STING degradation agent taking nitrogen ring-containing derivative as Linker as well as synthesis method and application of STING degradation agent

Abstract

The invention discloses an STING degradation agent taking a nitrogen ring-containing derivative as Linker as well as a synthesis method and application of the STING degradation agent. The STING degradation agent comprises compounds shown in general formulas I and II, expression of inflammatory factors is inhibited by down-regulating STING / NF-KB signal axes, and the STING degradation agent can be used as a kidney protective agent for treating / preventing acute kidney injury and has potential patent medicine prospects. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of STING targeted inhibition, and relates to a STING degrader using a nitrogen-containing ring derivative as a linker, and a synthesis method and use thereof. Background Art

[0002] Acute kidney injury (AKI) refers to a disease characterized by acute inflammation and a sharp deterioration of renal function caused by excessive activation of innate immunity. According to epidemiological statistics, 13.3 million people are diagnosed with acute kidney injury and 1.7 million patients die from it each year worldwide. In addition, 19%-31% of patients with a benign course of the disease will develop chronic kidney disease and eventually end-stage renal disease, which places a heavy burden on families and society.

[0003] Stimulator of interferon genes (STING) is an innate immune molecule that was discovered primarily as a mediator of type I interferon (IFN-I) immune signaling. In the past decade, STING has received extensive attention from the scientific community and pharmaceutical companies due to its target functions and important physiological roles. Increasing evidence has shown that activation of the innate immune pathway cGAS-STING is closely related to mitochondrial damage and the subsequent induced inflammatory response. Therefore, abnormal activation of STING is closely related to the occurrence of AKI and is an important potential target for the treatment of AKI.

[0004] In recent years, research on STING targeted inhibition has become increasingly in-depth, giving rise to a series of STING inhibitors with different skeleton types. Although a series of STING small molecule inhibitors have been reported, most of them have problems such as insufficient activity, large side effects, and poor drugability. Therefore, the new strategy of developing STING-PROTAC degraders will successfully make up for the shortcomings of existing small molecule STING inhibitors and can be used as renal protectors for the treatment / prevention of acute kidney injury, with potential drug prospects. Summary of the invention

[0005] The present invention provides a STING degrader with a nitrogen-containing ring derivative as a linker, a synthesis method and use thereof, and provides a series of STING-PROTAC degraders with nitrogen-containing ring derivatives as linkers for treating inflammation-related diseases by regulating the STING / NF-κB signaling pathway using protein degradation technology, as well as a preparation method thereof, and the effect of downregulating the STING / NF-KB signaling axis, thereby inhibiting the expression of inflammatory factors, and can be used as a renal protectant for treating / preventing acute kidney injury.

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

[0007] The present invention provides a nitrogen-containing ring derivative as a STING degrading agent of a linker, including compounds described in general formula I and II:

[0008]

[0009] Among them, Linker can be selected from

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

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

[0012]

[0013]

[0014] The present invention also provides a method for synthesizing a STING degrading agent using a nitrogen-containing ring derivative as a linker, comprising:

[0015]

[0016] (a) The compounds undergo intermolecular ring-opening and ring-closing reactions;

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

[0018] (c) removing the Boc protecting group from the compound;

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

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

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

[0022] Preferably, the solvent used for the nucleophilic substitution reaction in step (b) includes but is not limited to N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide or a mixed solvent optionally composed 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, ethyl acetate hydrochloride solution; and the reaction temperature is 25°C to 35°C.

[0024] Preferably, the solvent used in the sodium cyanoborohydride-mediated reductive amination reaction in step (d) is dichloromethane, methanol or a mixed solvent optionally composed of these solvents; the acid used is glacial acetic acid, and 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 mixed solvent optionally composed of these solvents; the reagent used is a Dess-Martin oxidant; and the reaction temperature is -5°C to 5°C.

[0026] The present invention further provides a method for synthesizing another nitrogen-containing ring derivative as a STING degrader linker, comprising:

[0027]

[0028] The Linker can be selected from

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

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

[0031] The present application also provides the use of the above-mentioned STING degrader, or a pharmaceutically acceptable salt, racemate, optical isomer or solvent compound thereof in the preparation of a degrader having STING / NF-κB signaling axis inhibitory activity.

[0032] The present application also provides the use of the STING degrader, or a pharmaceutically acceptable salt, racemate, optical isomer or solvent compound thereof in the preparation of a renal protection drug for treating / preventing acute kidney injury.

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

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

[0035] Beneficial effects: This application provides a new type of STING-PROTAC degrader with 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 renal protector for the treatment / prevention of acute kidney injury, with potential drug prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 .ST9 H NMR spectrum.

[0037] Figure 2 .ST9 carbon NMR spectrum.

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

[0039] Figure 4 .Show the activity characterization and degradation mechanism of ST9.

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

[0041] Figure 6 .Shows that ST9 has good protein degradation selectivity.

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

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

[0044] Fig. 9 .H&E staining results of heart, liver and kidney. DETAILED DESCRIPTION

[0045] The present invention is described in detail below in conjunction with specific implementation methods. The following specific embodiments are helpful for those skilled in the art to further understand the present invention, but do not limit the present invention in any form.

[0046] 1. Synthesis formula of SL5a-d and SQ5c-d

[0047]

[0048] Synthesis of compounds SL1, SQ1:

[0049] Dissolve SL0 (5 g, 30.12 mmol) in glacial acetic acid (100 mL). After complete dissolution, add 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). Heat to reflux at 120 ° C and react overnight. Cool the mixture to room temperature. Pour the solution into ice water (200 mL). Stir the mixture for 20 minutes. Filter the mixture. Purify the gray solid by flash column chromatography. Finally, brown solids SL1 and SQ1 are obtained.

[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, SQ2:

[0053] The 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), and then tert-butyl piperazine-1-carboxylate or the corresponding alcohol (23.0 mmol) was added, stirred at 90°C overnight, and monitored by TLC, and the reaction system was added to water (500 mL) to precipitate a yellow solid. After stirring for 30 minutes and vacuum filtration, 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, SQ3:

[0057] SL2 and SQ2 were dissolved in dioxane hydrochloric acid, reacted at room temperature overnight, and monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain SL3 and SQ3 as light yellow solids.

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

[0059] Intermediates SL3, 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 solution (v:v=1:1), and a few drops of AcOH were added, and sodium cyanoborohydride (3.98 mmol) was added to the system in batches. The reactants were then stirred at room temperature overnight and purified by flash 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, SQ5c-d:

[0067] SL4a-d and SQ4c-d were dissolved in dioxane hydrochloric acid, reacted at room temperature overnight, and monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain SL5a-d and SQ5c-d as light yellow solids.

[0068] 2. Synthesis formula of SL9a-b and SQ9b

[0069]

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

[0071] The 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), and then the corresponding alcohol (23.0 mmol) was added, stirred at 90 ° C overnight, and monitored by TLC, and the reaction system was added to water (500 mL) to precipitate a yellow solid. After stirring for 30 minutes and vacuum filtration, 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, SQ7b:

[0076] The 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, and the reaction was stirred overnight and monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, and the mixture was purified by flash 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, SQ8b:

[0081] The intermediates SL7a-b and SQ7b (1.32 mmol) were dissolved in a DCM and MeOH solution (v:v=1:1) with the corresponding aldehydes and ketones (1.99 mmol) and N,N-diisopropylethylamine (1.32 mmol), and a few drops of AcOH were added, and sodium cyanoborohydride (3.98 mmol) was added to the system in batches. The reactants were then stirred at room temperature overnight and monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure and purified by flash 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] Q8b: 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, SQ9b:

[0086] SL8a-b and SQ8b were dissolved in dioxane hydrochloric acid, reacted at room temperature overnight, and monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain SL9a-b and SQ9b as light yellow solids.

[0087] 3. Synthesis formula of SL13a-c and SQ13a-c

[0088]

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

[0090] The 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), and then the corresponding alcohol (23.0 mmol) was added, stirred at 90°C overnight, and monitored by TLC, and the reaction system was added to water (500 mL) to precipitate a yellow solid. After stirring for 30 minutes and vacuum filtration, 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, SQ11a-c:

[0098] The intermediate SL10a-c, SQ10a-c (1.68 mmol) was dissolved in DCM, and Dess-Martin oxidant (8.40 mmol) was slowly added in an ice-water bath, and the reaction was stirred overnight and monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, and the mixture was purified by flash column chromatography to obtain yellow solid SL11a-c, 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, SQ12a-c:

[0106] The intermediate SL11a-c, SQ11a-c (1.32 mmol) and the corresponding aldehyde and ketone (1.99 mmol) and N, N-diisopropylethylamine (1.32 mmol) were dissolved in a DCM and MeOH solution (v:v=1:1), and a few drops of AcOH were added, and sodium cyanoborohydride (3.98 mmol) was added to the system in batches. The reactants were then stirred at room temperature overnight and monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure and purified by flash column chromatography to obtain the desired yellow intermediate SL12a-c, 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, SQ13a-c:

[0114] SL12a-c and SQ12a-c were dissolved in dioxane hydrochloric acid, reacted at room temperature overnight, and monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain SL13a-c and SQ13a-c as light 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'-tetramethyluronium hexafluorophosphate were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine was added under stirring, and stirred for 10 minutes. In addition, SL3 (160 mg, 0.42 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine was added. The SL3 solution obtained by treatment was added dropwise to the reaction system, reacted at room temperature overnight, and monitored by TLC. After the reaction was completed, the reaction system was added to 15 mL of water, and the solid obtained by filtration was purified by flash column chromatography to obtain 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 3.073min, purity 99.4%.

[0120] Example 2

[0121]

[0122] Referring to the method of Example 1, compound ST2 can be prepared by replacing SL3 with SL5a. 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 3.011min, purity 98.9%.

[0123] Example 3

[0124]

[0125] Referring to the method of Example 1, compound ST3 can be prepared by replacing SL3 with SL5b. 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 2.959min, purity 99.3%.

[0126] Example 4

[0127]

[0128] Referring to the method of Example 1, compound ST4 can be prepared by replacing SL3 with SL5c. 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 3.082min, purity 96.3%.

[0129] Example 5

[0130]

[0131] Referring to the method of Example 1, compound ST5 can be prepared by replacing SL3 with SL5d. 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 3.033min, purity 97.5%.

[0132] Example 6

[0133]

[0134] Referring to the method of Example 1, compound ST6 can be prepared by replacing SL3 with SL9a. 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 2.967min, purity 96.5%.

[0135] Example 7

[0136]

[0137] Referring to the method of Example 1, compound ST7 can be prepared by replacing SL3 with SL9b. 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 2.782min, purity 99.0%.

[0138] Example 8

[0139]

[0140] Referring to the method of Example 1, compound ST8 can be prepared by replacing SL3 with SL13a. 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 3.059min, purity 99.2%.

[0141] Example 9

[0142]

[0143] Referring to the method of Example 1, compound ST9 can be prepared by replacing SL3 with SL13b. 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 3.024min, purity 98.7%.

[0144] Example 10

[0145]

[0146] Referring to the method of Example 1, compound ST10 can be prepared by replacing SL3 with SL13c. 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 3.129min, purity 98.6%.

[0147] Embodiment 11

[0148]

[0149] Referring to the method of Example 1, replacing SL3 with SQ5c can produce compound ST11. 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 3.119min, purity 99.3%.

[0150] Example 12

[0151]

[0152] Referring to the method of Example 1, replacing SL3 with SQ5d can produce compound ST12. 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 2.994min, purity 99.0%.

[0153] Embodiment 13

[0154]

[0155] Referring to the method of Example 1, replacing SL3 with SQ9b can produce compound ST13. 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 2.950min, purity 98.7%.

[0156] Embodiment 14

[0157]

[0158] Referring to the method of Example 1, compound ST14 can be prepared by replacing SL3 with SQ13a. 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 2.868min, purity 99.6%.

[0159] Embodiment 15

[0160]

[0161] Referring to the method of Example 1, replacing SL3 with SQ13b can produce compound ST15. 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 3.107min, purity 98.4%.

[0162] Example 16

[0163]

[0164] Referring to the method of Example 1, replacing SL3 with SQ13c can produce compound ST16. 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 3.128min, purity 98.1%.

[0165] Embodiment 17

[0166]

[0167] Referring to the method of Example 1, replacing S1 with S2 and SL3 with SL5d can produce compound ST17. 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 2.946min, purity 96.5%.

[0168] Embodiment 18

[0169]

[0170] Referring to the method of Example 1, replacing S1 with S3 and replacing SL3 with SL5d can produce compound ST18. 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 H 43 N8O 10 (M + H) + : calcd 783.3024; found, 783.3100. HPLC: t R 3.043 min, purity 95.2%.

[0171] Example 19

[0172]

[0173] Referring to the method of Example 1, replacing S1 with S4 and SL3 with SL5d can produce compound ST19. 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 3.085min, purity 96.1%.

[0174] Embodiment 20

[0175]

[0176] Referring to the method of Example 1, replacing S1 with S2 and SL3 with SL5c can produce compound ST20. 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 2.937min, purity 98.3%.

[0177] Embodiment 21

[0178]

[0179] Referring to the method of Example 1, replacing S1 with S3 and replacing SL3 with SL5c can produce compound ST21. 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 2.991min, purity 98.3%.

[0180] Embodiment 22

[0181]

[0182] Referring to the method of Example 1, replacing S1 with S4 and SL3 with SL5c can produce compound ST22. 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 3.194min, purity 98.1%.

[0183] Embodiment 23

[0184]

[0185] Referring to the method of Example 1, replacing S1 with S2 and replacing SL3 with SL13b can produce compound ST23. 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 3.052min, purity 98.1%.

[0186] Embodiment 24

[0187]

[0188] Referring to the method of Example 1, replacing S1 with S3 and replacing SL3 with SL13b can produce compound ST24. 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 3.062min, purity 96.0%.

[0189] Embodiment 25

[0190]

[0191] Referring to the method of Example 1, replacing S1 with S4 and replacing SL3 with SL13b can produce compound ST25. 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 3.083min, purity 98.6%.

[0192] Embodiment 26

[0193]

[0194] Referring to the method of Example 1, replacing S1 with S2 and replacing SL3 with SL9b can produce compound ST26. 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 3.153min, purity 98.3%.

[0195] Embodiment 27

[0196]

[0197] Referring to the method of Example 1, replacing S1 with S3 and replacing SL3 with SL9b can produce compound ST27. 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 3.113min, purity 96.2%.

[0198] Embodiment 28

[0199]

[0200] Referring to the method of Example 1, replacing S1 with S4 and SL3 with SL9b can produce compound ST28. 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 3.007min, purity 98.0%.

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

[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 used the human monocytic leukemia cell line THP-1 to preliminarily evaluate the degradation efficiency of these PROTACs. It was found that most compounds showed higher efficiency in degrading STING. Among them, the degradation efficiencies of compounds ST4, ST5 and ST10 were 72.3%, 71.1% and 77.7%, respectively, and the degradation efficiency of ST9 was the highest, reaching 90.6%. At the same time, we synthesized six compounds, ST11 to ST16, to study the effect of the CRBN attachment site on the degradation activity. When the attachment 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, which were significantly lower than those of ST5 and ST9. Only ST16 maintained activity comparable to that of ST10. It is worth noting that the degradation activity of ST14 was 63.6%, which was significantly better than that of ST8.

[0204]

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

[0206]

[0207] ND=No degradation

[0208] Next, we replaced the trans double bond with different types of flexible linking groups to obtain ST17 to 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=No degradation

[0213] Based on the above analysis, it can be inferred that the introduction of a rigid linker is beneficial to improving the degradation activity, and fixing the linker site at the 4' position is the best choice. At the same time, the prominent contribution of the trans double bond to the activity may be due to the restriction of the molecular conformation.

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

[0215] Based on the results of the initial activity screening, we finally selected the preferred compound ST9 for concentration gradient testing. Figure 1-3 The hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum of compound ST9 are shown respectively. Figure 4 As shown in A, DC of ST9 50 The value is 0.62μM. Generally, protein degradation mainly includes two major systems: ubiquitin-proteasome and lysosome. In order to explore the degradation mechanism of ST9, THP-1 cells were treated with C-170 (small molecule STING ligand), N-Me-ST9 (negative control), MG-132 (proteasome inhibitor) and bafilomycin A1 (BAF, lysosome inhibitor) alone or in combination with ST9. Figure 4 As shown in Figure B, only ST9 can induce efficient degradation of STING, and its degradation activity can only be blocked by MG132 but 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 HK-2 cells stimulated by cisplatin

[0217] We used the cisplatin-induced HK-2 cell model to evaluate whether ST9 could regulate downstream signaling pathways by degrading STING, thereby blocking inflammatory signal transduction. Figure 5 As shown in the figure, the STING protein content increased significantly after cisplatin modeling, but ST9 reversed this increasing trend. At the same time, we also observed that ST9 could inhibit the levels of pIRF3 and p-p65 in a concentration-dependent manner. In summary, ST9 can effectively degrade STING protein and thus block downstream inflammatory signaling. These results provide guidance for ST9 as an anti-inflammatory candidate drug to treat AKI at the molecular level.

[0218] Test Example 4: Verification of ST9 degradation selectivity

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

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

[0221] Considering that safety is an important indicator of anti-inflammatory drugs, we used MTT and acute toxicity tests to evaluate the safety of ST9 in vitro and in vivo. We used the MTT method to detect the effect of ST9 on the cell viability of four normal cell lines, including HEK293T, H2C9, BRL-3A and BV2. Figure 7 As shown in the figure, ST9 did not produce obvious cytotoxicity to the four normal cell lines, and only slightly affected the cell viability of BV2 at high concentrations (>60μM). At the same time, the single-dose toxicity test showed that C57BL / 6J mice did not die even at a concentration of 179mg / kg (Table 3). In short, ST9 has an ideal safety profile both in vivo and in vitro.

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

[0223]

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

[0225] Finally, we verified the anti-AKI efficacy of ST9 in vivo. After C57BL / 6J mice were fed normally for 3 days to adapt to the environment, they were randomly divided into 4 groups (solvent group, cisplatin group: 25 mg / kg, ST9 low-dose group: 25 mg / kg, high-dose group: 50 mg / kg). Figure 8 As shown, ST9 dose-dependently reduced the weight loss of mice ( Figure 8 A); improved the survival rate of mice: the survival rates of the cisplatin group, low-dose group and high-concentration group were 56%, 78% and 100% respectively ( Figure 8 B); reduced the disease activity index scores of mice, including body weight, fecal viscosity, fecal occult blood ( Figure 8 C). In addition, the increase in kidney weight was significantly reversed after cisplatin modeling ( Figure 8 D). At the same time, we also tested the serum levels of urea nitrogen (BUN) and creatinine, two key biochemical indicators for evaluating renal function, and found that BUN and creatinine levels increased sharply after cisplatin modeling, while ST9 could effectively reduce the increase of these two indicators ( Figure 8 EF). These results together confirmed that ST9 can achieve good therapeutic effects in AKI mice.

[0226] Test Example 7: ST9 did not cause damage to other important organs

[0227] To further confirm the therapeutic effect of ST9, kidney, heart, and liver tissues were stained with hematoxylin-eosin (H&E) and histopathological analysis was performed. Figure 8 As shown in the figure, the kidneys of cisplatin-treated mice showed obvious inflammatory cell infiltration, tubular enlargement, vacuolar changes, and most of the tubular structures were ruptured and difficult to identify. In contrast, ST9 was able to reduce renal injury in a dose-dependent manner. In addition, no obvious morphological abnormalities were observed in the liver and heart tissues during the treatment period.

[0228] Obviously, the above embodiments of the present invention are merely examples to more clearly illustrate the present invention, and are not limitations on the implementation methods of the present invention. For ordinary technicians in the relevant field, other different forms of changes or modifications can be made on the basis of the above description. It is impossible to list all the implementation methods here. All obvious changes or modifications derived from the technical solution of the present invention are still within the protection scope of the present invention.

Claims

1. A nitrogen-containing ring derivative as a STING degrader linker, comprising a compound of formula I and II: in, Linker is selected from X is selected from -(CH2)2-, -(CH2)3-, -CH2OCH2-.

2. The STING degrading agent according to claim 1, characterized in that The compound includes any one of the following compounds:

3. A method for synthesizing a STING degrader using a nitrogen-containing ring derivative as a linker, comprising: (a) The compounds undergo intermolecular ring-opening and ring-closing reactions; (b) the compound undergoes a nucleophilic substitution reaction; (c) removing the Boc protecting group from the compound; (d) subjecting the compound to a reductive amination reaction with a corresponding aldehyde or ketone; (e) The compound undergoes Dess-Martin oxidation reaction.

4. The synthesis method according to claim 3, characterized in that The solvent used in the intermolecular ring-opening and ring-closure reactions in step (a) includes glacial acetic acid, water, ethyl acetate or a mixed solvent optionally composed of these solvents, and the reaction temperature is 0°C to 140°C; the solvent used in the nucleophilic substitution reaction in step (b) includes N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide or a mixed solvent optionally composed of these solvents, the basic catalyst used is N,N-diisopropylethylamine, the reagents used include N,N-diisopropylethylamine and triethylamine, and the reaction temperature is 75°C to 85°C; the reagents used in step (c) include dioxane hydrochloride, methanol hydrochloride, ethyl acetate hydrochloride, ester solution, the reaction temperature is 25°C to 35°C; the solvent used in the sodium cyanoborohydride-mediated reductive amination reaction in step (d) is dichloromethane, methanol or a mixed solvent optionally composed 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; the solvent used in the Dess-Martin oxidation reaction in step (e) includes dichloromethane, methanol, tetrahydrofuran, N,N-dimethylformyl solution or a mixed solvent optionally composed of these solvents, the reagent used is a Dess-Martin oxidant, and the reaction temperature is -5°C to 5°C.

5. A method for synthesizing a STING degrader using a nitrogen-containing ring derivative as a linker, comprising: The Linker is selected from (a) The compound undergoes an amide condensation reaction.

6. The synthesis method according to claim 5, characterized in that The solvent used in the amide condensation reaction of step (a) includes N, N-dimethylformamide, tetrahydrofuran or a mixed solvent optionally composed of these solvents, the condensation agent includes HATU, EDCI, HOBT, T3P, the basic catalyst includes N, N-diisopropylethylamine, triethylamine, and the reaction temperature is 25° C. to 35° C.

7. Use of the STING degrader according to claim 1 or 2, or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof in the preparation of a degrader having STING / NF-κB signaling axis inhibitory activity.

8. Use of the STING degrader according to claim 1 or 2, or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof in the preparation of a renal protective drug for treating / preventing acute kidney injury.

9. A pharmaceutical composition comprising the STING degrader according to claim 1 or 2 or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof as an active ingredient, and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, characterized in that The pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.

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