Oxime ether spinosad derivative as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicines, and relates to an oxime ether spinosad derivative as well as a preparation method and application thereof. The oxime ether spinosad derivative is a compound as shown in a structural general formula (I), a salt thereof or an optical isomer thereof, wherein R1 is selected from NR8R9, a C5-C8 nitrogen-containing heteroaromatic ring, a C3-C7 nitrogen-containing aliphatic ring, a substituted C5-C8 nitrogen-containing heteroaromatic ring and a substituted C3-C7 nitrogen-containing aliphatic ring. The oxime ether spinosad derivative disclosed by the invention has strong anti-tumor activity and can be used as a potential drug for treating tumor diseases.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of medicine, and relates to an oxime ether spinosyn derivative and a preparation method and application thereof. BACKGROUND

[0002] Spinosyn compounds are secondary metabolites of Saccharopolyspora spinosa in culture medium after aerobic fermentation, and have insecticidal activity. At present, in the commercialized variety spinosad, spinosyn A (SPA) accounts for 85-90% in the mixture, spinosyn D (SPD) accounts for about 10-15% in the mixture, and the second generation spinosyn insecticide spinetoram.

[0003] The prior art CN114796254A discloses spinosyn A and derivatives thereof as activators of arginine-agmatine synthetase 1 (ASS1) and applications thereof, and the spinosyn derivatives have the structural general formula:

[0004]

[0005] The spinosyn and the derivatives thereof target the activation of arginine-agmatine synthetase 1 (ASS1) and serve as anti-tumor drugs. However, the compound of the structural general formula has poor acid resistance, and the in-vivo application is limited. SUMMARY

[0006] The purpose of the present application is to provide an oxime ether spinosyn derivative and a preparation method and application thereof.

[0007] In order to achieve the above purpose, the present application adopts the following technical solution:

[0008] An oxime ether spinosyn derivative is a compound shown in the structural general formula (I), a salt thereof or an optical isomer thereof:

[0009]

[0010] wherein R1 is selected from NR8R9, a nitrogen-containing aromatic heterocycle with 5-8 carbon atoms (C5-C8), a nitrogen-containing aliphatic ring with 3-7 carbon atoms (C3-C7), a substituted C5-C8 nitrogen-containing aromatic heterocycle, and a substituted C3-C7 nitrogen-containing aliphatic ring; the substituents on the substituted C5-C8 nitrogen-containing aromatic heterocycle and the substituted C3-C7 nitrogen-containing aliphatic ring are independently selected from alkyl with 1-4 carbon atoms (C1-C4), a halogen atom, a hydroxyl group, an alkoxy group, a nitro group, a carboxyl group, a cyano group, and an amine group;

[0011] R8 and R9 are independently selected from hydrogen, alkyl with 1-8 carbon atoms (C1-C8), R 10 NR11 R 12 ;

[0012] R 10 Selected from C1-C8 alkyl groups;

[0013] R 11 R 12 Independently selected from hydrogen and C1-C8 alkyl groups;

[0014] L is selected from C1-C8 alkyl, 1-8 carbon atoms (C1-C8) ether chain;

[0015] R2 is selected from C1-C8 alkyl, C1-C8 olefin, and C1-C8 alkyne groups;

[0016] R3 and R4 are selected from hydrogen and C1-C3 alkyl groups;

[0017] R5, R6, and R7 are independently selected from C1-C3 alkyl groups;

[0018] AB represents CH=CH and -CH2CH2-;

[0019] MQ is C=CH.

[0020] In one preferred embodiment, R1 is selected from pyrrole, indole, imidazole, oxazole, thiazole, purine, pyrazole, isoxazole, isothiazole, pyridine, quinoline, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, aziridine propane, aziridine butane, aziridine pentane, piperazine, morpholine, substituted pyrrole, substituted indole, substituted imidazole, substituted oxazole, substituted thiazole, substituted purine, substituted pyrazole, substituted isoxazole, substituted isothiazole, substituted pyridine, substituted quinoline, substituted pyridazine, substituted pyrimidine, substituted pyrazine, substituted quinoline, substituted isoquinoline, substituted aziridine propane, substituted aziridine butane, substituted aziridine pentane, substituted piperazine, substituted morpholine;

[0021] In this context, the substituents in substituted pyrrole, substituted indole, substituted imidazole, substituted oxazole, substituted thiazole, substituted purine, substituted pyrazole, substituted isoxazole, substituted isothiazole, substituted pyridine, substituted quinoline, substituted pyridazine, substituted pyrimidine, substituted pyrazine, substituted quinoline, substituted isoquinoline, substituted azircyclopropane, substituted azircyclobutane, substituted azircyclopentane, substituted piperazine, and substituted morpholine are independently selected from C1-C8 alkyl groups.

[0022] In one preferred embodiment, the substituents in substituted pyrrole, substituted indole, substituted imidazole, substituted oxazole, substituted thiazole, substituted purine, substituted pyrazole, substituted isoxazole, substituted isothiazole, substituted pyridine, substituted quinoline, substituted pyridazine, substituted pyrimidine, substituted pyrazine, substituted quinoline, substituted isoquinoline, substituted azircyclopropane, substituted azircyclobutane, substituted azircyclopentane, substituted piperazine, and substituted morpholine are optionally selected from C1-C4 alkyl groups.

[0023] In one preferred embodiment, R1 is selected from Where R 13 Selected from hydrogen and C1-C4 alkyl groups.

[0024] In one preferred embodiment, R1 is selected from NR8R9.

[0025] In one preferred embodiment, NR8R9 is selected from tetrahydropyrrolyl, piperidinyl, and morpholinyl.

[0026] In one preferred embodiment, R8, R9, R 10 R 11 R 12 Independently selected from hydrogen or C1-C4 alkyl

[0027] In one preferred embodiment, L is selected from C1-C6 alkyl groups.

[0028] In one preferred embodiment, R2 is selected from C1-C4 alkyl groups.

[0029] In one preferred embodiment, the oxime ether spinosad derivative comprises a compound, its salt, or an optical isomer thereof, as shown in the following structure:

[0030]

[0031]

[0032]

[0033] Salts of compounds of general formula (I) of the present invention can be prepared as acid addition salts using standard salt preparation techniques well known to those skilled in the art. Particularly useful acid addition salts include, but are not limited to, salts generated by standard reactions with organic and inorganic acids, such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, cholic acid, mucoic acid, glutamic acid, camphoric acid, glutaric acid, glycolic acid, phthalic acid, tartaric acid, formic acid, lauric acid, stearic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sorbic acid, picric acid, benzoic acid, and cinnamic acid.

[0034] Based on the same inventive concept, this invention also claims a method for preparing the oxime ether spinosad derivative, comprising the following steps:

[0035] S1. Hydrolyze spinosad A to obtain compound 14;

[0036] S2 and compound 14 are oxidized to obtain compound 15;

[0037] S3, compound 15 and O-hydroxyalkyl-substituted hydroxylamine derivatives react to give oxime ether compounds;

[0038] S4. The hydroxyl groups on the side chain of the oxime ether compound are subjected to oxidation and reduction amination reactions to obtain the oxime ether spinosad derivative;

[0039] The structure of the oxime ether compound is as follows:

[0040] n is an integer from 1 to 8.

[0041] In one preferred embodiment, the method for preparing the oxime ether spinosad derivative includes the following route:

[0042]

[0043] Based on the same inventive concept, this invention also claims a method for preparing the oxime ether spinosad derivative, comprising the following steps:

[0044] S1. Hydrolyze spinosad A to obtain compound 14;

[0045] S2 and compound 14 are oxidized to obtain compound 15;

[0046] S3 and compound 15 undergo an oxime reaction to yield an oxime ether compound;

[0047] S5. The oxime ether compound and sulfonyl chloride are reacted, and after the reaction is completed, amine alkylation is performed to obtain the oxime ether spinosad derivative.

[0048] The structure of the oxime ether compound is as follows:

[0049] n is an integer from 1 to 8.

[0050] In one preferred embodiment, the method for preparing the oxime ether spinosad derivative includes the following route:

[0051]

[0052]

[0053] Based on the same inventive concept, the present invention also claims protection for the use of the oxime ether spinosad derivative in the preparation of antitumor drugs.

[0054] In one preferred embodiment, the tumor includes: lung cancer, non-small cell lung cancer, liver cancer, pancreatic cancer, gastric cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, bladder cancer, cervical cancer, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary gland carcinoma, cystic adenocarcinoma, cystic carcinoma, medullary carcinoma, bronchial carcinoma, osteocyte carcinoma, epithelial carcinoma, bile duct carcinoma, choriocarcinoma, embryonic carcinoma, seminoma, Wilms' carcinoma, glioma, astrocytoma, neuroblastoma, cranial carcinoma, etc. Pharyngoductoma, ependymoma, pineal gland tumor, hematopoietic tumor, vocal cord neuroma, meningioma, neuroblastoma, optic neuroblastoma, retinoblastoma, neurofibroma, fibrosarcoma, fibroblastoma, fibroma, fibroadenoma, fibrochondroma, fibrocystoma, fibromixoma, fibromyxoma, fibroosteoma, fibromyxosarcoma, fibropapilloma, myxosarcoma, myxocytochondroma, myxochondrosarcoma, myxochondrofibrosarcoma, myxadenoma, myxoblastoma, liposarcoma, lipoma, lipadenoma, lipoblastoma, lipochondroma, lipofibrillaroma Fatty hemangioma, myxolipoma, chondrosarcoma, chondroma, chondromyoma, chordoma, chorioamnionoma, chorioepithelial tumor, choriocartilaginous tumor, osteosarcoma, osteoblastoma, osteochondrosarcoma, osteochondroma, bone cystoma, odontoma, osteofibroma, osteofibrosarcoma, angiosarcoma, hemangioma, angiolipoma, angiochondroma, hemangioblastoma, angiokeratoma, angioneurotic glioma, hemangioendothelioma, angiofibroma, angiomyoma, angiolipoma, angiolymphangioma, angiolipoma, angiomyolipoma, angiomyeloma, angioneurotic glioma, angioendothelioma, angiofibroma, angiomyoma, angiolipoma, angiolymphangioma, angiolipoma, angiomyolipoma, angiomyeloma Tumors, angiomyolipomas, hemangioretic endotheliomas, lymphangiosarcomas, lymphogranulomas, lymphangiomas, lymphomas, lymphomyolipomas, lymphosarcomas, lymphangiofibromas, lymphocytomas, lymphoepitheliomas, lymphoblastomas, endotheliomas, synovial tumors, synovial sarcomas, mesotheliomas, connective tissue tumors, Ewing tumors, leiomyomas, leiomyosarcomas, leiomyoblastomas, leiomyofibromas, rhabdomyomas, rhabdomyosarcomas, rhabdomyomyxomas, acute lymphoblastic leukemia, acute myeloid leukemia, chronic disease cells, polycythemia vera, lymphomas, multiple myeloma.

[0055] In one preferred embodiment, the tumor includes breast cancer cells, colorectal cancer cells, and liver cancer.

[0056] In one preferred embodiment, the drug further includes pharmaceutically commonly used excipients.

[0057] In one preferred embodiment, the dosage form of the drug is any one of granules, capsules, tablets, injections, infusions, or suppositories.

[0058] The beneficial effects of the present invention are as follows: the oxime ether spinosad of the present invention has better chemical stability than 17-glycoside spinosad and has a better effect on inhibiting tumors in the human body environment, and therefore is expected to be a potential anti-tumor drug. Attached Figure Description

[0059] Figure 1 The stability results are for representative 17-glycoside spinosad derivatives LM-2I and oxime ether compounds; among them, Figure 1 A is a stability photograph of the LM-2I. Figure 1 B is a stability photograph of the oxime ether compound A14 of the present invention. Detailed Implementation

[0060] This invention is not limited to the specific embodiments listed below. Those skilled in the art can implement this invention using various other specific embodiments based on the content disclosed herein. Any modifications or alterations made to the design structure and concept of this invention fall within the protection scope of this invention. It should be noted that, unless otherwise specified, the embodiments and features described in this invention can be combined with each other.

[0061] The preparation of intermediates involved in the preparation process of the spinosad oxime derivative of this invention is as follows:

[0062] Synthesis of 17-hydroxy-SPA (compound 14)

[0063]

[0064] Dissolve 1 g of SPA solid in 5 mL of methanol, slowly add 7.5 mL of 1 M hydrochloric acid, and stir at 60-70 °C for 4 h. After the reaction is completed by thin-layer chromatography (TLC), most of the methanol is removed by rotary evaporation, 15 mL of water is added, and then ethyl acetate is added for extraction (20 mL × 3). Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1, V / V) to give 750 mg of white solid, with a yield of 90%. 1H NMR(500MHz, CDCl3)δ6.75(s,1H),5.87(d,J=10.0Hz,1H),5.79(d,J=9.8Hz,1H),4.84(d,1H),4.69–4.63(m,1H),4.50–4.4 4(m,1H),4.33–4.27(m,1H),3.66–3.61(m,1H),3.57–3.53(m,4H),3.51–3.43(m,10H),3.30–3.25(m,1H),3.14–3.08(m,2H) ,3.03–2.98(m,1H),2.88–2.83(m,1H),2.48(s,3H),2.42–2.37(m,1H),2.29–2.21(m,2H),2.20–2.12(m,2H),1.96–1.89(m ,2H),1.80–1.71(m,1H),1.58–1.42(m,8H),1.37–1.25(m,9H),1.20–1.15(m,4H),0.94–0.85(m,1H),0.81(t,J=7.3Hz,3H).

[0065] Synthesis of 17-oxo-SPA (compound 15)

[0066]

[0067] Compound 14 (1 g, 1.7 mmol) was dissolved in 15 mL of dichloromethane in a round-bottom flask, and then pyridinium chlorochromate (PCC, 548 mg, 2.54 mmol, 1.5 eq) was added. The reaction mixture was stirred at room temperature for 24 h. After the starting material was basically completely reacted as monitored by TLC, the reaction mixture was filtered through diatomaceous earth, dichloromethane was removed by rotary evaporation, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1, V / V) to give 800 mg of white solid, yield 80%. 1H NMR (400MHz, CDCl3) δ6.95(d,J=2.4Hz,1H),5.89(d,J=9.9Hz,1H),5.79(dd,J=9.8,2.9Hz,1H),4.85(s,1H),4.37–4 .19(m,2H),3.60–3.44(m,13H),3.23(dt,J=13.2,4.0Hz,1H),3.15–3.03(m,2H),3.03–2.95(m,1H),2.85(ddd,J=11. 4,8.5,2.8Hz,1H),2.66–2.54(m,1H),2.43(dd,J=9.5,3.4Hz,1H),2.30(p,J=7.1Hz,1H),2.24–2.09(m,1H),2.00–1 .89(m,1H),1.78–1.63(m,2H),1.63–1.31(m,9H),1.29–1.23(m,4H),0.98–0.88(m,1H),0.82(td,J=7.5,3.3Hz,3H).

[0068] Synthesis of compounds 6-9

[0069]

[0070] Compound 1 (1 g, 7.51 mmol, 1 eq) and NaH (600.83 mg, 15 mmol, 2 eq) were dissolved in DMF. After stirring at room temperature for 10 minutes, compounds 2-5 (2 eq) were added and reacted at room temperature. After the reaction was completed by TLC monitoring, a large amount of water was added to remove the remaining NaOH and DMF. The mixture was then extracted three times with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a yellow viscous liquid 6-9. The crude product did not require further purification and was directly used in the next step.

[0071] Synthesis of compound 10-13

[0072]

[0073] The crude products of compounds 6-9 from the previous step were diluted with an appropriate amount of methanol, and then 1M HCl was added to adjust the pH to 2-3. The reaction was carried out at room temperature for 2 hours to obtain the reaction solution of compounds 10-13. Without further processing, the reaction was carried out directly to the next step.

[0074] Synthesis of intermediate M1 (17-(O-(3-hydroxypropyl)oxime)-SPA)

[0075]

[0076] Compound 15 (500 mg, 0.85 mmol) was added to the untreated reaction solution of compound 10 from the previous step. Methanol was added to dissolve the compound, and hydrochloric acid was added to adjust the pH to 3-4. The mixture was stirred at 70°C for approximately 4 hours. After the reaction was complete as monitored by TLC, most of the methanol was removed by rotary evaporation. 30 mL of water was added, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was evaporated. Finally, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1, V / V) to give 478.1 mg of a white solid, with a yield of 85%. 1 H NMR(500MHz, CDCl3)δ7.10(s,1H),5.89(dt,J=9.7,2.1Hz,1H),5.80(dt,J=9.9,3.0Hz ,1H),4.86(d,J=1.8Hz,1H),4.74(q,J=4.6Hz,1H),4.33(q,J=6.8Hz,1H),4.24–4.20(m ,2H),4.07(q,J=7.0Hz,1H),3.76(t,J=6.2Hz,2H),3.57–3.45(m,13H),3.42(ddd,J=9 .0,7.5,2.7Hz,1H),3.27(dd,J=14.0,5.3Hz,1H),3.12(t,J=9.4Hz,1H),2.98(ddq,J=1 0.0,5.3,2.7Hz,1H),2.89(ddt,J=11.4,8.6,2.6Hz,1H),2.45(dd,J=14.0,2.9Hz,1H) ,2.31(dt,J=13.6,7.1Hz,1H),2.19(dddd,J=22.0,13.5,10.0,5.0Hz,4H),1.93(q,J=6 .1Hz,3H),1.63(s,1H),1.54(d,J=7.4Hz,1H),1.49–1.45(m,1H),1.39–1.32(m,4H),1 .28(s,2H),1.27(d,J=7.0Hz,3H),0.94(tt,J=11.6,6.0Hz,1H),0.84(t,J=7.4Hz,3H).

[0077] Synthesis of intermediate M2 (17-(3-((but-2-imino)oxy)propionaldehyde)-SPA)

[0078]

[0079] Compound M1 (200 mg, 0.302 mmol, 1 eq) and pyridinium chlorochromate (PCC, 97.8 mg, 0.454 mmol, 1.5 eq) were dissolved in 5 mL of dichloromethane and stirred at room temperature for 24 h. After the reaction was completed by TLC, the reaction solution was filtered through diatomaceous earth, dichloromethane was removed by rotary evaporation, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. Finally, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3 / 1, V / V) to give 149 mg of white solid, with a yield of 75%.

[0080] 1 H NMR(500MHz, CDCl3)δ9.83(t,J=2.2Hz,1H),7.05(s,1H),5.89(d,J=9.9Hz,1H),5.80( dt,J=9.4,2.8Hz,1H),4.86(d,J=1.8Hz,1H),4.73(q,J=8.1Hz,1H),4.43(td,J=6.0,2 .1Hz,2H),4.33(q,J=6.9Hz,1H),4.04(q,J=7.0Hz,1H),3.59–3.44(m,13H),3.41(d,J =7.0Hz,1H),3.26(dd,J=14.0,5.2Hz,1H),3.12(t,J=9.4Hz,1H),3.00–2.95(m,1H),2. 92–2.87(m,1H),2.74(ddd,J=7.2,5.5,2.1Hz,2H),2.45(dd,J=14.0,2.9Hz,1H),2.31 (dt,J=13.5,7.0Hz,1H),2.22(t,J=7.6Hz,1H),2.14(d,J=8.6Hz,2H),2.04–1.98(m,1 H),1.93(dd,J=13.4,7.0Hz,1H),1.45(p,J=6.9Hz,2H),1.38–1.32(m,4H),1.29(d,J= 6.1Hz, 3H), 1.25 (d, J = 7.0Hz, 3H), 0.94 (dd, J = 11.5, 6.5Hz, 1H), 0.83 (t, J = 7.4Hz, 3H).

[0081] Synthesis of intermediate M3 (17-(O-(4-hydroxybutyl)oxime)-SPA)

[0082]

[0083] Following the synthetic method of M1, compound 15 (500 mg, 0.85 mmol) was added to the untreated reaction solution of compound 11. The mixture was stirred at 70 °C for about 6 hours. After the reaction was completed by TLC monitoring, the crude product was post-processed and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1, V / V) to give 447.8 mg of white solid, with a yield of 78%. 1 H NMR (500MHz, CDCl3) δ7.19(t,J=2.4Hz,1H),5.89(dt,J=9.7,2.1Hz,1H),5.79(dt,J=9.6,2.9H z,1H),4.86(d,J=1.7Hz,1H),4.73(tdd,J=7.4,6.1,3.4Hz,1H),4.36–4.31(m,1H),4.16–4.05 (m,3H),3.66(d,J=7.7Hz,2H),3.57–3.49(m,11H),3.47(dd,J=9.3,3.3Hz,1H),3.42(ddt,J=9 .1,6.0,2.8Hz,1H),3.27(dd,J=13.7,5.3Hz,1H),3.12(t,J=9.4Hz,1H),2.98(ddq,J=9.8,5.2, 2.6Hz,1H),2.89(ddt,J=11.5,8.8,2.6Hz,1H),2.46–2.36(m,2H),2.32(dt,J=13.6,7.1Hz,1H ),2.24–2.12(m,2H),2.09(ddd,J=13.0,7.7,4.5Hz,1H),1.93(dd,J=13.3,6.9Hz,1H),1.75–1 .71(m,2H),1.68–1.61(m,2H),1.59–1.51(m,2H),1.49–1.42(m,2H),1.36(dddd,J=15.6,12.8 ,5.8,3.6Hz,4H),1.30(s,2H),1.26(d,J=7.0Hz,3H),0.98–0.86(m,1H),0.84(t,J=7.4Hz,3H).

[0084] Synthesis of intermediate M4 (17-(4-((but-2-imideamino)oxy)butyraldehyde)-SPA)

[0085]

[0086] Following the synthetic method of M2, compound M3 (200 mg, 0.30 mmol, 1 eq) and pyridinium chlorochromate (PCC, 97.8 mg, 0.45 mmol, 1.5 eq) were dissolved in 5 mL of dichloromethane and reacted with the solution at room temperature for 24 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3 / 1, V / V) to give 279.1 mg of a white solid, with a yield of 70%. 1 H NMR (500MHz, CDCl3) δ9.80(t,J=1.6Hz,1H),7.09(t,J=2.5Hz,1H),5.89(dt,J=9.9,2.1Hz ,1H),5.80(dt,J=9.8,3.0Hz,1H),4.86(d,J=2.0Hz,1H),4.75(q,J=9.1Hz,1H),4.33(q,J =7.0Hz,1H),4.13–4.03(m,3H),3.59–3.45(m,13H),3.42(ddt,J=11.9,8.5,2.8Hz,1H),3 .27(dd,J=13.9,5.2Hz,1H),3.12(t,J=9.4Hz,1H),2.98(ddt,J=9.7,5.1,2.6Hz,1H),2.87 (ddt,J=11.4,8.6,2.6Hz,1H),2.54(td,J=7.2,1.6Hz,2H),2.44(dd,J=13.9,2.9Hz,1H), 2.30(dt,J=13.5,7.0Hz,1H),2.25–2.19(m,1H),2.12(dq,J=8.5,4.4Hz,1H),2.04–1.98(m ,2H),1.93(dd,J=13.3,7.1Hz,1H),1.58–1.50(m,2H),1.50–1.42(m,2H),1.41–1.31(m,4 H),1.29(d,J=6.2Hz,3H),1.26(d,J=6.9Hz,3H),0.99–0.86(m,1H),0.84(t,J=7.5Hz,3H).

[0087] Synthesis of compound M9 (17-(O-(4-methylsulfonyl butyl)oxime)-SPA)

[0088]

[0089] M3 (200 mg, 0.30 mmol, 1.0 eq), DMAP (18 mg, 0.15 mmol, 0.5 eq), and anhydrous TEA (132 μL, 1.50 mmol, 5 eq) were dissolved in 5 mL of anhydrous dichloromethane. The mixture was stirred at -20 °C for 10 min, and then methanesulfonyl chloride (MsCl, 116 μL, 1.50 mmol, 5 eq) was slowly added dropwise. The reaction was carried out at -20 °C for 30 min, then at 0 °C for 30 min, and finally at room temperature. After the reaction was monitored by TLC until complete, [the following was added]... The reaction solution was diluted with 10 mL of dichloromethane, washed with water, and the pH was adjusted to weakly acidic with saturated NH4Cl to remove DMAP and TEA. The aqueous phase was discarded, and the organic phase was retained. The solution was washed with water, and the pH was adjusted to weakly alkaline with saturated Na2CO3 to remove MsCl. The aqueous phase was discarded, and the organic phase was retained. The solution was washed once with saturated brine, and the organic phase was retained. The solution was dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness. Finally, the solution was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1, V / V) to give 179 mg of white solid compound M9, with a yield of 79%.

[0090] 1H NMR(500MHz, CDCl3)δ7.10(s,1H),5.89(dt,J=9.6,2.0Hz,1H),5.80(dt,J=9.8,3.0Hz,1H) ,4.86(d,J=1.8Hz,1H),4.75(q,J=8.6Hz,1H),4.33(q,J=6.9Hz,1H),4.28(t,J=6.4Hz,2H) ,4.12–4.04(m,3H),3.57–3.45(m,13H),3.42(ddd,J=11.8,5.9,2.7Hz,1H),3.26(dd,J=13 .9,5.3Hz,1H),3.12(t,J=9.4Hz,1H),3.03(s,3H),2.97(ddd,J=9.7,5.0,2.6Hz,1H),2.87 (ddt,J=11.3,8.6,2.6Hz,1H),2.44(dd,J=13.9,2.9Hz,1H),2.30(dt,J=13.3,7.0Hz,1H), 2.26–2.21(m,1H),2.14(ddd,J=13.3,8.7,4.6Hz,1H),1.93(dd,J=13.3,7.0Hz,1H),1.89– 1.83(m,2H),1.82–1.76(m,2H),1.57(s,3H),1.47–1.42(m,1H),1.38–1.33(m,3H),1.29(d ,J=6.2Hz,3H),1.26(d,J=6.9Hz,4H),0.94(td,J=11.7,6.5Hz,1H),0.84(t,J=7.4Hz,3H).

[0091] Synthesis of intermediate M5 (17-(O-(5-hydroxypentyl)oxime)-SPA)

[0092]

[0093] Following the synthetic method of M1, compound 15 (500 mg, 0.85 mmol) was added to the untreated reaction solution of compound 12, and the mixture was stirred overnight at 70 °C. After the reaction was completed by TLC monitoring, the crude product was post-processed and finally purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1, V / V) to give 392.6 mg of white solid, yield 67%. 1H NMR (500MHz, CDCl3) δ7.21(t,J=2.3Hz,1H),5.89(dt,J=9.7,2.1Hz,1H),5.80(dt,J =9.8,2.9Hz,1H),4.86(d,J=1.7Hz,1H),4.74(tdd,J=7.4,5.8,3.4Hz,1H),4.33(q,J =7.2Hz,1H),4.13–4.02(m,3H),3.68–3.62(m,2H),3.57–3.46(m,12H),3.42(tt,J= 9.0, 2.8Hz, 1H), 3.28 (dd, J=13.6, 5.2Hz, 1H), 3.12 (t, J=9.4Hz, 1H), 2.98 (ddd, J=9. 6,5.0,2.5Hz,1H),2.87(ddt,J=11.5,8.7,2.6Hz,1H),2.46–2.29(m,3H),2.18(dtd ,J=12.8,7.9,3.3Hz,1H),2.13–2.04(m,2H),1.93(dd,J=13.1,7.2Hz,1H),1.69(p,J =6.9Hz,2H),1.65–1.59(m,2H),1.58–1.51(m,2H),1.49–1.34(m,7H),1.29(d,J=6. 3Hz, 3H), 1.25 (d, J = 7.0Hz, 3H), 0.92 (qd, J = 11.6, 6.6Hz, 1H), 0.84 (t, J = 7.4Hz, 3H).

[0094] Synthesis of intermediate M6 (17-(5-((but-2-iminoamino)oxy)pentanal)-SPA)

[0095]

[0096] Following the synthetic method of M2, M5 (200 mg, 0.29 mmol, 1.0 eq) and PCC (97.8 mg, 0.45 mmol, 1.5 eq) were dissolved in 5 mL of dichloromethane and reacted with the solution at room temperature for 24 h. After post-treatment, the solution was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3 / 1, V / V), finally yielding 191.4 mg of a white solid, with a yield of 64%. 1H NMR (500MHz, CDCl3) δ9.79(t,J=1.7Hz,1H),7.11(t,J=2.3Hz,1H),5.89(dt,J=9.9,2.1 Hz,1H),5.81(dt,J=9.9,2.9Hz,1H),4.86(d,J=1.8Hz,1H),4.74(ddt,J=10.2,6.9,3.3H z,1H),4.33(q,J=7.2Hz,1H),4.10–4.04(m,3H),3.59–3.45(m,13H),3.42(tt,J=8.6,2 .7Hz,1H),3.27(dd,J=13.8,5.2Hz,1H),3.12(t,J=9.4Hz,1H),2.98(ddt,J=9.7,4.9,2. 6Hz,1H),2.87(ddt,J=11.4,8.6,2.6Hz,1H),2.52–2.48(m,2H),2.44(dd,J=13.8,3.0H z,1H),2.34–2.24(m,2H),2.20(ddt,J=12.1,7.5,2.3Hz,1H),2.12(ddd,J=13.3,8.7,4. 7Hz,1H),1.93(dd,J=13.3,7.1Hz,1H),1.73–1.71(m,2H),1.61–1.31(m,9H),1.29(d,J =6.2Hz, 3H), 1.26 (d, J = 6.9Hz, 3H), 0.93 (qd, J = 11.7, 6.5Hz, 1H), 0.84 (t, J = 7.5Hz, 3H).

[0097] Synthesis of intermediate M7 (17-(O-(6-hydroxyhexyl)oxime)-SPA)

[0098]

[0099] Following the synthetic method of M2, compound 15 (500 mg, 0.85 mmol) was added to the untreated compound 13 solution, and the mixture was stirred overnight at 70 °C. After the reaction was completed by TLC monitoring, the crude product was post-processed and finally purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1, V / V), yielding 346.8 mg of white solid, with a yield of 58%. 1H NMR (500MHz, CDCl3) δ7.18(t,J=2.4Hz,1H),5.89(dt,J=9.7,2.1Hz,1H),5.80(dt,J=9.8,2.9H z,1H),4.86(d,J=1.7Hz,1H),4.76(qd,J=7.2,3.5Hz,1H),4.33(q,J=7.1Hz,1H),4.11–4.00(m, 3H),3.64(t,J=6.6Hz,2H),3.58–3.45(m,13H),3.40(tq,J=8.7,2.8Hz,1H),3.29(dd,J=13.6, 5.2Hz,1H),3.13(t,J=9.4Hz,1H),2.98(ddt,J=10.0,5.1,2.6Hz,1H),2.87(ddt,J=11.4,8.8,2 .6Hz,1H),2.44(dd,J=13.5,3.1Hz,1H),2.41–2.34(m,1H),2.34–2.29(m,1H),2.23–2.14(m,1 H),2.07(ddd,J=13.1,8.4,4.4Hz,1H),1.93(dd,J=13.3,7.0Hz,1H),1.76(s,1H),1.70–1.64(m ,2H),1.61–1.56(m,3H),1.51–1.45(m,2H),1.44–1.39(m,4H),1.35(dd,J=12.8,5.3Hz,3H),1. 29(d,J=6.2Hz,3H),1.25(d,J=7.0Hz,3H),0.92(dt,J=11.6,5.8Hz,1H),0.84(t,J=7.4Hz,3H).

[0100] Synthesis of intermediate M8 (17-(6-((but-2-imino)oxy)hexanal)-SPA)

[0101]

[0102] Following the synthesis of M2, M7 (200 mg, 0.28 mmol, 1.0 eq) and PCC (91.3 mg, 0.42 mmol, 1.5 eq) were dissolved in 5 mL of dichloromethane and reacted with the solution at room temperature for 24 h. After post-treatment, the solution was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3 / 1, V / V) to give 197.2 mg of a white solid, yielding 66%.

[0103] 1H NMR (500MHz, CDCl3) δ9.79(d,J=1.8Hz,1H),7.12(t,J=2.3Hz,1H),5.89(d,J=9.8Hz,1H ),5.80(dt,J=9.8,3.0Hz,1H),4.86(d,J=1.8Hz,1H),4.75(qd,J=7.1,3.4Hz,1H),4.33 (q,J=6.8Hz,1H),4.06(td,J=6.7,2.1Hz,3H),3.53(d,J=30.3Hz,13H),3.43–3.38(m,1 H),3.28(dd,J=13.8,5.2Hz,1H),3.12(t,J=9.4Hz,1H),3.00–2.95(m,1H),2.86(ddt,J =11.4,8.7,2.6Hz,1H),2.49–2.41(m,3H),2.29(ddd,J=20.2,13.2,7.8Hz,2H),2.23–2 .15(m,1H),2.11(ddd,J=13.1,8.6,4.5Hz,1H),1.93(dd,J=13.4,7.0Hz,1H),1.70–1.6 6(m,3H),1.56(dd,J=13.9,7.0Hz,2H),1.50–1.41(m,5H),1.38–1.34(m,3H),1.29(d,J =6.2Hz, 3H), 1.26 (d, J = 6.9Hz, 3H), 0.93 (qd, J = 11.6, 6.4Hz, 1H), 0.84 (t, J = 7.4Hz, 3H).

[0104] Example 1

[0105] Synthesis of compound A1(17-(O-(3-(methylamino)propyl)oxime)-SPA)

[0106]

[0107] Compound M2 (80 mg, 0.1432 mmol, 1 eq), monomethylamine hydrochloride (11.8 mg, 0.1718 mmol, 1.2 eq), and TEA (24 μL, 0.1718 mmol, 1.2 eq) were dissolved in 2 mL of anhydrous dichloromethane. After stirring for 10 min, sodium triacetoxyborohydride (STAB, 45.6 mg, 0.2148 mmol, 1.5 eq) was added. The reaction was carried out at room temperature for 4 hours, and the reaction was monitored by TLC. After the reaction mixture was basically completed, 5 mL of dichloromethane was added to dilute the reaction solution. The reaction solution was then washed with saturated sodium bicarbonate solution (5 mL × 2), followed by one wash with 5 mL of saturated brine. The aqueous phases were combined and back-extracted with 5 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. Finally, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V) to obtain 54.5 mg of a pale yellow solid, with a yield of 56.4%. 1 H NMR (500MHz, CDCl3) δ7.10 (d, J=2.5Hz, 1H), 5.89 (dt, J=9.8, 2.1Hz, 1H), 5.80 (dt, J=9.8, 3.0Hz,1H),4.86(d,J=1.8Hz,1H),4.74(q,J=8.9Hz,1H),4.33(q,J=7.0Hz,1H),4.15(t,J= 6.1Hz,2H),4.06(q,J=7.0Hz,1H),3.58–3.45(m,13H),3.41(tt,J=8.4,2.7Hz,1H),3.26(d d,J=13.9,5.3Hz,1H),3.12(t,J=9.4Hz,1H),2.97(ddd,J=9.9,5.1,2.6Hz,1H),2.88(ddt, J=11.3,8.6,2.6Hz,1H),2.79(t,J=7.1Hz,2H),2.52(s,3H),2.45(dd,J=13.9,2.9Hz,1H), 2.30(dt,J=13.4,7.1Hz,1H),2.20(t,J=7.7Hz,3H),1.94(td,J=12.9,6.2Hz,3H),1.55(dt ,J=14.6,7.3Hz,2H),1.49–1.42(m,2H),1.37–1.35(m,2H),1.29(d,J=6.1Hz,3H),1.27(s, 1H),1.26(d,J=2.7Hz,3H),0.94(dt,J=11.5,5.7Hz,1H),0.84(t,J=7.4Hz,3H).ESI-HR-MS m / z[M+H] + calcd for C 37 H58 N2O9, 675.4215, found 675.4236.

[0108] Example 2

[0109] Synthesis of compound A2 (17-(O-(3-(dimethylamino)propyl)oxime)-SPA)

[0110]

[0111] Referring to Example 1, M2 (80 mg, 0.14 mmol, 1.0 eq), dimethylamine hydrochloride (14 mg, 0.17 mmol, 1.2 eq), and TEA (24 μL, 0.17 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 56.4 mg of a pale yellow solid, with a yield of 57.2%. 1H NMR (500MHz, CDCl3) δ7.11(t,J=2.3Hz,1H),5.89(dt,J=9.7,2.1Hz,1H),5.80(dt,J=10 .0,2.9Hz,1H),4.86(d,J=1.8Hz,1H),4.75(qd,J=7.2,3.3Hz,1H),4.37–4.29(m,1H),4. 08(dt,J=21.6,6.6Hz,3H),3.57–3.45(m,13H),3.41(ddt,J=11.8,8.5,2.7Hz,1H),3.3 1(d,J=11.1Hz,1H),3.27(dd,J=13.8,5.3Hz,1H),3.12(t,J=9.4Hz,1H),2.98(ddt,J=10 .2,5.5,2.8Hz,1H),2.87(ddt,J=11.6,8.7,2.7Hz,1H),2.49(d,J=7.6Hz,1H),2.46–2. 42(m,1H),2.33(s,6H),2.22–2.17(m,1H),2.13(ddd,J=13.2,8.6,4.5Hz,1H),1.91(tt, J=13.8,6.9Hz,3H),1.55(dt,J=14.5,7.3Hz,2H),1.49–1.43(m,2H),1.41–1.31(m,5H) ,1.29(d,J=6.2Hz,3H),1.26(d,J=6.9Hz,3H),0.97–0.91(m,1H),0.84(t,J=7.5Hz,3H).

[0112] ESI-HR-MS m / z[M+H] + calcd for C 38 H 60 N2O9,689.4372, found 689.4296.

[0113] Example 3

[0114] Synthesis of compound A3(17-(O-(3-(piperazin-1-yl)propyl)oxime)-SPA)

[0115]

[0116] Referring to Example 1, compound M2 (80 mg, 0.1432 mmol, 1 eq) and piperazine (37 mg, 0.4296 mmol, 3 eq) were dissolved in 2 mL of anhydrous dichloromethane. After stirring for 10 min, sodium triacetoxyborohydride (STAB, 45.6 mg, 0.2148 mmol, 1.5 eq) was added. The crude product was post-processed and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → ethyl acetate / methanol / TEA = 5 / 1 / 0.05, V / V) to give 57.9 mg of a pale yellow solid, with a yield of 55.4%. 1 H NMR(500MHz, CDCl3) δ7.12(d,J=2.4Hz,1H),5.89(dt,J=9.8,2.0Hz,1H),5.80(dt,J=9.9, 2.9Hz,1H),4.86(d,J=1.8Hz,1H),4.75(qd,J=6.9,3.3Hz,1H),4.33(q,J=6.8Hz,1H),4.08 (dt,J=19.4,6.7Hz,3H),3.59–3.44(m,13H),3.41(tq,J=8.5,2.8Hz,1H),3.27(dd,J=13.8 ,5.2Hz,1H),3.12(t,J=9.4Hz,1H),2.95(t,J=5.0Hz,4H),2.88(ddt,J=11.4,8.7,2.6Hz,1 H),2.57(s,2H),2.48(s,2H),2.47–2.42(m,4H),2.34–2.24(m,2H),2.22–2.15(m,1H),2.1 1(ddd,J=13.2,8.8,4.6Hz,1H),1.93(dd,J=13.3,7.0Hz,1H),1.86(p,J=6.5Hz,2H),1.55( dt,J=14.3,7.2Hz,2H),1.49–1.42(m,2H),1.36(dd,J=11.7,4.7Hz,3H),1.29(d,J=6.2Hz, 3H),1.26(d,J=6.9Hz,3H),0.93(tt,J=11.7,5.8Hz,1H),0.84(t,J=7.4Hz,3H).ESI-HR-MS m / z[M+H] + calcd for C 40 H 62 N3O9,730.4637, found 730.4662.

[0117] Example 4

[0118] Synthesis of compound A4 (17-(O-(3-morpholinopropyl)oxime)-SPA)

[0119]

[0120] Referring to Example 1, M2 (80 mg, 0.14 mmol, 1.0 eq) and morpholine (15 μL, 0.17 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 71.7 mg of a pale yellow-white solid, with a yield of 68.6%. 1 H NMR(500MHz, CDCl3) δ7.11(d,J=2.4Hz,1H),5.89(dt,J=9.8,2.1Hz,1H),5.80(dt,J=9 .8,3.0Hz,1H),4.86(d,J=1.8Hz,1H),4.75(td,J=10.4,5.4Hz,1H),4.33(q,J=6.9Hz,1 H),4.08(dt,J=23.6,6.7Hz,3H),3.73(t,J=4.7Hz,4H),3.58–3.45(m,13H),3.41(tq,J =8.6, 2.7Hz, 1H), 3.27 (dd, J = 13.8, 5.2Hz, 1H), 3.12 (t, J = 9.4Hz, 1H), 2.97 (ddq, J = 10. 2,5.2,2.5Hz,1H),2.88(ddt,J=11.3,8.6,2.6Hz,1H),2.49–2.45(m,4H),2.45–2.42( m,2H),2.29(dd,J=13.1,7.0Hz,1H),2.25–2.18(m,1H),2.13(dt,J=9.0,4.6Hz,1H),1. 93(dd,J=13.3,7.0Hz,1H),1.86(dt,J=13.9,6.5Hz,2H),1.58–1.32(m,9H),1.29(d,J= 6.2Hz, 3H), 1.26 (d, J = 6.8Hz, 3H), 0.93 (dq, J = 11.7, 5.2Hz, 1H), 0.84 (t, J = 7.4Hz, 3H).

[0121] ESI-HR-MS m / z[M+H] + calcd for C 40 H 62 N2O 10 ,731.4477,found 731.4477.

[0122] Example 5

[0123] Synthesis of compound A5 (17-(O-(3-aminopropyl)oxime)-SPA)

[0124]

[0125] Referring to Example 1, M2 (80 mg, 0.14 mmol, 1.0 eq) and ammonium acetate (13 mg, 0.17 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 52.9 mg of a pale yellow-white solid, with a yield of 56%. 1 H NMR (500MHz, CDCl3) δ7.07(t,J=2.5Hz,1H),5.89(dt,J=9.7,2.0Hz,1H),5.81(dt,J =9.9,2.9Hz,1H),4.86(d,J=1.8Hz,1H),4.76(qd,J=7.0,3.0Hz,1H),4.33(q,J=6.8H z,1H),4.13–4.03(m,3H),3.53(d,J=29.2Hz,12H),3.46(dd,J=9.3,3.3Hz,1H),3.42 (tt,J=8.7,2.7Hz,1H),3.27(dd,J=14.0,5.3Hz,1H),3.12(t,J=9.4Hz,1H),2.97(dd q,J=10.3,5.2,2.4Hz,1H),2.87(ddt,J=11.2,8.3,2.5Hz,1H),2.55(t,J=7.4Hz,2H ),2.45(dd,J=14.1,2.9Hz,1H),2.29(dt,J=13.4,7.0Hz,1H),2.16(t,J=7.7Hz,2H), 1.93(dd,J=13.3,7.0Hz,1H),1.82(d,J=7.7Hz,2H),1.57–1.35(m,8H),1.29(d,J=6. 2Hz,3H),1.26(d,J=7.0Hz,3H),0.97–0.90(m,1H),0.84(t,J=7.4Hz,3H).ESI-HR-MS m / z[M+H] + calcd for C 36 H 56 N2O9,661.4057, found 661.4058.

[0126] Example 6

[0127] Synthesis of compound A6(17-(O-(3-(pyrrolidone-1-yl)propyl)oxime)-SPA)

[0128]

[0129] Referring to Example 1, M2 (80 mg, 0.14 mmol, 1.0 eq) and tetrahydropyrrole (14 μL, 0.17 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 68.4 mg of a pale yellow oil, with a yield of 66.9%.

[0130] 1 H NMR (500MHz, CDCl3) δ7.11(t,J=2.4Hz,1H),5.89(dt,J=9.7,2.1Hz,1H),5.81(dt,J =9.8,3.0Hz,1H),4.86(d,J=1.8Hz,1H),4.74(qd,J=7.2,3.2Hz,1H),4.33(q,J=6.7H z,1H),4.11(t,J=6.2Hz,2H),4.07(q,J=7.0Hz,1H),3.59–3.49(m,12H),3.47(dd,J =9.3,3.2Hz,1H),3.41(tq,J=8.6,2.7Hz,1H),3.27(dd,J=13.9,5.2Hz,1H),3.12(t, J=9.4Hz,1H),2.97(ddq,J=10.2,5.2,2.5Hz,1H),2.87(ddt,J=11.4,8.6,2.6Hz,1H ),2.67(d,J=7.0Hz,4H),2.44(dd,J=13.9,3.0Hz,1H),2.34–2.22(m,2H),2.21–2.10 (m,2H),1.99–1.91(m,3H),1.88–1.83(m,4H),1.58–1.31(m,9H),1.29(d,J=6.2Hz, 3H), 1.26 (d, J=6.9Hz, 3H), 0.93 (dq, J=11.6, 5.9, 5.2Hz, 1H), 0.84 (t, J=7.4Hz, 3H).

[0131] ESI-HR-MS m / z[M+H] + calcd for C 40H 62 N2O9,715.4528, found 715.4529.

[0132] Example 7

[0133] Synthesis of compound A7 (17-(O-(3-(diethylamino)propyl)oxime)-SPA)

[0134]

[0135] Referring to Example 1, M2 (80 mg, 0.14 mmol, 1.0 eq) and diethylamine (18 μL, 0.17 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 60.7 mg of a pale yellow oil, with a yield of 59.2%. 1H NMR (500MHz, CDCl3) δ7.10(t,J=2.4Hz,1H),5.89(dt,J=9.8,2.0Hz,1H),5.81(dt,J=9.8,2 .9Hz,1H),4.86(d,J=1.8Hz,1H),4.74(ddt,J=9.0,6.8,3.4Hz,1H),4.33(q,J=7.0Hz,1H),4 .11(t,J=6.1Hz,2H),4.07(q,J=7.0Hz,1H),3.58–3.49(m,12H),3.47(dd,J=9.3,3.3Hz,1H) ,3.41(tq,J=8.6,2.7Hz,1H),3.27(dd,J=13.9,5.3Hz,1H),3.12(t,J=9.4Hz,1H),2.97(ddt ,J=9.9,5.1,2.6Hz,1H),2.87(ddt,J=11.4,8.6,2.6Hz,1H),2.70(d,J=7.1Hz,4H),2.45(d d,J=13.9,2.9Hz,1H),2.30(dt,J=13.4,7.0Hz,1H),2.18(dddd,J=30.5,13.4,8.3,4.4Hz,3 H),1.92(dt,J=15.2,7.5Hz,3H),1.60–1.31(m,9H),1.29(d,J=6.1Hz,3H),1.26(d,J=6.9Hz ,3H),1.14(t,J=7.2Hz,6H),0.93(dq,J=11.6,5.1Hz,1H),0.84(t,J=7.5Hz,3H).ESI-HR-MS m / z[M+H] + calcdfor C 40 H 64 N2O9, 717.4685, found 717.4706.

[0136] Example 8

[0137] Synthesis of compound A8(17-(O-(3-(4-methylpiperazin-1-yl)propyl)oxime)-SPA)

[0138]

[0139] Referring to Example 1, M2 (80 mg, 0.14 mmol, 1.0 eq) and N-methylpiperazine (19 μL, 0.17 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 10 / 1, V / V) to give 59 mg of a pale yellow oil, with a yield of 55.4%. 1 H NMR (500MHz, CDCl3) δ7.12 (t, J=2.3Hz, 1H), 5.89 (dt, J=9.7, 2.0Hz, 1H), 5.80 (dt, J=9. 8,3.0Hz,1H),4.86(d,J=1.8Hz,1H),4.75(qd,J=7.1,3.3Hz,1H),4.33(q,J=6.8Hz,1H) ,4.08(dt,J=20.7,6.6Hz,3H),3.58–3.45(m,13H),3.41(tq,J=8.6,2.7Hz,1H),3.27(d d,J=13.8,5.2Hz,1H),3.12(t,J=9.4Hz,1H),2.97(ddt,J=10.1,5.1,2.6Hz,1H),2.88(d dt,J=11.4,8.6,2.6Hz,1H),2.51(s,4H),2.46(t,J=7.8Hz,4H),2.43(d,J=3.0Hz,1H), 2.31(s,3H),2.29–2.22(m,2H),2.22–2.16(m,1H),2.11(ddd,J=13.2,8.8,4.6Hz,1H),1 .93(dd,J=13.3,7.0Hz,1H),1.89–1.83(m,2H),1.59–1.31(m,9H),1.29(d,J=6.2Hz,3H ),1.26(d,J=6.9Hz,3H),0.93(dq,J=11.6,5.2Hz,1H),0.84(t,J=7.4Hz,3H).ESI-HR-MS m / z[M+H] + calcd for C 41 H 65 N3O9, 744.4794, found 744.4808.

[0140] Example 9

[0141] Synthesis of compound A9 (17-(O-(3-(4-ethylpiperazin-1-yl)propyl)oxime)-SPA)

[0142]

[0143] Referring to Example 1, M2 (80 mg, 0.14 mmol, 1.0 eq) and N-ethylpiperazine (22 μL, 0.17 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 10 / 1, V / V) to give 62.5 mg of a pale yellow oil, with a yield of 57.6%. 1 H NMR (500MHz, CDCl3) δ7.11(t,J=2.4Hz,1H),5.89(dt,J=9.8,2.0Hz,1H),5.81(dt,J =9.8,2.9Hz,1H),4.86(d,J=1.9Hz,1H),4.75(qd,J=7.2,6.6,3.3Hz,1H),4.33(q,J= 7.1Hz,1H),4.08(dt,J=21.4,6.6Hz,3H),3.59–3.45(m,13H),3.41(tq,J=8.6,2.7Hz ,1H),3.27(dd,J=13.8,5.3Hz,1H),3.12(t,J=9.4Hz,1H),2.97(ddq,J=10.1,5.2,2. 6Hz,1H),2.88(ddt,J=11.3,8.6,2.6Hz,1H),2.60–2.42(m,10H),2.33–2.22(m,3H), 2.21–2.16(m,1H),2.11(ddd,J=13.3,8.9,4.6Hz,1H),1.93(dd,J=13.3,7.0Hz,1H), 1.90–1.83(m,2H),1.59–1.31(m,9H),1.29(d,J=6.2Hz,3H),1.26(d,J=7.0Hz,3H),1 .10(t,J=7.2Hz,3H),0.93(dt,J=11.5,5.8Hz,1H),0.84(t,J=7.4Hz,3H).ESI-HR-MS m / z[M+H] + calcd for C 42 H 67 N3O9, 758.4950, found 758.4973.

[0144] Example 10

[0145] Synthesis of compound A10(17-(O-(3-((2-(dimethylamino)ethyl)(methyl)amino)propyl)oxime)-SPA)

[0146]

[0147] Referring to Example 1, M2 (80 mg, 0.14 mmol, 1.0 eq) and N,N,N'-trimethylethylenediamine (22 μL, 0.17 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → ethyl acetate / methanol / TEA = 5 / 1 / 0.05, V / V) to give 57 mg of a pale yellow oil, with a yield of 55.6%. 1 H NMR (500MHz, CDCl3) δ7.11(t,J=2.4Hz,1H),5.89(dt,J=9.8,2.1Hz,1H),5.80(dt ,J=9.9,3.0Hz,1H),4.86(d,J=1.8Hz,1H),4.75(h,J=6.5Hz,1H),4.33(q,J=6.9Hz ,1H),4.07(dt,J=17.9,6.6Hz,3H),3.58–3.45(m,13H),3.41(ddd,J=9.1,7.5,2. 7Hz,1H),3.27(dd,J=13.8,5.2Hz,1H),3.12(t,J=9.4Hz,1H),2.97(ddt,J=10.0,5 .2,2.6Hz,1H),2.87(ddt,J=11.4,8.6,2.6Hz,1H),2.54–2.43(m,7H),2.28(s,6H ),2.27(s,3H),2.24–2.19(m,1H),2.12(ddd,J=13.3,8.8,4.5Hz,1H),1.93(dd,J= 13.3,7.1Hz,1H),1.88–1.81(m,2H),1.59–1.31(m,9H),1.29(d,J=6.1Hz,3H),1.2 6(d,J=6.8Hz,3H),0.93(dt,J=11.6,5.8Hz,1H),0.84(t,J=7.4Hz,3H).ESI-HR-MS m / z[M+H] + calcd for C 41 H 67 N3O9, 746.4950, found 746.4965.

[0148] Example 11

[0149] Synthesis of compound A11(17-(O-(3-(piperidin-1-yl)propyl)oxime)-SPA)

[0150]

[0151] Referring to Example 1, M2 (80 mg, 0.14 mmol, 1.0 eq) and piperidine (17 μL, 0.17 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 65 mg of a pale yellow oil, with a yield of 62.3%.

[0152] 1 H NMR (500MHz, CDCl3) δ7.12 (t, J = 2.3 Hz, 1H), 5.89 (dt, J = 9.7, 2.0 Hz, 1H), 5.81 (dt, J = 9. 9,2.9Hz,1H),4.86(d,J=1.8Hz,1H),4.75(qd,J=6.8,3.3Hz,1H),4.32(dt,J=13.4,6.9 Hz,1H),4.11–4.03(m,3H),3.58–3.44(m,13H),3.40(tq,J=8.4,2.7Hz,1H),3.28(dd,J =13.8,5.2Hz,1H),3.12(t,J=9.4Hz,1H),2.97(ddq,J=10.1,5.2,2.6Hz,1H),2.87(ddt ,J=11.4,8.7,2.6Hz,1H),2.46–2.45(m,1H),2.42(d,J=9.0Hz,4H),2.33–2.22(m,3H), 2.19(dd,J=11.6,6.2Hz,1H),2.11(ddd,J=13.6,9.1,4.9Hz,1H),1.96–1.85(m,3H),1. 62(p,J=5.7Hz,4H),1.55(dt,J=14.6,7.4Hz,2H),1.49–1.42(m,4H),1.38–1.32(m,4H) ,1.29(d,J=6.2Hz,3H),1.26(d,J=6.9Hz,3H),0.95–0.90(m,1H),0.84(t,J=7.5Hz,3H).

[0153] ESI-HR-MS m / z[M+H] + calcd for C41 H 64 N2O9, 729.4685, found 729.4707.

[0154] Example 12

[0155] Synthesis of compound A12 (17-(O-(4-(dimethylamino)butyl)oxime)-SPA)

[0156]

[0157] Referring to Example 1, M4 (80 mg, 0.12 mmol, 1.0 eq), dimethylamine hydrochloride (11 mg, 0.14 mmol, 1.2 eq), and TEA (20 μL, 0.14 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 46.5 mg of a pale yellow solid, with a yield of 55.8%. 1H NMR (500MHz, CDCl3) δ7.11(t,J=2.4Hz,1H),5.89(dt,J=9.7,2.1Hz,1H),5.80(dt,J=9.8,3.0H z,1H),4.86(d,J=1.9Hz,1H),4.74(qd,J=6.6,3.3Hz,1H),4.33(q,J=6.8Hz,1H),4.06(q,J=6. 9Hz,3H),3.57–3.49(m,12H),3.46(dd,J=9.3,3.3Hz,1H),3.41(ddt,J=11.8,8.5,2.7Hz,1H), 3.28(dd,J=13.9,5.4Hz,1H),3.12(t,J=9.4Hz,1H),2.97(ddq,J=10.2,5.2,2.6Hz,1H),2.87(d dt,J=11.5,8.7,2.7Hz,1H),2.44(dd,J=13.8,3.0Hz,1H),2.38(t,J=7.5Hz,2H),2.30(s,6H), 2.22–2.16(m,1H),2.12(td,J=8.9,4.6Hz,1H),1.93(dd,J=13.4,7.0Hz,1H),1.68(p,J=6.6Hz, 2H),1.62–1.56(m,3H),1.55–1.51(m,1H),1.49–1.41(m,2H),1.40–1.31(m,5H),1.29(d,J=6. 2Hz, 3H), 1.26 (d, J=7.0Hz, 3H), 0.93 (dq, J=11.6, 5.2Hz, 1H), 0.84 (t, J=7.4Hz, 3H).ESI-HR-MS m / z[M+H] + calcd forC 39 H 62 N2O9, 703.4528, found 703.4545.

[0158] Example 13

[0159] Synthesis of compound A13(17-(O-(4-(pyrrolidone-1-yl)butyl)oxime)-SPA)

[0160]

[0161] Referring to Example 1, M4 (80 mg, 0.12 mmol, 1.0 eq) and tetrahydropyrrole (12 μL, 0.14 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 48.1 mg of a pale yellow oil, with a yield of 55.6%.

[0162] 1 H NMR (500MHz, CDCl3) δ7.11(t,J=2.4Hz,1H),5.89(dt,J=9.8,2.0Hz,1H),5.80(dt,J=9.8,3.0Hz, 1H),4.86(d,J=1.8Hz,1H),4.74(tt,J=10.0,5.0Hz,1H),4.33(q,J=6.7Hz,1H),4.07(td,J=7.3,6 .8,2.3Hz,3H),3.57–3.49(m,12H),3.46(dd,J=9.3,3.3Hz,1H),3.41(ddt,J=11.8,8.6,2.8Hz,1H ),3.27(dd,J=13.8,5.2Hz,1H),3.12(t,J=9.4Hz,1H),2.97(ddq,J=10.3,5.3,2.6Hz,1H),2.87(d dt,J=11.4,8.6,2.6Hz,1H),2.65–2.53(m,6H),2.44(dd,J=13.8,3.1Hz,1H),2.33–2.22(m,2H),2 .22–2.15(m,1H),2.12(ddd,J=13.3,9.0,4.8Hz,1H),1.93(dd,J=13.4,7.0Hz,1H),1.86–1.80(m, 4H),1.70–1.65(m,3H),1.59–1.51(m,2H),1.50–1.42(m,2H),1.35(tdd,J=10.5,6.2,3.0Hz,4H), 1.29(d,J=6.3Hz,3H), 1.26(d,J=7.0Hz,3H), 0.93(dq,J=11.7,5.2Hz,1H), 0.84(t,J=7.4Hz,3H).

[0163] ESI-HR-MS m / z[M+H] + calcd for C 41 H 64N2O9,729.4685,,found 729.4706.

[0164] Method 2:

[0165]

[0166] Compound M9 (80 mg, 0.11 mmol, 1.0 eq), tetrahydropyrrole (28 μL, 0.33 mmol, 3 eq), and TEA (19 μL, 0.13 mmol, 1.2 eq) were dissolved in 2 mL of DMF and reacted at 70 °C for 4 h under TLC monitoring. After the reaction was complete, 10 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was retained, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. Finally, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V) to obtain compound A13.

[0167] Example 14

[0168] Synthesis of compound A14 (17-(O-(4-(piperazin-1-yl)butyl)oxime)-SPA)

[0169]

[0170] Referring to Example 1, compound M4 (80 mg, 0.1188 mmol, 1 eq) and piperazine (30.7 mg, 0.3564 mmol, 3 eq) were dissolved in 2 mL of anhydrous dichloromethane. After stirring for 10 min, sodium triacetoxyborohydride (STAB, 37.8 mg, 0.1782 mmol, 1.5 eq) was added. The crude product was post-processed and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → ethyl acetate / methanol / TEA = 5 / 1 / 0.05, V / V) to give 51.9 mg of a pale yellow solid, with a yield of 58.8%. 1H NMR (500MHz, CDCl3) δ7.11(d,J=2.5Hz,1H),5.89(d,J=9.6Hz,1H),5.80(dt,J=9.9, 3.0Hz,1H),4.86(d,J=1.8Hz,1H),4.75(tt,J=9.8,5.0Hz,1H),4.33(q,J=6.8Hz,1H) ,4.06(q,J=6.5Hz,3H),3.58–3.49(m,12H),3.46(dd,J=9.3,3.2Hz,1H),3.41(td,J= 9.0,2.6Hz,1H),3.27(dd,J=13.7,5.3Hz,1H),3.12(t,J=9.4Hz,1H),3.00(t,J=5.1H z,4H),2.87(ddt,J=11.4,8.7,2.5Hz,1H),2.53(s,3H),2.48–2.37(m,4H),2.33–2.2 3(m,2H),2.20–2.08(m,2H),1.93(dd,J=13.3,7.0Hz,1H),1.66(dt,J=12.2,6.3Hz,2 H),1.63–1.53(m,4H),1.50–1.42(m,2H),1.38–1.32(m,4H),1.29(d,J=6.2Hz,3H),1 .25(d,J=2.8Hz,3H),0.93(dd,J=11.5,6.5Hz,1H),0.84(t,J=7.5Hz,3H).ESI-HR-MS m / z[M+H] + calcd forC 41 H 65 N3O9, 744.4794, found 744.4808.

[0171] Method 2:

[0172]

[0173] Compound M9 (80 mg, 0.11 mmol, 1.0 eq), piperazine (27 mg, 0.33 mmol, 3 eq), and TEA (19 μL, 0.13 mmol, 1.2 eq) were dissolved in 2 mL of DMF and reacted at 70 °C for 4 h under TLC monitoring. After the reaction was complete, 10 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was retained, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. Finally, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V) to obtain compound A14.

[0174] Example 15

[0175] Synthesis of compound A15 (17-(O-(4-(diethylamino)butyl)oxime)-SPA)

[0176]

[0177] Referring to Example 1, M4 (80 mg, 0.12 mmol, 1.0 eq) and diethylamine (14 μL, 0.14 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 49.2 mg of a pale yellow oil, with a yield of 56.7%. 1 H NMR (500MHz, CDCl3) δ7.11(t,J=2.3Hz,1H),5.89(dt,J=9.8,2.0Hz,1H),5.80(dt,J=9.9,3.0 Hz,1H),4.86(d,J=1.8Hz,1H),4.75(tt,J=9.8,4.9Hz,1H),4.33(q,J=6.8Hz,1H),4.06(dt,J =10.1,6.5Hz,3H),3.59–3.44(m,13H),3.41(tq,J=8.6,2.7Hz,1H),3.28(dd,J=13.9,5.1Hz, 1H),3.12(t,J=9.4Hz,1H),2.97(ddq,J=10.3,5.2,2.5Hz,1H),2.87(ddt,J=11.4,8.6,2.6Hz, 1H),2.62(p,J=9.2,8.2Hz,4H),2.54(d,J=7.5Hz,2H),2.44(dd,J=13.8,3.0Hz,1H),2.33–2. 23(m,2H),2.21–2.09(m,2H),1.93(dd,J=13.3,7.0Hz,1H),1.66(p,J=6.5Hz,2H),1.60–1.52( m,3H),1.46(dq,J=13.9,7.0Hz,2H),1.39–1.32(m,4H),1.29(d,J=6.2Hz,3H),1.26(d,J=6.9 Hz,3H),1.08(t,J=7.2Hz,6H),0.93(dd,J=11.5,6.4Hz,1H),0.84(t,J=7.5Hz,3H).ESI-HR-MS m / z[M+H] + calcd for C 41 H 66N2O9, 731.4841, found 731.4864.

[0178] Example 16

[0179] Synthesis of compound A16(17-(O-(4-(4-methylpiperazin-1-yl)butyl)oxime)-SPA)

[0180]

[0181] Referring to Example 1, M4 (80 mg, 0.12 mmol, 1.0 eq) and N-methylpiperazine (16 μL, 0.14 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 10 / 1, V / V) to give 52.5 mg of a pale yellow oil, with a yield of 58.4%. 1 H NMR (400MHz, CDCl3) δ7.11 (d, J=2.4Hz, 1H), 5.89 (dt, J=9.8, 2.0Hz, 1H), 5.8 0(dt,J=9.8,2.9Hz,1H),4.86(d,J=1.8Hz,1H),4.74(qd,J=7.1,6.7,3.3Hz,1 H),4.33(q,J=6.8Hz,1H),4.06(q,J=6.3Hz,3H),3.59–3.45(m,13H),3.41(t t,J=8.5,2.6Hz,1H),3.28(dd,J=13.8,5.2Hz,1H),3.12(t,J=9.3Hz,1H),2.9 7(ddq,J=9.9,5.1,2.6Hz,1H),2.87(ddt,J=11.4,8.7,2.6Hz,1H),2.52(s,4 H),2.47–2.37(m,5H),2.31(s,3H),2.29–2.24(m,2H),2.23–2.07(m,3H),1.9 3(dd,J=13.3,7.0Hz,1H),1.72–1.31(m,14H),1.29(d,J=6.2Hz,3H),1.25(d, J=6.9Hz, 3H), 0.93 (dd, J=11.4, 6.4Hz, 1H), 0.84 (t, J=7.4Hz, 3H).ESI-HR-MS m / z[M+H] + calcd for C 42 H 67N3O9, 758.4950, found 758.4980.

[0182] Example 17

[0183] Synthesis of compound A17 (17-(O-(4-(4-ethylpiperazin-1-yl)butyl)oxime)-SPA)

[0184]

[0185] Referring to Example 1, M4 (80 mg, 0.12 mmol, 1.0 eq) and N-ethylpiperazine (18 μL, 0.14 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 10 / 1, V / V) to give 56 mg of a pale yellow oil, with a yield of 61.1%. 1 H NMR (400MHz, CDCl3) δ7.03 (d, J = 2.4Hz, 1H), 5.82 (dt, J = 9.8, 2.0Hz, 1H), 5.73 (dt, J = 9. 8,2.9Hz,1H),4.79(d,J=2.0Hz,1H),4.71–4.63(m,1H),4.26(q,J=6.8Hz,1H),4.02–3.9 6(m,3H),3.51–3.42(m,12H),3.39(dd,J=9.3,3.3Hz,1H),3.33(dt,J=8.7,3.0Hz,1H), 3.20(dd,J=13.8,5.2Hz,1H),3.05(t,J=9.4Hz,1H),2.94–2.87(m,1H),2.83–2.55(m,10 H),2.44(t,J=7.3Hz,2H),2.37(dd,J=13.8,3.0Hz,1H),2.22(dd,J=13.2,6.9Hz,1H),2 .17–2.01(m,3H),1.86(dd,J=13.3,7.0Hz,1H),1.60(q,J=11.3,9.1Hz,4H),1.50–1.44( m,2H),1.42–1.36(m,2H),1.33–1.26(m,4H),1.22(d,J=6.2Hz,3H),1.19(d,J=6.9Hz,3H ),1.14(t,J=7.2Hz,3H),0.85(dt,J=11.5,5.8Hz,1H),0.77(t,J=7.4Hz,3H).ESI-HR-MS m / z[M+H] +calcd for C 43 H 69 N3O9, 772.5107, found 772.5132.

[0186] Example 18

[0187] Synthesis of compound A18 (17-(O-(4-(piperidin-1-yl)butyl)oxime)-SPA)

[0188]

[0189] Referring to Example 1, M4 (80 mg, 0.12 mmol, 1.0 eq) and piperidine (14 μL, 0.14 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 51.8 mg of a pale yellow oil, with a yield of 58.8%. 1H NMR (400MHz, CDCl3) δ7.11(t,J=2.4Hz,1H),5.89(dt,J=9.8,2.0Hz,1H),5.80(dt,J=9.8,2. 9Hz, 1H), 4.86 (d, J=1.8Hz, 1H), 4.74 (qd, J=6.8, 3.2Hz, 1H), 4.33 (q, J=5.8, 4.9Hz, 1H), 4.0 7(dd,J=6.6,4.7Hz,3H),3.58–3.45(m,13H),3.41(tt,J=7.4,2.1Hz,1H),3.28(dd,J=13.7, 5.2Hz,1H),3.12(t,J=9.3Hz,1H),2.97(ddq,J=10.2,5.3,2.5Hz,1H),2.87(ddt,J=11.4,8. 7,2.6Hz,1H),2.44(dt,J=22.1,8.1Hz,6H),2.29(td,J=13.6,7.0Hz,2H),2.19(dt,J=9.6,2 .2Hz,1H),2.12(ddd,J=13.2,8.6,4.4Hz,1H),1.93(dd,J=13.3,7.0Hz,1H),1.64(dp,J=9.8 ,5.1,4.1Hz,8H),1.54(dd,J=14.3,7.1Hz,2H),1.50–1.42(m,4H),1.40–1.32(m,4H),1.29( d,J=6.3Hz,3H),1.26(d,J=6.9Hz,3H),0.96–0.89(m,1H),0.84(t,J=7.4Hz,3H).ESI-HR-MS m / z[M+H] + calcd for C 42 H 66 N2O9, 743.4841, found 743.4865.

[0190] Example 19

[0191] Synthesis of compound A19 (17-(O-(4-((2-(dimethylamino)ethyl)(methyl)amino)butyl)oxime)-SPA)

[0192]

[0193] Referring to Example 1, M4 (80 mg, 0.12 mmol, 1.0 eq) and N,N,N'-trimethylethylenediamine (18 μL, 0.14 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 10 / 1, V / V) to give 53.6 mg of a pale yellow oil, with a yield of 59.4%. 1 H NMR (500MHz, CDCl3) δ7.11(t,J=2.3Hz,1H),5.89(dt,J=9.7,2.1Hz,1H),5.80(dt,J=9.8,3.0Hz ,1H),4.86(d,J=1.8Hz,1H),4.75(tt,J=10.2,5.1Hz,1H),4.33(q,J=6.9Hz,1H),4.06(q,J=6.3H z,3H),3.53(d,J=29.6Hz,12H),3.46(dd,J=9.3,3.2Hz,1H),3.42(tt,J=9.1,2.8Hz,1H),3.27( dd,J=13.8,5.2Hz,1H),3.12(t,J=9.4Hz,1H),2.97(ddq,J=10.2,5.2,2.6Hz,1H),2.87(ddt,J=1 1.5,8.8,2.6Hz,1H),2.61–2.50(m,4H),2.49–2.42(m,3H),2.31(d,J=8.2Hz,9H),2.25(dt,J=1 3.3,5.7Hz,1H),2.14(dddd,J=17.8,13.3,8.7,5.3Hz,2H),1.93(dd,J=13.4,7.0Hz,1H),1.70–1 .63(m,2H),1.62–1.51(m,4H),1.46(dq,J=13.9,7.0Hz,2H),1.38–1.32(m,4H),1.29(d,J=6.2Hz ,3H),1.26(d,J=6.9Hz,3H),0.93(dq,J=11.6,6.1,5.1Hz,1H),0.84(t,J=7.4Hz,3H).ESI-HR-MS m / z[M+H] + calcd for C 42 H 69 N3O9, 760.5107, found 760.5132.

[0194] Example 20

[0195] Synthesis of compound A20 (17-(O-(5-(dimethylamino)pentyl)oxime)-SPA)

[0196]

[0197] Referring to Example 1, M6 (80 mg, 0.12 mmol, 1.0 eq), dimethylamine hydrochloride (11 mg, 0.14 mmol, 1.2 eq), and TEA (20 μL, 0.14 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 48.1 mg of a pale yellow solid, with a yield of 57.7%. 1 H NMR(500MHz, CDCl3) δ7.12(d,J=2.4Hz,1H),5.89(dt,J=9.8,2.1Hz,1H),5.80(dt,J=9.8,3.0 Hz,1H),4.86(d,J=1.9Hz,1H),4.75(dq,J=10.4,7.0,5.1Hz,1H),4.33(q,J=6.8Hz,1H),4.06( q,J=7.2Hz,3H),3.58–3.49(m,12H),3.47(dd,J=9.3,3.3Hz,1H),3.41(tq,J=8.7,2.7Hz,1H), 3.28(dd,J=13.7,5.2Hz,1H),3.12(t,J=9.3Hz,1H),2.97(ddq,J=10.0,5.0,2.4Hz,1H),2.87( ddt,J=11.4,8.8,2.6Hz,1H),2.44(dd,J=13.8,3.1Hz,1H),2.30(dd,J=8.9,6.7Hz,4H),2.25( s,6H),2.22–2.15(m,1H),2.11(ddd,J=13.3,8.9,4.5Hz,1H),1.93(dd,J=13.4,7.0Hz,1H),1. 71–1.64(m,2H),1.59–1.50(m,4H),1.48–1.44(m,1H),1.36(dtt,J=13.1,7.6,3.5Hz,6H),1.2 9(d,J=6.3Hz,3H),1.26(d,J=6.8Hz,3H),0.93(dq,J=11.7,5.2Hz,1H),0.84(t,J=7.5Hz,3H).

[0198] ESI-HR-MS m / z[M+H]+ calcd for C 40 H 64 N2O9, 717.4685, found 717.4706.

[0199] Example 21

[0200] Synthesis of compound A21 (17-(O-(5-(pyrrolidone-1-yl)pentyl)oxime)-SPA)

[0201]

[0202] Referring to Example 1, M6 (80 mg, 0.12 mmol, 1.0 eq) and tetrahydropyrrole (12 μL, 0.14 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 50.4 mg of a pale yellow oil, with a yield of 58.4%.

[0203] 1H NMR (500MHz, CDCl3) δ7.12(t,J=2.4Hz,1H),5.89(dt,J=9.8,2.0Hz,1H),5.80(dt,J=9.8,3.0Hz,1H),4 .86(d,J=1.9Hz,1H),4.75(qd,J=6.8,3.3Hz,1H),4.33(q,J=6.8Hz,1H),4.06(q,J=7.3,6.8Hz,3H),3.5 8–3.49(m,12H),3.47(dd,J=9.3,3.3Hz,1H),3.41(tq,J=8.6,2.7Hz,1H),3.28(dd,J=13.7,5.2Hz,1H) ,3.12(t,J=9.4Hz,1H),2.97(ddq,J=10.2,5.2,2.5Hz,1H),2.87(ddt,J=11.4,8.6,2.6Hz,1H),2.56(d, J=6.1Hz,4H),2.49(dd,J=9.1,6.7Hz,2H),2.44(dd,J=13.8,3.1Hz,1H),2.30(dt,J=14.5,7.8Hz,2H), 2.22–2.14(m,1H),2.11(ddd,J=13.2,8.8,4.5Hz,1H),1.93(dd,J=13.4,7.0Hz,1H),1.83–1.78(m,4H), 1.67(p,J=6.8Hz,2H),1.62–1.52(m,4H),1.48–1.44(m,1H),1.44–1.39(m,2H),1.38–1.31(m,4H),1.29 (d,J=6.2Hz,3H),1.26(d,J=6.8Hz,3H),0.93(dq,J=11.8,5.2Hz,1H),0.84(t,J=7.5Hz,3H).ESI-HR-MS m / z[M+H] + calcd for C 42 H 66 N2O9, 743.4841, found 743.4864.

[0204] Example 22

[0205] Synthesis of compound A22(17-(O-(5-((2-(dimethylamino)ethyl)(methyl)amino)pentyl)oxime)-SPA)

[0206]

[0207] Referring to Example 1, M6 (80 mg, 0.12 mmol, 1.0 eq) and N,N,N'-trimethylethylenediamine (18 μL, 0.14 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 10 / 1, V / V) to give 50.4 mg of a pale yellow oil, with a yield of 56%.

[0208] 1 H NMR (500MHz, CDCl3) δ7.12(t,J=2.4Hz,1H),5.89(dt,J=9.7,2.0Hz,1H),5.80(dt,J=9.8,3.0Hz, 1H),4.86(d,J=1.9Hz,1H),4.75(qd,J=6.8,3.3Hz,1H),4.33(q,J=6.8Hz,1H),4.05(td,J=6.8,3 .8Hz,3H),3.57–3.49(m,12H),3.47(dd,J=9.3,3.3Hz,1H),3.41(ddt,J=11.8,8.7,2.7Hz,1H),3 .28(dd,J=13.8,5.2Hz,1H),3.12(t,J=9.4Hz,1H),2.97(ddq,J=10.3,5.2,2.5Hz,1H),2.87(ddt, J=11.3,8.7,2.6Hz,1H),2.50(dd,J=7.9,5.0Hz,2H),2.44(dt,J=9.8,2.8Hz,3H),2.41–2.37(m, 2H), 2.26 (s, 9H), 2.18 (q, J = 11.1Hz, 1H), 2.11 (ddd, J = 13.3, 8.9, 4.6Hz, 1H), 1.93 (dd, J = 13.3, 7. 0Hz, 1H), 1.67 (p, J=6.8Hz, 2H), 1.61–1.41 (m, 7H), 1.36 (dtt, J=9.8, 7.3, 3.3Hz, 6H), 1.29 (d, J= 6.2Hz,3H),1.26(d,J=6.9Hz,3H),0.93(dq,J=11.6,5.2Hz,1H),0.84(t,J=7.5Hz,3H).ESI-HR-MS m / z[M+H] + calcd for C 43 H 71 N3O9, 774.5263, found 774.5284.

[0209] Example 23

[0210] Synthesis of compound A23 (17-(O-(5-(piperazin-1-yl)pentyl)oxime)-SPA)

[0211]

[0212] Referring to Example 1, M6 (80 mg, 0.12 mmol, 1.0 eq) and piperazine (12 mg, 0.14 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 10 / 1, V / V), finally yielding 52.4 mg of a pale yellow solid, with a yield of 59.7%. 1 H NMR (500MHz, CDCl3)δ

[0213] 7.12(d,J=2.5Hz,1H),5.89(dt,J=9.9,2.0Hz,1H),5.80(dt,J=9.8,3.0Hz,1H),4.86(d,J= 1.8Hz,1H),4.79–4.72(m,1H),4.33(q,J=6.7Hz,1H),4.09–4.03(m,3H),3.58–3.48(m,12H ),3.47(dd,J=9.3,3.3Hz,1H),3.41(tq,J=8.8,2.7Hz,1H),3.28(dd,J=13.7,5.2Hz,1H),3 .12(t,J=9.4Hz,1H),2.97(dtd,J=10.4,5.2,2.4Hz,1H),2.94–2.84(m,5H),2.65–2.56(m, 2H),2.47–2.41(m,4H),2.36–2.32(m,2H),2.32–2.25(m,2H),2.23–2.15(m,1H),2.11(ddd ,J=13.0,8.7,4.4Hz,1H),1.93(dd,J=13.4,7.0Hz,1H),1.67(p,J=6.9Hz,2H),1.54(dtd,J =15.0,7.3,3.3Hz,4H),1.46(dt,J=14.2,7.1Hz,2H),1.39–1.34(m,4H),1.29(d,J=6.2Hz, 3H),1.26(d,J=6.8Hz,3H),0.93(dt,J=11.5,5.7Hz,1H),0.84(t,J=7.4Hz,3H).ESI-HR-MS m / z[M+H] +calcd for C 42 H 67 N3O9, 758.4950, found 758.4965.

[0214] Example 24

[0215] Synthesis of compound A24 (17-(O-(6-(dimethylamino)hexyloxime)-SPA)

[0216]

[0217] Referring to Example 1, M8 (80 mg, 0.11 mmol, 1.0 eq), dimethylamine hydrochloride (11 mg, 0.13 mmol, 1.2 eq), and TEA (18 μL, 0.13 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 45.8 mg of a pale yellow solid, with a yield of 55%. 1H NMR (500MHz, CDCl3) δ7.12(t,J=2.4Hz,1H),5.89(dt,J=9.7,2.1Hz,1H),5.80(dt,J=9.8,3 .0Hz,1H),4.86(d,J=1.8Hz,1H),4.75(qd,J=6.5,3.3Hz,1H),4.33(q,J=7.1Hz,1H),4.09–4 .03(m,3H),3.58–3.45(m,13H),3.41(ddt,J=11.6,5.3,2.8Hz,1H),3.28(dd,J=13.7,5.2H z,1H),3.12(t,J=9.4Hz,1H),2.97(dh,J=9.9,2.5Hz,1H),2.87(ddt,J=11.3,8.6,2.6Hz,1H ),2.44(dd,J=13.7,3.1Hz,1H),2.30–2.26(m,3H),2.24(s,6H),2.20–2.16(m,1H),2.13–2 .09(m,1H),1.93(dd,J=13.4,7.0Hz,1H),1.67–1.63(m,2H),1.56(dt,J=13.8,6.5Hz,2H),1 .49(tdd,J=9.3,6.3,2.8Hz,4H),1.36(dtd,J=12.8,8.9,8.0,5.5Hz,8H),1.29(d,J=6.2Hz ,3H),1.26(d,J=7.0Hz,3H),0.93(dd,J=11.5,6.5Hz,1H),0.84(t,J=7.4Hz,3H).ESI-HR-MS m / z[M+H] + calcd for C 41 H 66 N2O9, 731.4841, found 731.4867.

[0218] Example 25

[0219] Synthesis of compound A25 (17-(O-(6-(pyrrolidone-1-yl)hexane)-SPA)

[0220]

[0221] Referring to Example 1, M8 (80 mg, 0.12 mmol, 1.0 eq) and tetrahydropyrrole (11 μL, 0.13 mmol, 1.2 eq) were dissolved in 2 mL of dichloromethane. After stirring at room temperature for 10 min, STAB (46 mg, 0.21 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 4 h. After post-treatment, the mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 → dichloromethane / methanol = 15 / 1, V / V), finally yielding 47.2 mg of a pale yellow oil, with a yield of 54.8%.

[0222] A25-1: 1 H NMR (500MHz, CDCl3) δ7.12(t,J=2.4Hz,1H),5.89(dt,J=9.8,2.0Hz,1H),5.80(dt,J=9.8,3.0 Hz,1H),4.86(d,J=1.8Hz,1H),4.80–4.71(m,1H),4.36–4.29(m,1H),4.06(dt,J=12.5,6.8Hz, 3H),3.59–3.44(m,13H),3.41(ddt,J=11.7,8.7,2.9Hz,1H),3.28(dd,J=13.7,5.2Hz,1H),3. 12(t,J=9.4Hz,1H),2.97(ddq,J=10.2,5.2,2.6Hz,1H),2.87(ddt,J=11.4,8.6,2.6Hz,1H),2. 51(q,J=5.0,3.8Hz,4H),2.47–2.42(m,3H),2.33–2.24(m,2H),2.23–2.15(m,1H),2.11(ddd, J=13.0,8.7,4.4Hz,1H),1.93(dd,J=13.3,7.0Hz,2H),1.78(p,J=3.1Hz,4H),1.65(p,J=6.8Hz ,2H),1.55(dt,J=12.4,7.5Hz,4H),1.50–1.45(m,2H),1.37(ddd,J=13.1,8.4,4.9Hz,7H),1.2 9(d,J=6.2Hz,3H),1.26(d,J=7.1Hz,3H),0.93(dt,J=11.5,5.8Hz,1H),0.84(t,J=7.5Hz,3H).

[0223] ESI-HR-MS m / z[M+H] + calcd for C 43 H 68 N2O9, 757.4998, found 757.5020.

[0224] Example 26

[0225] Compound stability determination

[0226] The stability of compounds has a significant impact on their drug-likeness. Representative 17-glycoside spinosad derivatives LM-2I, SPA, and oxime ether compounds were selected, and their stability was determined at pH ≤ 1 and pH ≥ 12 after standing at 60°C for 4 hours. The components of each compound were analyzed using thin-layer chromatography (TLC) with a developing solvent of ethyl acetate:methanol:triethylamine = 5:1:0.05 (v / v).

[0227] The results are as follows Figure 1 As shown. Figure 1 A represents the stability results of LM-2I. Figure 1 B represents the stability result of the oxime ether compound A14 of the present invention. Figure 1 In A, “1” represents the result of LM-21 standing at 60℃ for 4 hours with pH ≤ 1; “2” represents a mixture of “1” and “3”; “3” represents the LM-21 reference standard (pH = 7); “4” represents a mixture of “3” and “5”; and “5” represents the result of LM-21 standing at 60℃ for 4 hours with pH > 12. Figure 1 In B, "1" represents the result of A14 reacting at pH < 1 and 60℃ for 4 hours; "2" represents a mixture of "1" and "3", "3" represents the A14 standard (pH = 7), "4" represents a mixture of "3" and "5", and "5" represents the result of A14 reacting at pH > 12 and 60℃ for 4 hours.

[0228] The results showed that LM-2I completely decomposed, while oxime ether A14 decomposed slightly, indicating that A14 was more stable than LM-21. Similarly, SPA also completely decomposed after standing at 60°C for 4 hours at pH ≤ 1 and pH ≥ 12, with stability results similar to LM-2I. These results indicate that the 17-oxime ether spinosad derivative has better stability than the 17-glycoside spinosad derivative. Likewise, the other compounds A1-A25 were also significantly more stable than LM-2I, with stability close to that of A14.

[0229] Example 27

[0230] Cell proliferation inhibitory activity of the compound

[0231] Assay for cell proliferation inhibition activity

[0232] The MTT assay was used to test the cell viability of the compound.

[0233] Experimental Methods: a) Select MDA-MB-231 (breast cancer cells), HT-29 (colorectal cancer cells), HepG2 (liver cancer cells), and HUVEC (normal human umbilical vein endothelial cells) in logarithmic growth phase and seed them into 96-well plates. Determine the number of cells per well based on cell growth, generally around 3000. b) Weigh the drug and prepare an initial concentration of 10 mM (dissolved in DMSO). Then, dilute it to 3-5 concentration gradients using complete medium (DMEM + 10% FBS + 1% penicillin antibody) as needed, setting up 3 replicates. c) Add the drug 12 hours after seeding. d) Add MTT (protected from light) after 48 hours and continue incubation for 4 hours. e) Pour out the liquid from the plate, absorb it with filter paper, and add 100 μl of DMSO to each well to dissolve the crystals. f) Shake at low speed for 10 minutes on a shaker and monitor the OD value (570 nm) using a microplate reader.

[0234] Test results: The average OD value of each replicate well was taken, and the cell viability and inhibition rate were calculated.

[0235] Survival rate = (average OD value of the drug group / average OD value of the control group) × 100%.

[0236] Inhibition rate = 100% - survival rate.

[0237] IC50 of the compound was calculated using GraphPad Prism 9 software. 50 The cell proliferation inhibitory activity of the compound was determined by measuring its value. The results are shown in Table 1.

[0238] Table 1. IC50 values ​​of the compounds inhibiting MDA-MB-231, HT-29, HepG2, and HUVEC. 50 Value (μM)

[0239]

[0240] As can be seen, the compounds of this invention can effectively inhibit the activity of MDA-MB-231 (breast cancer cells), HT-29 (colorectal cancer cells), HepG2 (liver cancer cells), and HUVEC (normal human umbilical vein endothelial cells). They exhibit good therapeutic effects for treating tumors.

[0241] It should be noted that the above embodiments are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is impossible to exhaustively list all possible implementations here. All obvious variations or modifications derived from the technical solutions of this invention are still within the scope of protection of this invention.

Claims

1. A spinosad oxime derivative, characterized in that, Compounds represented by general structural formula (I), their salts, or their optical isomers: R1 is selected from NR8R9, nitrogen-containing aromatic heterocycles with 5-8 carbon atoms (C5-C8), nitrogen-containing aliphatic rings with 3-7 carbon atoms (C3-C7), substituted C5-C8 nitrogen-containing aromatic heterocycles, and substituted C3-C7 nitrogen-containing aliphatic rings; The substituents on the C5-C8 nitrogen-containing aromatic heterocycles and the C3-C7 nitrogen-containing aliphatic rings are independently selected from 1-4 carbon atoms (C1-C4) alkyl, halogen, hydroxy, alkoxy, nitro, carboxyl, cyano, and amino groups; R8 and R9 are independently selected from hydrogen, alkyl groups with 1-8 carbon atoms (C1-C8), and R 10 NR 11 R 12 ; R 10 Selected from C1-C8 alkyl groups; R 11 R 12 Independently selected from hydrogen and C1-C8 alkyl groups; L is selected from C1-C8 alkyl, 1-8 carbon atom (C1-C8) ether chain; R2 is selected from C1-C8 alkyl, C1-C8 olefin, and C1-C8 alkyne groups; R3 and R4 are selected from hydrogen and C1-C3 alkyl groups; R5, R6, and R7 are independently selected from C1-C3 alkyl groups; AB represents CH=CH and -CH2CH2-; MQ is C=CH.

2. The oxime ether spinosad derivative according to claim 1, characterized in that, R1 is selected from pyrrolyl, tetrahydropyrrolyl, piperazinyl, piperidinyl, morpholinyl, indolyl, imidazolyl, oxazolyl, thiazolyl, purinyl, pyrazole, isoxazole, isothiazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, azircyclopropane, azircyclobutane, azircyclopentane, substituted pyrrolyl, substituted indolyl, substituted imidazol, substituted oxazole, substituted thiazol, substituted purine, substituted pyrazole, substituted isoxazole, substituted isothiazol, substituted pyridine, substituted quinoline, substituted pyridazine, substituted pyrimidinyl, substituted pyrazine, substituted quinoline, substituted isoquinoline, substituted azircyclopropane, substituted azircyclobutane, substituted azircyclopentane, substituted tetrahydropyrrolyl, substituted piperazine, substituted piperidinyl, substituted morpholinyl; Among them, substituted pyrrolyl, substituted indolyl, substituted imidazolyl, substituted oxazolyl, substituted thiazolyl, substituted purine, substituted pyrazole, substituted isoxazolyl, substituted isothiazolyl, substituted pyridinyl, substituted quinolinyl, substituted pyridazinyl, substituted pyrazinyl, substituted quinolinyl, substituted isoquinolinyl, substituted azircyclopropane, substituted azircyclobutane, substituted azircyclopentane, substituted tetrahydropyrrolyl, The substituents in substituted piperazine, substituted morpholine, and other groups are independently selected from C1-C4 alkyl, halogen, hydroxyl, alkoxy, nitro, carboxyl, cyano, and amino groups.

3. The oxime ether spinosad derivative according to claim 1, characterized in that, R1 is selected from Where R 13 Selected from hydrogen and C1-C4 alkyl groups.

4. The oxime ether spinosad derivative according to claim 1, characterized in that, R8, R9, R 10 R 11 R 12 Independently selected from hydrogen, alkyl with 1-4 carbon atoms (C1-C4); L selected from alkyl chain with 1-6 carbon atoms (C1-C6), ether chain with 1-6 carbon atoms (C1-C6); R2 selected from C1-C4 alkyl, C1-C4 alkenyl.

5. The oxime ether spinosad derivative according to any one of claims 1-4, characterized in that, The oxime ether spinosad derivatives include compounds, their salts, or optical isomers thereof, as shown in the following structures:

6. The method for preparing the oxime ether spinosad derivative according to any one of claims 1-5, characterized in that, Includes the following steps: S1. Hydrolyze spinosad A to obtain compound 14; S2 and compound 14 are oxidized to obtain compound 15; S3, compound 15 and O-hydroxyalkyl-substituted hydroxylamine react to give oxime ether compounds; S4. The hydroxyl groups on the side chain of the oxime ether compound are subjected to oxidation and reduction amination reactions to obtain the oxime ether spinosad derivative.

7. The method for preparing the oxime ether spinosad derivative according to any one of claims 1-5, characterized in that, Includes the following steps: S1. Hydrolyze spinosad A to obtain compound 14; S2 and compound 14 are oxidized to obtain compound 15; S3 and compound 15 undergo an oxime reaction to yield an oxime ether compound; S5. The oxime ether compound and sulfonyl chloride are reacted, and after the reaction is completed, amine alkylation is performed to obtain the oxime ether spinosad derivative. The structure of the oxime ether compound is as follows: n is an integer from 1 to 8.

8. The use of the oxime ether spinosad derivative according to any one of claims 1-5 in the preparation of antitumor drugs.

9. The application according to claim 8, characterized in that, The tumors mentioned include: lung cancer, non-small cell lung cancer, liver cancer, pancreatic cancer, stomach cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, bladder cancer, cervical cancer, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary gland carcinoma, cystic adenocarcinoma, cystic carcinoma, medullary carcinoma, bronchial carcinoma, osteocyte carcinoma, epithelial carcinoma, bile duct carcinoma, choriocarcinoma, embryonic carcinoma, seminoma, Wilms' carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, and others. Glandular tumor, hemangioma, vocal cord neuroma, meningioma, neuroblastoma, optic neuroblastoma, retinoblastoma, neurofibroma, fibrosarcoma, fibroblastoma, fibroma, fibroadenoma, fibrochondroma, fibrocystoma, fibromixoma, fibromyxoma, fibroosteoma, fibromyxoid sarcoma, fibromyxoid papilloma, myxosarcoma, myxoid cystoma, myxochondroma, myxochondrosarcoma, myxochondrofibrosarcoma, myxadenoma, myxoblastoma, liposarcoma, lipoma, lipadenoma, lipoblastoma, lipochondroma, lipofuscinoma, lipofibroma, hemangioma Myxolipomas, chondrosarcomas, chondromas, chondromyomas, chordomas, chorioamisomas, chorioepithelial adenomas, chorioepitheliomas, chorioblastomas, osteochondromas, osteochondrosarcomas, osteochondromas, bone cysts, odontomas, osteofibromas, osteofibrosarcomas, angiosarcomas, hemangiomas, angiolipomas, angiochondromas, hemangioblastomas, angiokeratomas, angioneurotic gliomas, hemangioendotheliomas, angiofibromas, angiomyomas, angiolipomas, angiolymphangiomas, angiolipoleiomyomas, angiomyolipomas, angioneurotic neuromas, angiomas Myxoma, hemangiosarcoma, lymphangiosarcoma, lymphogranuloma, lymphangioma, lymphoma, lymphomyxoma, lymphosarcoma, lymphangiofibroma, lymphocytoma, lymphoepithelioma, lymphoblastoma, lymphoblastoma, endothelioma, endothelioma, synovoma, synovial sarcoma, mesothelioma, connective tissue tumor, Ewing's tumor, leiomyoma, leiomyosarcoma, leiomyoblastoma, leiomyofibroma, rhabdomyosarcoma, rhabdomyomyxoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic disease cells, polycythemia vera, lymphoma, multiple myeloma.

10. The application according to claim 8, characterized in that, The dosage form of the drug is any one of granules, capsules, tablets, injections, infusions, or suppositories.

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