevention of acute kidney injury.

[0033] This application also provides a pharmaceutical composition comprising the STING degrader or its pharmaceutically acceptable salt, racemate, optical isomer or solvent compound as an active ingredient, and a pharmaceutically acceptable carrier.

[0034] Preferably, the pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhaler, ointment, suppository, or patch.

[0035] Beneficial effects: This application provides a novel STING-PROTAC degrading agent with a novel structure, simple preparation, and convenient industrial production; it can inhibit the expression of inflammatory factors by downregulating the STING / NF-κB signaling axis, and can be used as a nephroprotective agent for the treatment / prevention of acute kidney injury, showing potential for drug development. Attached Figure Description

[0036] Figure 1 .ST9 1H NMR spectrum.

[0037] Figure 2 .ST9 NMR carbon spectrum.

[0038] Figure 3 .ST9 high-resolution mass spectrometry.

[0039] Figure 4 The activity characterization and degradation mechanism of ST9 are shown.

[0040] Figure 5 The results show that ST9 effectively regulates downstream signaling pathways by degrading STING.

[0041] Figure 6 The results show that ST9 exhibits good protein degradation selectivity.

[0042] Figure 7 .ST9 toxicity test results on normal cells.

[0043] Figure 8 The results showed that ST9 has significant anti-AKI efficacy in vivo.

[0044] Figure 9 H&E staining results of heart, liver, and kidney. Detailed Implementation

[0045] The present invention will now be described in detail with reference to specific embodiments. The following specific embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any way.

[0046] I. General formula for the synthesis of SL5a-d and SQ5c-d

[0047]

[0048] Synthesis of compounds SL1 and SQ1:

[0049] SL0 (5 g, 30.12 mmol) was dissolved in glacial acetic acid (100 mL). After complete dissolution, 3-aminopiperidine-2,6-dione hydrochloride (4.96 g, 30.12 mmol), 4-fluoroisobenzofuran-1,3-dione or 5-fluoroisobenzofuran-1,3-dione, and sodium acetate (2.69 g, 36.14 mmol) were added. The mixture was heated under reflux at 120 °C overnight. The mixture was cooled to room temperature. The solution was poured into ice water (200 mL). The mixture was stirred for 20 minutes. The mixture was filtered. The gray solid was purified by rapid column chromatography. The final product was brown solids SL1 and SQ1.

[0050] SL1: 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),7.95(td,J=7.9,4.5Hz,1H),7.79(d,J=7.3Hz,1H),7.73(t,J=8.9Hz,1H), 5.15(dd,J=12.9,5.4Hz,1H),2.89(ddd,J=17.2,13.9,5.4Hz,1H),2.67-2.51(m,2H),2.14-1.97(m,1H).ESI-MS m / z 277.25[M+H] + 275.15 [MH] - .

[0051] SQ1: 1 H NMR (400MHz, DMSO) δ11.15(s,1H),8.01(dd,J=8.1,4.4Hz,1H),7.87–7.81(m,1H),7.73(dd,J=12.4,5.2Hz,1H),5.17(d d,J=12.7,5.2Hz,1H),2.97–2.84(m,1H),2.62(d,J=18.8Hz,1H),2.57–2.51(m,1H),2.09(dd,J=9.0,3.6Hz,1H).ESI-MS m / z277.30[M+H] + 275.20 [MH] - .

[0052] Synthesis of compounds SL2 and SQ2:

[0053] Intermediate SL1 or SQ1 (19.2 mmol) and N,N-diisopropylethylamine (5.1 mL, 28.8 mmol) were dissolved in N,N-dimethylformamide (50 mL), followed by the addition of tert-butyl piperazine-1-carboxylate or the corresponding alcohol (23.0 mmol). The mixture was stirred overnight at 90 °C and monitored by TLC. The reaction mixture was then added to water (500 mL), precipitating a yellow solid. After stirring for 30 minutes and filtering under reduced pressure, yellow solids SL2 and SQ2 were obtained.

[0054] SL2: 1 H NMR (400MHz, DMSO) δ11.09(s,1H),7.73(t,J=7.8Hz,1H),7.40(d,J=7.0Hz,1H),7.36(d,J=8.4Hz,1H),5.11(dd,J=13.1,5.2Hz,1H),3 .52(t,J=5.0Hz,4H),3.26(d,J=4.9Hz,4H),2.88(dt,J=14.1,10.0Hz,1H),2.64–2.53(m,2H),2.09–1.99(m,1H),1.43(s,9H).ESI-MS m / z 442.95[M+H] + 464.95 [M+Na] + 441.15 [MH] - .

[0055] SQ2 1 H NMR (400MHz, DMSO) δ11.07(s,1H),7.69(d,J=8.4Hz,1H),7.34(s,1H),7.24(d,J=8.4Hz,1H),5.0 7(dd,J=12.7,5.1Hz,1H),3.47(s,8H),3.14–2.81(m,2H),2.75–2.55(m,2H),1.43(s,9H).ESI-MS m / z 441.20[MH] - .

[0056] Synthesis of compounds SL3 and SQ3:

[0057] SL2 and SQ2 were dissolved in dioxane hydrochloride and reacted overnight at room temperature. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum evaporation to obtain SL3 and SQ3 as pale yellow solids.

[0058] Synthesis of compounds SL4a-d and SQ4c-d:

[0059] Intermediates SL3 and SQ3 (1.32 mmol), the corresponding aldehydes and ketones (1.99 mmol), and N,N-diisopropylethylamine (1.32 mmol) were dissolved in DCM and MeOH solutions (v:v = 1:1). A few drops of AcOH were then added dropwise, followed by the addition of sodium cyanoborohydride (3.98 mmol) in portions. The reaction mixture was then stirred overnight at room temperature and purified by rapid column chromatography to obtain the desired yellow intermediates SL4a-d and SQ4c-d.

[0060] SL4a: 1 H NMR (400MHz, DMSO) δ11.10(s,1H),7.75–7.65(m,1H),7.41–7.29(m,2H),5.09(d,J=7.8Hz,1H),3.98(s,2H),3 .61(s,4H),3.33–3.27(m,4H),3.14(d,J=6.3Hz,2H),2.70(s,5H),1.91(t,J=48.4Hz,4H),1.39(s,9H).ESI-MS m / z 526.40[M+H] + 524.38 [MH] - .

[0061] SL4b: 1 H NMR (400MHz, DMSO) δ11.11(s,1H),7.77–7.67(m,1H),7.37(dd,J=9.7,8.0Hz,2H),5.11(dd,J=12.8,5.4Hz,1H),3.88(s,2H),3.72(s,2H),3.35(s,4H ),3.13(dd,J=10.9,6.1Hz,1H),2.90(dd,J=22.8,8.3Hz,1H),2.58(dd,J= 21.8,10.9Hz,2H),2.49(s,4H),2.08–1.99(m,1H),1.40(s,9H).ESI-MSm / z 498.25[M+H] + 496.20 [MH] - .

[0062] SL4c: 1H NMR(400MHz,DMSO)δ11.09(s,1H),7.70(t,J=7.7Hz,1H),7.34(dd,J=11.4,8.0Hz,2H),5.09(dd,J=12.8,5.0Hz,1H),3.92(s,2H),3.51(s,2H),3.28(s,4H),2.89(dd,J=22.4,8.6Hz,1H),2.77(s,1H),2.58(dd,J=17.2,10.4Hz,8H),2.08–1.97(m,1H),1.38(s,9H).ESI-MS m / z 512.00[M+H] + ;511.20[M-H] - .

[0063] SL4d: 1 H NMR(400MHz,DMSO)δ11.08(s,1H),7.70(t,J=7.8Hz,1H),7.37–7.31(m,2H),5.09(dd,J=12.8,5.4Hz,1H),3.92(d,J=11.4Hz,2H),3.32(s,2H),2.94–2.83(m,1H),2.70(s,2H),2.59(d,J=17.2Hz,2H),2.53(s,4H),2.50(s,1H),2.18(d,J=6.4Hz,2H),2.06–1.99(m,1H),1.69(d,J=11.2Hz,2H),1.39(s,9H),1.24(dd,J=5.6,4.0Hz,4H).ESI-MS m / z 540.25[M+H] + ;538.25[M-H] - .

[0064] SQ4c: 1 H NMR(400MHz,CDCl3)δ8.51(s,1H),7.67(d,J=8.5Hz,1H),7.04(d,J=8.5Hz,1H),4.93(dd,J=11.9,5.0Hz,1H),4.02(t,J=8.3Hz,2H),3.63–3.58(m,2H),3.40(s,4H),2.83(dd,J=26.6,14.3Hz,2H),2.73(d,J=14.6Hz,2H),2.64(d,J=7.3Hz,2H),2.57(s,4H),2.14–2.08(m,1H),1.43(s,9H).ESI-MS m / z 510.35[M-H] - .

[0065] SQ4d: 1 H NMR (400MHz, CDCl3) δ7.69(d,J=8.5Hz,1H),7.29(s,1H),7.07(d,J=8.4Hz,1H),4.95(dd,J=11.8,5.0Hz,1H),4.11(s,4H),2.93(d,J=13.7Hz,4H) ,2.82(d,J=13.1Hz,1H),2.73(d,J=9.2Hz,4H),2.60(s,4H),2.27(d,J=6 .6Hz,2H),2.17–2.09(m,1H),1.76(d,J=11.8Hz,4H),1.47(s,9H).ESI-MS m / z 540.25[M+H] + 538.25 [MH] - .

[0066] Synthesis of compounds SL5a-d and SQ5c-d:

[0067] SL4a-d and SQ4c-d were dissolved in dioxane hydrochloride and reacted overnight at room temperature. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum evaporation to obtain SL5a-d and SQ5c-d as pale yellow solids.

[0068] II. General formula for the synthesis of SL9a-b and SQ9b

[0069]

[0070] Synthesis of compounds SL6a-b and SQ6b:

[0071] Intermediate SL1 or SQ1 (19.2 mmol) and N,N-diisopropylethylamine (5.1 mL, 28.8 mmol) were dissolved in N,N-dimethylformamide (50 mL), followed by the addition of the corresponding alcohol (23.0 mmol). The mixture was stirred overnight at 90 °C and monitored by TLC. The reaction mixture was then added to water (500 mL), resulting in the precipitation of a yellow solid. After stirring for 30 minutes and filtering under reduced pressure, yellow solids SL6a-b and SQ6b were obtained.

[0072] SL6a: 11H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.7 Hz, 2H), 5.10 (dd, J = 12.9, 5.3 Hz, 1H), 4.74 (d, J = 4.0 Hz, 1H), 3.69 (dd, J = 7.8, 3.9 Hz, 1H), 3.60–3.49 (m, 2H), 3.03 (t, J = 9.8 Hz, 2H), 2.95–2.82 (m, 1H), 2.57 (dd, J = 18.5, 10.3 Hz, 2H), 2.02 (dd, J = 12.6, 7.0 Hz, 1H), 1.88 (d, J = 10.1 Hz, 2H), 1.65–1.51 (m, 2H). ESI-MS m / z 358.50 [M+H] + ; 356.45 [M-H] - .

[0073] SL6b: 1 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.32 (t, J = 7.3 Hz, 2H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 4.52 (t, J = 5.2 Hz, 1H), 3.70 (d, J = 11.7 Hz, 2H), 2.87 (d, J = 11.8 Hz, 2H), 2.57 (dd, J = 18.8, 10.3 Hz, 2H), 2.10–1.97 (m, 1H), 1.77 (d, J = 11.3 Hz, 2H), 1.35 (dd, J = 22.4, 11.0 Hz, 2H). ESI-MS m / z 344.20 [M+H] + ; 342.40 [M-H] - .

[0074] SQ6b: 1 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 6.67 (dd, J = 8.5, 2.1 Hz, 1H), 5.29 (s, 1H), 4.93 (dd, J = 12.2, 5.3 Hz, 1H), 4.66 (s, 1H), 3.59 (dd, J = 11.0, 5.1 Hz, 2H), 2.86–2.75 (m, 2H), 2.15 (tdd, J = 12.3, 9.6, 4.6 Hz, 4H), 1.69 (s, 2H).

[0075] Synthesis of compounds SL7a-b and SQ7b

[0076] Intermediates SL6a-b and SQ6b (1.68 mmol) were dissolved in DCM, and Dess-Martin oxidant (8.40 mmol) was slowly added in an ice-water bath with stirring overnight. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the mixture was purified by rapid column chromatography to obtain yellow solids SL7a-b and SQ7b.

[0077] SL7a: 1 H NMR(400MHz,DMSO)δ11.08(s,1H),7.65(d,J=8.5Hz,1H),7.32(s,1H),7.26–7.22(m ,1H),5.07(dd,J=12.9,5.4Hz,1H),3.86–3.71(m,2H),3.28(s,1H),3.24–3.19(m,1 H),3.17(d,J=5.2Hz,1H),2.90(ddt,J=17.4,14.3,8.8Hz,2H),2.56(dd,J=10.1,3. 6Hz, 1H), 2.46–2.40 (m, 1H), 2.02 (ddd, J=10.4, 5.8, 3.3Hz, 1H), 1.86–1.77 (m, 2H).

[0078] SL7b: 1 H NMR (400MHz, DMSO) δ11.09(s,1H),7.69(dd,J=8.3,7.3Hz,1H),7.36(d,J=2.9Hz,1H),7.34(s,1H),5.10(dd,J=12.8,5.2Hz, 1H),3.61(d,J=12.0Hz,2H),3.03(t,J=10.5Hz,2H),2.96–2.80(m,1H),2.08–1.94(m,3H),1.71(d,J=10.8Hz,2H).ESI-MSm / z 342.20[M+H] + 340.25 [MH] - .

[0079] SQ7b: 1 H NMR (400MHz, CDCl3) δ8.25(s,1H),7.74(d,J=8.4Hz,1H),7.06(s,1H),6.81(d,J=8.3Hz,1H),4.9 5(dd,J=12.1,5.2Hz,1H),3.90–3.84(m,4H),2.88–2.77(m,4H),1.67(s,2H).LC-MS:342.25[M+H] +340.20 [MH] - .

[0080] Synthesis of compounds SL8a-b and SQ8b:

[0081] Intermediates SL7a-b and SQ7b (1.32 mmol) were dissolved in DCM and MeOH solution (v:v = 1:1) with the corresponding aldehyde and ketone (1.99 mmol) and N,N-diisopropylethylamine (1.32 mmol). A few drops of AcOH were then added dropwise, and sodium cyanoborohydride (3.98 mmol) was added to the system in portions. The reaction mixture was then stirred overnight at room temperature and monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the mixture was purified by rapid column chromatography to obtain the desired yellow intermediates SL8a-b and SQ8b.

[0082] SL8a: 1 H NMR (400MHz, CDCl3) δ7.59(t,J=7.8Hz,1H),7.40(d,J=7.1Hz,1H),7.18(d,J=8.4Hz,1H),4.98(dd,J=12.2,5.2Hz,1H),3.83(t,J=10.4Hz,2H),3.49( d,J=12.5Hz,4H),2.94(t,J=8.9Hz,2H),2.59(s,4H),2.16–2.10(m,1H),1 .97(d,J=11.6Hz,2H),1.90–1.79(m,2H),1.67(s,4H),1.48(s,9H).ESI-MS m / z 526.30[M+H] + 524.40 [MH] - .

[0083] SL8b: 1 H NMR (400MHz, DMSO) δ11.09 (s, 1H), 7.67 (t, J = 7.7Hz, 1H), 7.37–7.27 (m, 2H), 5. 08(dd,J=12.8,5.0Hz,1H),3.68(d,J=11.1Hz,2H),3.17(d,J=5.1Hz,1H),2.88 (dd,J=23.2,12.8Hz,3H),2.65–2.51(m,2H),2.30(s,4H),2.19(d,J=6.6Hz,2H ),2.09–1.96(m,1H),1.81(d,J=12.2Hz,2H),1.71(s,1H),1.40(s,9H).ESI-MS m / z 512.35 [M+H] + 510.10 [MH]- .

[0084] SQ8b: 1 H NMR (400MHz, CDCl3) δ7.66(d,J=8.4Hz,1H),6.94(d,J=1.5Hz,1H),6.68(d,J=8.5Hz,1H),4.93(dd, J=12.1,5.3Hz,1H),3.67–3.56(m,2H),3.51–3.44(m,4H),3.31(t,J=8.9Hz,1H),3.10–2.99(m,1H), 2.85(ddd,J=16.5,14.1,3.6Hz,2H),2.74(dd,J=15.6,4.2Hz,1H),2.53(s,2H),2.49–2.42(m,2H), 2.31(dt,J=12.3,6.2Hz,1H),2.16–2.10(m,1H),2.08–1.97(m,2H),1.47(s,9H).LC-MS:510.20[MH] -

[0085] Synthesis of compounds SL9a-b and SQ9b:

[0086] SL8a-b and SQ8b were dissolved in dioxane hydrochloride and reacted overnight at room temperature. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum evaporation to obtain SL9a-b and SQ9b as pale yellow solids.

[0087] III. General formulas for the synthesis of SL13a-c and SQ13a-c

[0088]

[0089] Synthesis of compounds SL10a-c and SQ10a-c:

[0090] Intermediate SL1 or SQ1 (19.2 mmol) and N,N-diisopropylethylamine (5.1 mL, 28.8 mmol) were dissolved in N,N-dimethylformamide (50 mL), followed by the addition of the corresponding alcohol (23.0 mmol). The mixture was stirred overnight at 90 °C and monitored by TLC. The reaction mixture was then added to water (500 mL), resulting in the precipitation of a yellow solid. After stirring for 30 minutes and filtering under reduced pressure, yellow solids SL10a-c and SQ10a-c were obtained.

[0091] SL10a: 1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.56(t,J=7.8Hz,1H),7.36(d,J=7.1Hz,1H),7.18(d,J=8.4Hz,1H),4.96(dd,J=12.0,5.4Hz,1H),3.76(s,2H),3.57(t,J=5.0Hz,2H),2.96–2.80(m,4H),2.14–2.06(m,1H),1.89(d,J=12.4Hz,2H),1.67(s,2H),1.56(d,J=12.8Hz,2H).

[0092] SL10b: 1 H NMR(400MHz,DMSO)δ11.07(s,1H),7.55(t,J=7.8Hz,1H),7.10(dd,J=13.9,7.8Hz,2H),5.06(dd,J=12.8,5.3Hz,1H),4.74(t,J=4.9Hz,1H),3.58(dd,J=14.6,6.3Hz,3H),3.50–3.39(m,3H),2.95–2.81(m,1H),2.64–2.51(m,2H),2.38(dt,J=13.5,6.8Hz,1H),2.08–1.95(m,2H),1.72(dq,J=15.3,7.6Hz,1H).ESI-MS m / z 358.10[M+H] + ;356.25[M-H] - .

[0093] SL10c: 1 H NMR(400MHz,DMSO)δ11.03(s,1H),7.56(t,J=7.6Hz,1H),7.25(d,J=8.5Hz,1H),7.14(t,J=6.4Hz,1H),5.14–4.98(m,1H),4.70(d,J=5.2Hz,1H),4.38(s,1H),3.94(d,J=7.3Hz,1H),3.43(s,1H),3.24(s,1H),2.89(t,J=13.7Hz,1H),2.58(t,J=13.9Hz,2H),2.12–1.90(m,4H),1.83–1.69(m,1H).ESI-MS m / z 358.35[M+H] + ;356.10[M-H] - .

[0094] SQ10a: 1H NMR(400MHz,DMSO)δ11.07(s,1H),7.65(d,J=8.5Hz,1H),7.31(s,1H),7.24(d,J=8.5Hz,1H),5.06(dd,J=12.7,5.3Hz,1H),4.49(t,J=5.1Hz,1H),4.05(s,1H),3.28(t,J=5.4Hz,2H),2.96(t,J=12.6Hz,2H),2.87(dd,J=17.9,4.1Hz,1H),2.65–2.51(m,4H),2.08–1.97(m,1H),1.75(d,J=13.4Hz,2H),1.26–1.16(m,2H).

[0095] SQ10b: 1 H NMR(400MHz,CDCl3)δ8.36(s,1H),7.66(d,J=8.3Hz,1H),6.96(s,1H),6.69(d,J=8.2Hz,1H),4.95(dd,J=11.7,4.8Hz,1H),3.79–3.72(m,1H),3.69(t,J=8.6Hz,1H),3.57(t,J=8.8Hz,1H),3.50(s,1H),3.48–3.40(m,1H),3.32–3.23(m,1H),2.83(dt,J=29.5,15.4Hz,3H),2.69–2.58(m,1H),2.27–2.17(m,1H),2.17–2.09(m,1H),1.98–1.84(m,2H).ESI-MS m / z 358.25[M+H] + ;356.40[M-H] - .

[0096] SQ10c: 1 H NMR(400MHz,CDCl3)δ8.37(s,1H),7.66(d,J=8.5Hz,1H),7.10(s,1H),6.82(d,J=8.4Hz,1H),4.97(dd,J=11.6,4.8Hz,1H),4.03(s,1H),3.75(d,J=10.3Hz,1H),3.66–3.53(m,2H),3.30(t,J=8.8Hz,1H),2.92–2.81(m,2H),2.77(d,J=13.9Hz,1H),2.26–2.04(m,6H).ESI-MS m / z 358.35[M+H] + ;356.20[M-H] - .

[0097] Synthesis of compounds SL11a-c and SQ11a-c:

[0098] Intermediates SL10a-c and SQ10a-c (1.68 mmol) were dissolved in DCM, and Dess-Martin oxidant (8.40 mmol) was slowly added in an ice-water bath with stirring overnight. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the mixture was purified by rapid column chromatography to obtain yellow solids SL11a-c and SQ11a-c.

[0099] SL11a: 1 H NMR (400MHz, CDCl3) δ9.72 (s, 1H), 7.58 (dd, J = 8.3, 7.3Hz, 1H), 7.40 (d, J = 7.1 Hz,1H),7.17(d,J=8.3Hz,1H),4.97(dd,J=12.3,5.3Hz,1H),3.65(dd,J=12.0, 8.0Hz,2H),3.49(s,2H),3.06(ddd,J=9.7,8.5,5.4Hz,2H),2.47(dd,J=9.8,5 .2Hz,1H),2.14–2.07(m,4H),1.95(dd,J=8.1,4.3Hz,2H).LC-MS:370.40[M+H] + 368.30 [MH] -

[0100] SL11b: 1 H NMR (400MHz, DMSO) δ11.06(s,1H),9.71–9.67(m,1H),7.59(dd,J=8.6,6.9Hz,1H),7.18(d,J=6 .9Hz,1H),7.14(d,J=8.7Hz,1H),5.08(dd,J=12.8,5.5Hz,1H),3.88(dd,J=10.9,4.6Hz,1H),3. 75(td,J=10.1,8.6,4.5Hz,1H),3.52(q,J=7.4,6.4Hz,2H),3.31–3.23(m,1H),2.95–2.81(m,1H ),2.57(dd,J=14.2,10.1Hz,3H),2.31–2.13(m,2H),2.03(ddd,J=13.3,7.1,3.0Hz,1H).ESI-MS m / z 353.35[M+H] + 354.20 [MH] - .

[0101] SL11c: 1 H NMR(400MHz,DMSO)δ11.03(s,1H),9.56(d,J=1.6Hz,1H),7.64–7.56(m,1H),7.21–7.09(m,2H),5.11–4.99(m,2H),3.70(ddt,J=11.5,7.7,3.8Hz,1H),3.53–3.46(m,1H),2.93–2.81(m,1H),2.59(d,J=16.9Hz,1H),2.17–2.09(m,2H),2.04–1.91(m,2H),1.83–1.72(m,1H).ESI-MS m / z356.20[M+H] + ;354.35[M-H] - .

[0102] SQ11a: 1 H NMR(400MHz,CDCl3)δ9.73(s,1H),8.26(s,1H),7.71(d,J=8.5Hz,1H),7.31(d,J=1.9Hz,1H),7.08(dd,J=8.5,2.1Hz,1H),4.96(dd,J=12.1,5.1Hz,1H),3.87(d,J=13.3Hz,2H),3.25–3.14(m,2H),2.95–2.81(m,2H),2.81–2.73(m,1H),2.62–2.54(m,1H),2.14(dd,J=12.8,5.1Hz,1H),2.11–2.04(m,2H),1.84–1.77(m,2H).

[0103] SQ11b: 1 H NMR(400MHz,CDCl3)δ9.77(s,1H),7.67(d,J=8.4Hz,1H),6.98(s,1H),6.73(d,J=8.4Hz,1H),4.96(dd,J=11.7,4.8Hz,1H),3.82(dd,J=10.3,4.4Hz,1H),3.59(t,J=9.0Hz,1H),3.29(dd,J=11.2,6.4Hz,1H),2.92–2.83(m,2H),2.78(dd,J=18.0,8.3Hz,2H),2.49–2.41(m,1H),2.41–2.32(m,1H),2.19–2.06(m,2H).ESI-MS m / z 358.45[M+Na] + ;354.25[M-H] - .

[0104] SQ11c: 1 H NMR (400MHz, CDCl3) δ9.52(d,J=2.0Hz,1H),7.60(d,J=8.4Hz,1H),6.90(d,J=2.0Hz,1H),6.64(dd,J=8.4,2.2Hz,1H),4.91–4.85(m,1H),4.27 (t,J=6.0Hz,1H),3.67–3.60(m,1H),3.45(d,J=8.5Hz,1H),2.84–2.75(m,2H),2.75–2.58(m,3H),2.26–2.20(m,2H),2.09–2.03(m,2H).ESI-MS m / z 356.40[M+H] + 388.35 [M+Na] + 524.15 [MH] - .

[0105] Synthesis of compounds SL12a-c and SQ12a-c:

[0106] Intermediates SL11a-c and SQ11a-c (1.32 mmol) were dissolved in DCM and MeOH solutions (v:v = 1:1) with the corresponding aldehyde and ketone (1.99 mmol) and N,N-diisopropylethylamine (1.32 mmol). A few drops of AcOH were then added dropwise, and sodium cyanoborohydride (3.98 mmol) was added to the system in portions. The reaction mixture was then stirred overnight at room temperature and monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the mixture was purified by rapid column chromatography to obtain the desired yellow intermediates SL12a-c and SQ12a-c.

[0107] SL12a: 1 H NMR (400MHz, CDCl3) δ7.56(t,J=7.8Hz,1H),7.35(d,J=7.1Hz,1H),7.16(d,J=8.4Hz,1H),4.95(dd,J=12.1,5.3Hz,1H),3.74(t,J=10.0Hz,2H),3. 42(s,4H),2.92–2.77(m,4H),2.36(s,4H),2.25(d,J=7.0Hz,2H),2.10(d d,J=13.2,4.4Hz,1H),1.90(d,J=12.3Hz,2H),1.72(s,4H),1.46(s,9H).

[0108] SL12b: 1H NMR(400MHz,DMSO)δ11.03(s,1H),7.56(dd,J=8.6,7.0Hz,1H),7.12(dd,J=11.9,5.1Hz,2H),5.06(dd,J=12.8,5.4Hz,1H),3.62(t,J=7.7Hz,2H),3.58–3.49(m,1H),3.36(d,J=7.5Hz,2H),2.94–2.81(m,1H),2.63–2.51(m,4H),2.50(d,J=1.8Hz,2H),2.35(dd,J=12.5,7.8Hz,6H),2.10–1.97(m,2H),1.69(dd,J=17.7,9.1Hz,1H),1.40(s,9H).ESI-MS m / z 526.50[M+H] + ;524.30[M-H] - .

[0109] SL12c: 1 H NMR(400MHz,DMSO)δ11.06(s,1H),7.58(t,J=7.7Hz,1H),7.21(d,J=8.6Hz,1H),7.16(d,J=6.6Hz,1H),5.13–5.02(m,1H),4.63(s,1H),3.88(d,J=9.3Hz,1H),3.21(s,4H),2.89(t,J=12.8Hz,1H),2.58(d,J=17.5Hz,2H),2.42–2.31(m,3H),2.31–2.11(m,4H),1.99(s,2H),1.80(dd,J=19.7,10.8Hz,2H),1.41(s,1H),1.38(s,9H).ESI-MSm / z 526.45[M+H] + ;523.20[M-H] - .

[0110] SQ12a: 1H NMR(400MHz,DMSO)δ7.65(d,J=8.3Hz,1H),7.30(s,1H),7.22(d,J=8.0Hz,1H),5.12–5.00(m,1H),4.03(d,J=12.3Hz,2H),3.31(s,4H),2.96(t,J=12.2Hz,2H),2.87(d,J=12.9Hz,1H),2.64–2.52(m,2H),2.29(s,4H),2.14(d,J=5.1Hz,2H),2.02(d,J=10.8Hz,1H),1.79(d,J=11.8Hz,3H),1.40(s,9H),1.14(d,J=11.2Hz,2H).ESI-MSm / z 540.35[M+H] + .

[0111] SQ12b: 1 H NMR(400MHz,CDCl3)δ7.65(d,J=8.4Hz,1H),6.95(s,1H),6.69(d,J=8.5Hz,1H),4.94(dd,J=11.8,5.2Hz,1H),3.61–3.53(m,1H),3.52–3.43(m,6H),3.43–3.37(m,1H),3.23–3.15(m,1H),2.91–2.71(m,3H),2.63(dt,J=14.3,7.3Hz,1H),2.53–2.33(m,6H),2.26–2.18(m,1H),2.17–2.09(m,1H),1.83(dd,J=12.3,8.0Hz,1H),1.47(s,9H).ESI-MS m / z 526.35[M+H] + ;524.55[M-H] - .

[0112] SQ12c: 1 H NMR(400MHz,CDCl3)δ7.66(d,J=8.5Hz,1H),7.05(s,1H),6.78(d,J=8.2Hz,1H),4.95(dd,J=12.1,5.2Hz,1H),3.57–3.39(m,6H),3.31(d,J=9.3Hz,1H),2.94–2.67(m,5H),2.55(dd,J=10.0,4.7Hz,2H),2.45(s,2H),2.37–2.29(m,1H),2.19–2.08(m,4H),1.48(s,9H).ESI-MS m / z 526.25[M+H] +524.20 [MH] - .

[0113] Synthesis of compounds SL13a-c and SQ13a-c:

[0114] SL12a-c and SQ12a-c were dissolved in dioxane hydrochloride and reacted overnight at room temperature. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum evaporation to obtain SL13a-c and SQ13a-c as pale yellow solids.

[0115] Example 1: Synthesis of ST1

[0116]

[0117] Synthesis route:

[0118]

[0119] S1 (120 mg, 0.34 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine was added while stirring, and the mixture was stirred for 10 minutes. Separately, SL3 (160 mg, 0.42 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine was added. The resulting SL3 solution was added dropwise to the reaction mixture, and the reaction was allowed to proceed overnight at room temperature, monitored by TLC. After the reaction was complete, the reaction mixture was added to 15 mL of water, and the resulting solid was purified by rapid column chromatography. Filtration yielded a yellow solid, ST1 (78 mg, 65.0%). 1 H NMR (400MHz, DMSO) δ11.08 (s, 1H), 10.62 (s, 1H), 10.34 (s, 1H), 7.81 (d, J = 3.9Hz, 1H), 7 .76–7.71(m,1H),7.66(dd,J=18.1,8.9Hz,4H),7.62(d,J=3.9Hz,1H),7.41–7.34(m,2H) ,6.59(d,J=11.7Hz,1H),6.27(d,J=11.8Hz,1H),5.10(dd,J=12.8,5.3Hz,1H),3.70(s, 2H),3.55(s,2H),3.31(s,4H),2.89–2.81(m,1H),2.63–2.52(m,2H),2.07–1.98(m,1H). 13C NMR (101MHz, DMSO) δ173.27,170.44,167.49,167.03,166.81,162.56,154.82,152.20,149.91,148.50,136.41,135.85,134.08,1 33.94,126.35,124.37,121.70,120.04,117.41,116.83,115.69,113.96,50.86,50.48,49.29,46.08,41.02,31.42,22.50. HPLC: R 3.073 min, purity 99.4%.

[0120] Example 2

[0121]

[0122] Compound ST2 can be prepared by replacing SL3 with SL5a according to the method in Example 1. 1 H NMR (400MHz, DMSO) δ11.10(s,1H),10.61(s,1H),10.31(s,1H),7.81(d,J=3.7Hz,1H),7.69(d,J=8.9Hz,3H),7.66–7.5 8(m,3H),7.34(dd,J=12.4,7.9Hz,2H),6.57(d,J=11.8Hz,1H),6.23(d,J=11.8Hz,1H),5.09(dd,J=12.7,5.1Hz,1H),4. 41(d,J=11.8Hz,1H),3.75(d,J=12.2Hz,1H),3.30(s,4H),3.01(t,J=11.9Hz,1H),2.94–2.80(m,1H),2.69(d,J=13.8Hz ,4H),2.65–2.52(m,3H),2.09–1.97(m,1H),1.88(d,J=28.2Hz,1H),1.75(s,1H),1.43(t,J=22.1Hz,2H).HRMS(ESI)for C 37 H 36 N8O 10 (M+H) + :calcd 753.2554; found,753.2633.HPLC:t R 3.011 min, purity 98.9%.

[0123] Example 3

[0124]

[0125] Compound ST3 can be prepared by replacing SL3 with SL5b, following the method in Example 1. 1 H NMR (400MHz, DMSO) δ11.09(s,1H),10.79(s,1H),10.62(s,1H),7.82(d,J=3.9Hz,1H),7.72–7.70(m,1H) ,7.68(d,J=2.7Hz,2H),7.65(s,1H),7.65–7.61(m,2H),7.35(t,J=8.3Hz,2H),6.39–6.26(m,2H),5.08(d d,J=12.9,5.4Hz,1H),4.10(t,J=7.9Hz,1H),3.96(t,J=8.6Hz,2H),3.81(dd,J=10.4,4.8Hz,1H),3.32– 3.29(m,4H),3.28–3.21(m,1H),2.93–2.80(m,1H),2.55(dd,J=22.8,11.0Hz,6H),2.02(d,J=5.2Hz,1H). 13 C NMR (101MHz, DMSO) δ173.21,170.41,167.44,166.81,166.72,162.81,154. 75,152.14,151.41,149.97,148.43,136.29,135.77,134.05,133.86,130.7 8,130.53,129.22,124.16,121.63,121.08,120.02,116.95,116.76,115.3 0,113.91,53.89,51.77,51.75,50.55,49.20,31.35,22.45.HRMS(ESI)forC 35 H 32 N8O 10 (M+H) + :calcd 725.2241; found,725.2315.HPLC:t R 2.959 min, purity 99.3%.

[0126] Example 4

[0127]

[0128] Compound ST4 can be prepared by replacing SL3 with SL5c, following the method in Example 1. 1H NMR (400MHz, DMSO) δ11.09(s,1H),10.89(s,1H),10.64(s,1H),7.82(d,J=3.8Hz,1H),7.73–7 .62(m,6H),7.34(dd,J=15.4,7.8Hz,2H),6.31(dd,J=27.5,12.2Hz,2H),5.09(dd,J=12.7,5. 2Hz,1H),4.16(t,J=8.1Hz,1H),4.03(t,J=8.9Hz,1H),3.81–3.70(m,1H),3.62(dd,J=9.4,5. 1Hz,1H),3.28(s,4H),2.93–2.81(m,2H),2.67(s,2H),2.64–2.52(m,6H),2.07–1.98(m,1H). 13 CNMR(101MHz,DMSO)δ173.21,170.40,167.43,166.92,166.70,162.81,154.76,152.14,149.94,148.42,136.29,135.78,134.03,133.8 6,130.73,130.49,124.15,121.64,120.01,117.00,116.77,115.35,113.91,54.44,52.90,52.19,49.19,31.35,22.43.HRMS(ESI)forC 36 H 35 N8O 10 (M+H) + :calcd 739.2398; found,739.2471.HPLC:t R 3.082 min, purity 96.3%.

[0129] Example 5

[0130]

[0131] Compound ST5 can be prepared by replacing SL3 with SL5d according to the method in Example 1. 1H NMR(400MHz,DMSO)δ11.10(s,1H),10.62(s,1H),10.28(s,1H),7.82(s,1H) ,7.66(m,J=17.2Hz,6H),7.34(s,2H),6.55(d,J=7.5Hz,1H),6.22(s,1H),5. 10(s,1H),4.39(s,1H),3.71(s,1H),3.29(s,6H),2.94(d,J=47.3Hz,2H),2. 61(s,5H),2.20(s,2H),2.03(s,1H),1.79(s,2H),1.68(s,1H),1.07(s,2H). 13 C NMR (101MHz, DMSO) δ173.21,170.41,167.45,166.69,166.16,162.52,154.74,152.13,150.11,148.44,136.27,135.87,134.06,133.78,125.66 ,124.10,121.61,119.90,116.90,116.76,115.21,113.91,64.14,53.44 ,50.91,49.19,46.08,33.20,31.36,30.71,30.12,22.45.HRMS(ESI)for C 38 H 39 N8O 10 (M+H) + :calcd 767.2711; found,767.2788.HPLC:t R 3.033 min, purity 97.5%.

[0132] Example 6

[0133]

[0134] Compound ST6 can be prepared by replacing SL3 with SL9a, following the method in Example 1. 1H NMR (400MHz, DMSO) δ11.09(s,1H),10.62(s,1H),10.32(s,1H),7.81(d,J=3.5Hz,1H),7.65(dt ,J=8.9,6.1Hz,6H),7.32(d,J=7.1Hz,2H),6.55(d,J=11.7Hz,1H),6.25(d,J=11.8Hz,1H),5.0 9(dd,J=12.6,5.1Hz,1H),3.74(d,J=9.7Hz,2H),3.52(s,4H),2.87(t,J=11.2Hz,3H),2.59(d, J=14.4Hz,7H),2.11–1.97(m,1H),1.87(d,J=9.7Hz,2H),1.64(d,J=10.2Hz,2H).HRMS(ESI)for C 37 H 36 N8O 10 (M+H) + :calcd 753.2554; found,753.2630.HPLC:t R 2.967 min, purity 96.5%.

[0135] Example 7

[0136]

[0137] Compound ST7 can be prepared by replacing SL3 with SL9b, following the method in Example 1. 1 H NMR (400MHz, DMSO) δ11.03(s,1H),10.59(s,1H),10.28(s,1H),7.80(d,J=3.9Hz,1H),7.65(dt,J=10 .0,6.5Hz,5H),7.56(dd,J=8.4,7.2Hz,1H),7.16–7.06(m,2H),6.54(d,J=11.8Hz,1H),6.25(d,J=11. 8Hz,1H),5.07(dd,J=12.7,5.3Hz,1H),3.71–3.49(m,6H),3.38(s,2H),3.00–2.80(m,2H),2.55(dd, J=24.7,12.5Hz,4H),2.49–2.35(m,2H),2.17(d,J=4.8Hz,1H),2.06–1.95(m,1H),1.87–1.74(m,1H). 13C NMR (101MHz, DMSO) δ173.28,170.54,167.52,167.02,166.54,162.52,154. 81,152.19,148.50,146.31,146.28,135.89,135.78,135.29,134.37,133.8 9,126.29,121.68,120.00,116.82,113.96,110.61,63.84,55.83,51.38,51 .09,50.50,49.24,49.18,45.90,31.46,29.29,22.62,22.56.HRMS(ESI)for C 36 H 35 N8O 10 (M+H) + :calcd 739.2398; found,739.2475.HPLC:t R 2.782 min, purity 99.0%.

[0138] Example 8

[0139]

[0140] Compound ST8 can be prepared by replacing SL3 with SL13a, following the method in Example 1. 1 H NMR (400MHz, DMSO) δ11.09(s,1H),10.60(d,J=13.0Hz,1H),10.31(s,1H),7.81(d,J=3.9Hz,1 H),7.72–7.60(m,6H),7.32(d,J=7.5Hz,2H),6.55(d,J=11.8Hz,1H),6.24(d,J=11.8Hz,1H),5 .09(dd,J=12.8,5.3Hz,1H),3.74(d,J=10.7Hz,2H),3.51(s,2H),2.87(t,J=12.1Hz,3H),2.5 6(dd,J=24.7,15.5Hz,7H),2.09–1.97(m,1H),1.86(d,J=10.5Hz,2H),1.63(d,J=10.6Hz,2H). 13C NMR(101MHz,DMSO)δ173.28,170.50,167.54,166.78,166.58,162.55,154 .82,152.20,150.22,148.50,136.21,135.89,135.84,134.10,133.90,126 .25,124.39,121.68,120.02,116.86,116.82,115.01,113.96,61.03,50. 82,49.25,48.89,48.56,46.26,41.34,31.43,28.31,22.54.HRMS(ESI)for C 38 H 38 N8O 10 (M+H) + :calcd 767.2711; found,767.2793.HPLC:t R 3.059 min, purity 99.2%.

[0141] Example 9

[0142]

[0143] Compound ST9 can be prepared by replacing SL3 with SL13b, following the method described in Example 1. 1 H NMR (400MHz, DMSO) δ11.03(s,1H),10.59(s,1H),10.27(s,1H),7.80(d,J=3.6Hz,1H),7.69(d,J=8. 8Hz,2H),7.66–7.59(m,3H),7.55(t,J=7.7Hz,1H),7.10(t,J=8.0Hz,2H),6.54(d,J=11.8Hz,1H),6 .24(d,J=11.8Hz,1H),5.06(dd,J=12.5,5.1Hz,1H),3.62(s,2H),3.55(s,1H),3.51(s,2H),3.33(s ,4H),2.88(t,J=12.9Hz,1H),2.58(d,J=18.5Hz,2H),2.48–2.33(m,6H),2.04(s,2H),1.68(s,1H). 13C NMR (101MHz, DMSO) δ173.29,170.56,167.61,167.57,166.99,166.60,162. 52,154.82,152.20,148.51,146.45,135.88,135.26,134.41,133.90,126.1 9,121.68,120.01,116.83,113.96,111.81,110.41,61.10,55.97,53.19,52 .81,51.22,49.21,45.95,41.01,36.10,31.44,29.98,22.62.HRMS(ESI)for C 37 H 37 N8O 10 (M+H) + :calcd753.2554; found,753.2630.HPLC:t R 3.024 min, purity 98.7%.

[0144] Example 10

[0145]

[0146] Compound ST10 can be prepared by replacing SL3 with SL13c, following the method described in Example 1. 1 H NMR (400MHz, DMSO) δ11.07(s,1H),10.61(s,1H),10.28(s,1H),7.81(d,J=3.8Hz,1H),7.69(d,J=8.8Hz ,2H),7.66–7.60(m,3H),7.56(t,J=7.6Hz,1H),7.23–7.11(m,2H),6.51(d,J=11.8Hz,1H),6.21(d,J=1 1.8Hz,1H),5.13–5.01(m,1H),4.62(s,1H),3.88(d,J=8.9Hz,1H),3.39(s,2H),3.23(s,3H),2.95–2.7 8(m,1H),2.57(d,J=16.5Hz,2H),2.47–2.31(m,5H),2.27–2.10(m,2H),1.97(s,2H),1.90–1.72(m,2H). 13C NMR (101MHz, DMSO) δ173.27,170.55,167.60,167.51,166.98,166.53,162.48,154. 81,152.20,148.52,146.26,135.87,135.24,134.35,134.29,133.90,126.16,122.8 2,121.65,119.98,116.82,113.96,112.34,112.07,111.98,60.41,57.54,53.47,5 3.00,49.22,49.16,46.02,41.07,31.44,30.34,24.03,22.69,22.51.HRMS(ESI)for C 37 H 37 N8O 10 (M+H) + :calcd 753.2554; found,753.2636.HPLC:t R 3.129 min, purity 98.6%.

[0147] Example 11

[0148]

[0149] Compound ST11 can be prepared by replacing SL3 with SQ5c according to the method in Example 1. 1 H NMR (400MHz, DMSO) δ11.08 (s, 1H), 10.90 (s, 1H), 10.65 (s, 1H), 7.81 (d, J = 3.2Hz, 1H), 7.70 (s,2H),7.66(d,J=5.2Hz,4H),7.32(s,1H),7.24(d,J=7.8Hz,1H),6.32(q,J=12.3Hz,2H), 5.11–5.02(m,1H),4.09(dt,J=17.1,8.0Hz,2H),3.75(dd,J=13.2,8.4Hz,2H),3.63(s,1H) ,3.41(s,6H),2.96–2.78(m,2H),2.59(d,J=16.9Hz,6H),2.08–1.97(m,1H).HRMS(ESI)forC 36 H 35 N8O 10 (M+H) + :calcd 739.2398; found,739.2469.HPLC:t R 3.119 min, purity 99.3%.

[0150] Example 12

[0151]

[0152] Compound ST12 can be prepared by replacing SL3 with SQ5d according to the method in Example 1. 1 H NMR(400MHz,DMSO)δ11.07(s,1H),10.61(s,1H),10.28(s,1H),7.81(s,1H),7.74–7.58(m,6H ),7.37–7.18(m,2H),6.55(d,J=11.5Hz,1H),6.21(d,J=11.5Hz,1H),5.07(d,J=7.7Hz,1H),4 .39(d,J=10.1Hz,1H),3.71(d,J=10.6Hz,1H),3.42(s,4H),3.10–2.81(m,2H),2.71–2.52(m, 4H), 2.49 (s, 3H), 2.18 (s, 2H), 2.03 (s, 1H), 1.79 (s, 2H), 1.68 (d, J = 9.7Hz, 1H), 1.08 (s, 2H). 13 CNMR(101MHz,DMSO)δ173.26,170.53,168.02,167.44,166.22,162.61,155. 69,154.82,152.20,148.53,136.34,135.95,134.32,133.86,125.81,125.3 4,121.69,119.99,118.78,118.21,116.82,113.96,108.32,64.09,53.16,4 9.26,47.36,46.14,40.83,33.28,31.46,30.76,30.17,22.66.HRMS(ESI)for C 38 H 39 N8O 10 (M+H) + :calcd 767.2711; found,767.2786.HPLC:t R 2.994 min, purity 99.0%.

[0153] Example 13

[0154]

[0155] Compound ST13 can be prepared by replacing SL3 with SQ9b according to the method in Example 1. 1H NMR (400MHz, DMSO) δ11.07(s,1H),10.61(s,1H),10.32(s,1H),7.66(s,6H),6.88(d,J=48.1Hz,2H),6.41(d,J=113.7Hz,2 H),5.06(s,1H),3.61(d,J=50.7Hz,6H),3.24(s,2H),2.95(d,J=52.0Hz,3H),2.55(s,3H),2.32–1.81(m,4H),1.24(s,2H). 13 C NMR (101MHz, DMSO) δ173.28,170.61,168.16,167.69,166.58,162.54,154 .81,152.19,148.51,135.89,135.78,134.45,133.91,126.34,125.35,12 1.69,120.02,116.81,116.27,115.64,113.94,105.99,63.75,52.27,51. 23,50.93,49.17,47.40,45.88,40.93,31.47,29.16,22.73.HRMS(ESI)for C 36 H 35 N8O 10 (M+H) + :calcd 739.2398; found,739.2474.HPLC:t R 2.950 min, purity 98.7%.

[0156] Example 14

[0157]

[0158] Compound ST14 can be prepared by replacing SL3 with SQ13a, following the method in Example 1. 1H NMR (400MHz, DMSO) δ11.07(s,1H),10.61(s,1H),10.29(s,1H),7.81(d,J=3.3Hz,1H),7.70(d,J=8.4Hz,2H), 7.64(d,J=9.7Hz,4H),7.29(s,1H),7.21(d,J=8.2Hz,1H),6.54(d,J=11.7Hz,1H),6.24(d,J=11.7Hz,1H),5. 11–5.02(m,1H),4.02(d,J=11.7Hz,2H),3.50(s,2H),3.35(s,2H),2.92(dt,J=25.1,12.5Hz,3H),2.59(d,J= 17.8Hz,2H),2.36(s,4H),2.17(s,2H),2.02(d,J=9.8Hz,1H),1.80(d,J=10.8Hz,3H),1.15(d,J=10.8Hz,2H). 13 CNMR(101MHz,DMSO)δ173.26,170.57,168.10,167.43,166.58,162.51,155. 47,154.82,152.20,148.53,135.90,134.51,133.91,126.21,125.45,121.6 8,120.01,118.04,117.82,116.82,113.95,108.18,63.99,53.32,52.88,49 .22,47.71,46.02,41.09,40.64,32.93,31.46,30.01,22.68.HRMS(ESI)for C 38 H 39 N8O 10 (M+H) + :calcd 767.2711; found,767.2783.HPLC:t R 2.868 min, purity 99.6%.

[0159] Example 15

[0160]

[0161] Compound ST15 can be prepared by replacing SL3 with SQ13b, following the method in Example 1. 1H NMR(400MHz,DMSO)δ11.05(s,1H),10.63(s,1H),10.32(s,1H),7.81(s,1H),7.69(s,2 H),7.65(s,4H),6.89(s,1H),6.80(d,J=6.5Hz,1H),6.54(d,J=11.3Hz,1H),6.25(d,J= 11.4Hz,1H),5.05(d,J=7.9Hz,1H),3.52(s,6H),3.13(s,1H),2.87(d,J=13.1Hz,1H), 2.58(d,J=19.3Hz,4H),2.42(d,J=16.3Hz,6H),2.12(s,1H),2.02(s,1H),1.75(s,1H). 13 C NMR (101MHz, DMSO) δ173.27,170.61,168.18,167.70,166.61,162.53,154. 82,152.33,152.20,148.53,135.90,134.47,133.91,126.22,125.39,121.6 7,120.00,116.83,115.95,115.72,113.95,105.91,61.16,53.09,52.59,49 .16,47.67,45.96,41.01,35.94,31.47,29.63,29.48,22.73.HRMS(ESI)for C 37 H 37 N8O 10 (M+H) + :calcd 753.2554; found,753.2630.HPLC:t R 3.107 min, purity 98.4%.

[0162] Example 16

[0163]

[0164] Compound ST16 can be prepared by replacing SL3 with SQ13c, following the method in Example 1. 1H NMR (400MHz, DMSO) δ11.04(s,1H),10.60(s,1H),10.30(s,1H),7.81(s,1H),7.68(s,2H),7. 63(s,4H),6.99(s,1H),6.87(s,1H),6.54(d,J=11.4Hz,1H),6.24(d,J=11.5Hz,1H),5.04(d ,J=8.3Hz,1H),4.14(s,1H),3.52(s,3H),3.35(s,2H),3.28–3.21(m,1H),2.88(s,1H),2.57 (d,J=16.8Hz,4H),2.40(d,J=16.0Hz,4H),2.06(s,2H),2.00(s,2H),1.25(d,J=6.1Hz,1H). 13 C NMR (101MHz, DMSO) δ173.26,170.62,168.15,167.62,166.56,162.53,154. 81,152.20,151.95,148.53,135.88,134.46,133.91,126.28,125.45,121.6 8,120.01,116.82,116.19,116.05,113.95,106.40,59.10,57.26,53.55,53 .16,49.17,48.75,46.07,41.09,31.46,29.74,22.88,22.71.HRMS(ESI)for C 37 H 37 N8O 10 (M+H) + :calcd 753.2554; found,753.2627.HPLC:t R 3.128 min, purity 98.1%.

[0165] Example 17

[0166]

[0167] Compound ST17 can be prepared by replacing S1 with S2 and SL3 with SL5d, following the method of Example 1. 1H NMR (400MHz, DMSO) δ11.09(s,1H),10.57(s,1H),9.99(s,1H),7.82(d,J=3.9Hz,1H),7.71(t,J=7.7Hz,1H),7.66( s,1H),7.64(s,1H),7.61(t,J=6.7Hz,3H),7.35(t,J=8.4Hz,2H),5.10(dd,J=12.8,5.3Hz,1H),4.37(d,J=11.6Hz, 1H),3.92(d,J=12.6Hz,1H),3.33(s,6H),3.02(t,J=12.4Hz,1H),2.93–2.83(m,1H),2.62(d,J=5.4Hz,3H),2.57( s,2H),2.55(s,5H),2.20(s,2H),2.08–1.95(m,2H),1.79(d,J=12.3Hz,2H),1.73(d,J=13.0Hz,1H).HRMS(ESI)for C 38 H 41 N8O 10 (M+H) + :calcd 769.2867; found,769.2943.HPLC:t R 2.946 min, purity 96.5%.

[0168] Example 18

[0169]

[0170] Compound ST18 can be prepared by replacing S1 with S3 and SL3 with SL5d, following the method of Example 1. 11H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 10.58 (s, 1H), 9.93 (s, 1H), 7.81 (d, J = 3.9 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 9.4 Hz, 3H), 7.34 (dd, J = 11.0, 8.0 Hz, 2H), 5.09 (dd, J = 12.7, 5.3 Hz, 1H), 4.36 (t, J = 5.1 Hz, 1H), 4.11 (q, J = 5.2 Hz, 1H), 3.86 (d, J = 12.7 Hz, 1H), 3.47–3.42 (m, 1H), 3.29 (s, 4H), 3.18 (d, J = 5.2 Hz, 3H), 2.99 (t, J = 12.2 Hz, 1H), 2.94–2.83 (m, 1H), 2.60 (d, J = 17.7 Hz, 2H), 2.54 (s, 2H), 2.36 (t, J = 7.1 Hz, 4H), 2.19 (d, J = 5.3 Hz, 2H), 2.07–1.99 (m, 1H), 1.81 (dd, J = 14.3, 7.1 Hz, 3H), 1.73 (d, J = 13.7 Hz, 2H). 13 13C NMR (101 MHz, DMSO) δ 173.27, 171.31, 170.47, 170.34, 167.52, 166.76, 154.78, 152.18, 150.19, 148.57, 136.47, 136.34, 134.13, 133.29, 124.17, 121.62, 119.80, 116.99, 116.75, 115.29, 113.97, 64.15, 56.50, 53.50, 51.01, 49.27, 49.07, 45.43, 41.53, 36.00, 33.22, 32.19, 31.42, 30.69, 22.52, 21.29, 19.03. HRMS (ESI) for C 39 1H 43 14N8O 10 (M + H) + : calcd 783.3024; found, 783.3100. HPLC: t R r 3.043 min, purity = 95.2%.

[0171] Example 19

[0172]

[0173] Compound ST19 can be prepared by replacing S1 with S4 and SL3 with SL5d, following the method of Example 1. 1 H NMR (400MHz, DMSO) δ11.09(s,1H),10.59(d,J=18.9Hz,2H),7.82(s,1H),7.65(d,J=22.1Hz,6H),7.35(s,2H),5.76(s,1H),5.08(s,1H),4 .43(d,J=10.8Hz,3H),4.16(s,2H),3.69(s,1H),3.33(s,6H),2.93(d,J=42.6Hz,2H),2.61(s,6H),2.20(s,2H),2.03(s,1H),1.77(s,3H). 13 C NMR (101MHz, DMSO) δ173.27,170.47,168.56,168.17,167.52,166.76,154.83 ,152.20,150.19,148.53,136.35,135.62,134.14,133.78,124.19,121.73,1 20.01,116.99,116.82,115.29,113.97,72.01,70.43,64.10,55.38,53.51,5 1.01,49.27,44.38,41.90,33.01,31.43,31.13,30.52,22.52.HRMS(ESI)for C 38 H 41 N8O 11 (M+H) + :calcd 785.2857; found,785.2894.HPLC:t R 3.085 min, purity 96.1%.

[0174] Example 20

[0175]

[0176] Compound ST20 can be prepared by replacing S1 with S2 and SL3 with SL5c, following the method of Example 1. 1H NMR (400MHz, DMSO) δ11.09 (s, 1H), 10.57 (s, 1H), 10.00 (s, 1H), 7.81 (d, J = 3.3Hz, 1H), 7.70(t,J=7.6Hz,1H),7.62(dd,J=22.3,8.8Hz,5H),7.40–7.30(m,2H),5.10(dd,J=12. 6,4.7Hz,1H),4.24(t,J=7.9Hz,1H),3.92(t,J=8.5Hz,1H),3.83(s,1H),3.50(s,1H), 3.33(s,6H),2.93–2.79(m,2H),2.63–2.53(m,8H),2.35(s,2H),2.02(d,J=5.8Hz,1H). 13 C NMR(101MHz,DMSO)δ173.27,172.26,171.17,171.06,170.47,167.50,166.75 ,154.79,154.76,152.18,152.17,150.15,148.55,136.45,136.32,134.10,1 33.32,121.63,119.80,116.75,113.97,62.01,54.43,53.04,51.93,50.89,4 9.26,46.86,35.85,31.42,30.01,26.05,22.52,20.93,20.71.HRMS(ESI)for C 36 H 37 N8O 10 (M+H) + :calcd 741.2554; found,741.2540.HPLC:t R 2.937 min, purity 98.3%.

[0177] Example 21

[0178]

[0179] Compound ST21 can be prepared by replacing S1 with S3 and SL3 with SL5c, following the method of Example 1. 1H NMR (400MHz, DMSO) δ11.09(s,1H),10.57(s,1H),9.94(s,1H),7.81(d,J=4.1Hz,1H),7.69(d,J=6.9Hz,1H ),7.64(s,2H),7.61(d,J=6.3Hz,3H),7.33(t,J=9.4Hz,2H),5.09(dd,J=12.6,5.3Hz,1H),4.22–4.10(m,1 H),3.92(t,J=8.8Hz,1H),3.75(t,J=6.7Hz,1H),3.50(d,J=7.7Hz,1H),3.33(s,8H),2.83(d,J=30.8Hz,2H ), 2.57 (s, 4H), 2.34 (d, J = 7.4Hz, 2H), 2.28 (t, J = 7.0Hz, 1H), 2.08 (t, J = 8.0Hz, 2H), 1.80 (q, J = 7.5Hz, 2H). 13 C NMR(101MHz,DMSO)δ173.27,172.26,171.17,171.06,170.47,167.50,166.75 ,154.79,154.76,152.18,152.17,150.15,148.55,136.45,136.32,134.10,1 33.32,121.63,119.80,116.75,113.97,62.01,54.43,53.04,51.93,50.89,4 9.26,46.86,35.85,31.42,30.01,26.05,22.52,20.93,20.71.HRMS(ESI)for C 37 H 39 N8O 10 (M+H) + :calcd 755.2711; found,755.2750.HPLC:t R 2.991 min, purity 98.3%.

[0180] Example 22

[0181]

[0182] Compound ST22 can be prepared by replacing S1 with S4 and SL3 with SL5c, following the method of Example 1. 1H NMR (400MHz, DMSO) δ11.09(s,1H),10.68(s,1H),10.41(s,1H),7.82(d,J=3.8Hz,1H),7.72(s,1H),7.7 0(s,2H),7.67(d,J=8.7Hz,3H),7.34(dd,J=12.4,7.8Hz,2H),5.10(dd,J=12.8,5.3Hz,1H),4.28–4.17( m,4H),4.15(s,2H),4.03(t,J=8.5Hz,1H),3.89–3.82(m,1H),3.60(dd,J=9.1,5.4Hz,1H),3.28(s,4H) ,2.89(t,J=15.1Hz,2H),2.62(d,J=4.8Hz,3H),2.56(d,J=3.1Hz,4H),2.07–2.00(m,1H).HRMS(ESI)for C 36 H 37 N8O 11 (M+H) + :calcd 757.2504; found,755.2579.HPLC:t R 3.194 min, purity 98.1%.

[0183] Example 23

[0184]

[0185] Compound ST23 can be prepared by replacing S1 with S2 and SL3 with SL13b, following the method of Example 1. 1 HNMR(400MHz,DMSO)δ11.06(s,1H),10.57(s,1H),9.99(s,1H),7.81(s,1H),7.62(s,6H),7.11(s,2H),5.08(s,1H),3 .62(s,4H),3.48(s,4H),3.18(s,1H),2.89(s,1H),2.62(s,2H),2.57(s,4H),2.39(s,6H),2.04(s,2H),1.69(s,1H). 13C NMR(101MHz,DMSO)δ177.43,173.28,170.93,170.55,170.13,167.61,167.57,16 6.99,154.77,152.17,148.59,146.46,136.60,135.27,134.42,133.18,127.98,1 21.64,119.60,116.73,113.95,111.82,110.44,61.07,56.03,55.37,53.69,53. 26,51.17,49.22,45.11,36.03,31.80,31.45,30.01,27.96,22.63.HRMS(ESI)for C 37 H 39 N8O 10 (M+H) + :calcd 755.2711; found,755.2792.HPLC:t R 3.052 min, purity 98.1%.

[0186] Example 24

[0187]

[0188] Compound ST24 can be prepared by replacing S1 with S3 and SL3 with SL13b, following the method of Example 1. 1 HNMR (400MHz, DMSO) δ11.06 (s, 1H), 10.57 (s, 1H), 9.92 (s, 1H), 7.81 (d, J = 3.8Hz, 1H), 7.6 5(d,J=8.8Hz,3H),7.61(s,2H),7.58–7.52(m,1H),7.10(t,J=9.3Hz,2H),5.06(dd,J=12.9 ,5.4Hz,1H),3.68–3.52(m,4H),3.46(d,J=6.9Hz,4H),2.94–2.81(m,1H),2.63–2.52(m,3H ),2.43–2.32(m,10H),2.12–1.96(m,2H),1.80(dd,J=14.9,7.4Hz,2H),1.73–1.62(m,1H). 13C NMR(101MHz,DMSO)δ173.29,171.27,170.59,170.56,167.60,167.57,166.99,154.78,1 52.18,151.11,148.57,146.45,136.47,135.27,134.44,133.29,129.12,121.64,120.96 ,119.80,116.75,113.97,111.83,110.44,61.04,56.02,55.38,53.78,53.29,51.17,49. 21,45.26,41.39,35.96,33.46,32.05,31.44,30.02,22.62,21.17,20.92.HRMS(ESI)for C 38 H 41 N8O 10 (M+H) + :calcd 769.2867; found,769.2946.HPLC:t R 3.062 min, purity 96.0%.

[0189] Example 25

[0190]

[0191] Compound ST25 can be prepared by replacing S1 with S4 and SL3 with SL13b, following the method of Example 1. 1 HNMR (400MHz, DMSO) δ11.07(s,1H),10.62(s,1H),10.47(s,1H),7.81(d,J=3.9Hz,1H),7.69(t, J=6.1Hz,4H),7.62(d,J=3.9Hz,1H),7.58–7.53(m,1H),7.10(dd,J=13.0,7.8Hz,2H),5.07(dd, J=12.8,5.3Hz,1H),4.44(s,2H),4.16(s,2H),3.66–3.50(m,6H),3.39(s,2H),2.94–2.83(m,1H) ),2.61(s,1H),2.56(d,J=8.4Hz,2H),2.49–2.39(m,6H),2.09–1.98(m,2H),1.74–1.64(m,1H). 13C NMR (101MHz, DMSO) δ173.29,170.56,168.47,168.35,167.60,167.57,166.99,154.83,15 2.19,151.03,148.53,146.43,135.59,135.27,134.42,134.32,133.79,129.07,121.72, 120.90,120.04,116.81,113.96,111.83,110.44,71.86,70.26,60.97,56.00,55.95,55. 38,53.40,53.06,51.12,49.19,44.23,41.66,35.95,31.44,29.99,22.61.HRMS(ESI)for C 37 H 39 N8O 11 (M+H) + :calcd 771.2660; found,771.2739.HPLC:t R 3.083 min, purity 98.6%.

[0192] Example 26

[0193]

[0194] Compound ST26 can be prepared by replacing S1 with S2 and SL3 with SL9b, following the method of Example 1. 1 H NMR(400MHz,DMSO)δ11.06(s,1H),10.57(s,1H),10.00(s,1H),7.80(s,1H),7.61(s,6H),7.13(s,2H),5.07(s,1H),3.64 (s,3H),3.53(s,6H),3.04–2.75(m,3H),2.57(s,4H),2.50(s,4H),2.20(s,1H),2.01(s,1H),1.84(s,1H).HRMS(ESI)for C 36 H 37 N8O 10 (M+H) + :calcd741.2554; found,741.2630.HPLC:t R 3.153 min, purity 98.3%.

[0195] Example 27

[0196]

[0197] Compound ST27 can be prepared by replacing S1 with S3 and SL3 with SL9b, following the method of Example 1. 1 H NMR (400MHz, DMSO) δ11.07(s,1H),10.57(s,1H),9.93(s,1H),7.80(d,J=3.5Hz,1H),7.63 (dd,J=19.3,8.6Hz,6H),7.55(d,J=7.8Hz,1H),7.12(dd,J=14.8,7.2Hz,2H),5.08(dd,J= 12.5,4.9Hz,1H),3.64(s,3H),3.52(d,J=20.5Hz,6H),3.01–2.81(m,2H),2.63–2.51(m,4 H),2.37(s,4H),2.19(s,1H),2.01(d,J=5.0Hz,1H),1.83(d,J=6.0Hz,3H).HRMS(ESI)for C 37 H 39 N8O 10 (M+H) + :calcd 755.2711; found,755.2786.HPLC:t R 3.113 min, purity 96.2%.

[0198] Example 28

[0199]

[0200] Compound ST28 can be prepared by replacing S1 with S4 and SL3 with SL9b, following the method of Example 1. 1 H NMR(400MHz,DMSO)δ11.06(s,1H),10.60(s,1H),10.45(s,1H),7.81(s,1H),7.67(s,6H),7.12(s,2H),5.07(s,1H),4.43(s,2H), 4.16(s,2H),3.58(d,J=33.4Hz,6H),3.40(s,4H),2.91(s,2H),2.58(s,1H),2.46–2.31(m,2H),2.30–1.64(m,4H).HRMS(ESI)for C 36 H 37 N8O 11 (M+H) + :calcd 757.2504; found,755.2581.HPLC:t R 3.007 min, purity 98.0%.

[0201] In vitro and in vivo pharmacological experiments have demonstrated that the novel STING-PROTAC degrader of this invention, which acts on the STING / NF-KB signaling axis, exerts an effective renal protective effect in a cisplatin-induced acute kidney injury model, and is expected to become a new generation of renal protective agents for the treatment of AKI. The pharmacological experimental results of the compounds of this invention are as follows:

[0202] Experimental Example 1: Degradation Activity Screening and Structure-Activity Relationship

[0203] We successfully prepared 10 potential STING degraders (ST1-ST10), as shown in Table 1. At a fixed concentration of 5 μM, we conducted a preliminary evaluation of the degradation efficiency of these PROTACs using the human monocytic leukemia cell line THP-1. We found that most compounds exhibited higher efficiency in degrading STING. Specifically, compounds ST4, ST5, and ST10 showed degradation efficiencies of 72.3%, 71.1%, and 77.7%, respectively, while ST9 showed the highest efficiency at 90.6%. Simultaneously, we synthesized six compounds, ST11–ST16, to investigate the effect of the CRBN linker site on degradation activity. When the linker site changed from 4' to 5', ST11 and ST13 completely lost their degradation activity (ST11 vs ST4; ST13 vs ST7), and the degradation efficiencies of ST12 and ST15 were 52.3% and 73.6%, respectively, significantly lower than ST5 and ST9. Only ST16 maintained activity comparable to ST10. It is worth noting that ST14 has a degradation activity of 63.6%, which is significantly better than ST8.

[0204]

[0205] Table 1. Structure and activity of ST1-16

[0206]

[0207] ND = Non-degradable

[0208] Next, we replaced the trans double bonds with different types of flexible linker groups to obtain ST17–ST28 (Table 2). The results showed that the activity of these compounds was significantly reduced or even disappeared.

[0209]

[0210] Table 2. Structure and activity of ST17-28

[0211]

[0212] ND = Non-degradable

[0213] Based on the above analysis, it can be inferred that introducing rigid linking groups is beneficial to improving degradation activity, and fixing the linking site at the 4' position is the optimal choice. Meanwhile, the significant contribution of the trans double bond to the activity may be due to conformational limitations.

[0214] Experimental Example 2: ST9 degrades STING via the ubiquitin-proteasome mechanism

[0215] Based on the results of the initial activity screening, we ultimately selected the preferred compound ST9 for concentration gradient testing. Figure 1-3 The 1H NMR spectrum, 1C NMR spectrum, and high-resolution mass spectrum of compound ST9 are displayed respectively. For example... Figure 4 As shown in A, the DC of ST9 50 The value was 0.62 μM. Typically, protein degradation mainly involves two major systems: ubiquitin-proteasome and lysosome. To explore the degradation mechanism of ST9, THP-1 cells were treated alone or in combination with ST9 using C-170 (small molecule STING ligand), N-Me-ST9 (negative control), MG-132 (proteasome inhibitor), and bafenoxam A1 (BAF, lysosome inhibitor). Figure 4 As shown in B, only ST9 can induce effective degradation of STING, and its degradation activity can only be blocked by MG132, not BAF. These results indicate that compound ST9 induces STING degradation through a CRBN-dependent ubiquitin-proteasome mechanism.

[0216] Experimental Example 3: ST9 blocks the STING downstream signaling pathway in cisplatin-stimulated HK-2 cells

[0217] We used a cisplatin-induced HK-2 cell model to assess whether ST9 can regulate downstream signaling pathways by degrading STING, thereby blocking inflammatory signal transduction. Figure 5 As shown, STING protein levels significantly increased after cisplatin-induced modeling, but ST9 reversed this upward trend. Furthermore, we observed that ST9 also inhibited pIRF3 and p-p65 levels in a concentration-dependent manner. In summary, ST9 can effectively degrade STING protein, thereby blocking downstream inflammatory signaling. These results provide guidance for ST9 as an anti-inflammatory candidate drug for the molecular treatment of AKI.

[0218] Experimental Example 4: Verifying the Degradation Selectivity of ST9

[0219] To verify whether the preferred compound ST9 exhibits good degradation selectivity, we examined its effects on a range of representative proteins along the inflammatory signaling axis, including AKT, STAT3, AMPK, ERK, and LKB1. Figure 6As shown, no significant protein degradation was detected. These results indicate that ST9 can selectively and efficiently degrade STING protein.

[0220] Example 5: ST9 has good in vitro and in vivo safety.

[0221] Considering that safety is an important indicator for anti-inflammatory drugs, we evaluated the in vitro and in vivo safety of ST9 using MTT assays and acute toxicity tests. We used the MTT assay to examine the effect of ST9 on the cell viability of four normal cell lines: HEK293T, H2C9, BRL-3A, and BV2. Figure 7 As shown, ST9 did not produce significant cytotoxicity in any of the four normal cell lines, and only had a slight effect on BV2 cell viability at high concentrations (>60 μM). Furthermore, single-dose toxicity tests showed that even at a concentration of 179 mg / kg, C57BL / 6J mice did not die (Table 3). In conclusion, ST9 exhibits ideal safety both in vivo and in vitro.

[0222] Table 3. Acute toxicity of ST9 in C57BL / 6J mice

[0223]

[0224] Experimental Example 6: ST9 exhibits significant anti-AKI efficacy in vivo.

[0225] Finally, we verified the in vivo anti-AKI efficacy of ST9. C57BL / 6J mice were normally fed for 3 days to acclimatize to their environment and then randomly divided into 4 groups (solvent group, cisplatin group: 25 mg / kg, low-dose ST9 group: 25 mg / kg, high-dose ST9 group: 50 mg / kg). Figure 8 As shown, ST9 dose-dependently reduced the weight loss in mice. Figure 8 (A) It improved the survival rate of mice: the survival rates of the cisplatin group, the low-dose group, and the high-concentration group were 56%, 78%, and 100%, respectively. Figure 8 (B in the text); reduced the disease activity index score in mice, including body weight, fecal viscosity, and fecal occult blood (B); Figure 8 (C in the text). Furthermore, the increase in kidney weight following cisplatin-induced modeling was significantly reversed ( Figure 8 (D in the text). Simultaneously, we also measured serum levels of blood urea nitrogen (BUN) and creatinine, two key biochemical indicators for evaluating renal function. We found that BUN and creatinine levels increased sharply after cisplatin-induced modeling, while ST9 effectively reduced the increase in these two indicators. Figure 8 (EF in the text). These results collectively confirm that ST9 can induce good therapeutic effects in AKI mice.

[0226] Case 7: ST9 did not cause damage to other vital organs.

[0227] To further confirm the therapeutic effect of ST9, kidney, heart, and liver tissues were stained with hematoxylin and eosin (H&E) and subjected to pathological histological analysis. Figure 8 As shown, cisplatin-induced kidney damage in mice exhibited significant inflammatory cell infiltration, renal tubular enlargement, and vacuolar changes, with most renal tubular structures ruptured and difficult to identify. In contrast, ST9 was able to reduce kidney damage in a dose-dependent manner. Furthermore, no significant morphological abnormalities were observed in the liver and heart tissues during treatment.

[0228] Obviously, the above embodiments of the present invention are merely examples to illustrate the present invention more clearly, and are not intended to limit the implementation of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is impossible to exhaustively list all implementation methods here. Any obvious variations or modifications derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims

1. A nitrogen-containing ring derivative as a Linker STING degrader, the structure is: .

2. Use of the STING degrader of claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of a degrader having STING / NF-κB axis inhibitory activity.

3. Use of the STING degrader of claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of a kidney protective drug for the treatment / prevention of acute kidney injury.

4. A pharmaceutical composition containing the STING degrader of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4, wherein, The pharmaceutical composition is a capsule, a powder, a tablet, a granule, a pill, an injection, a syrup, an oral solution, an inhalant, an ointment, a suppository, or a patch.

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