Reutamycin derivative and application thereof

Abstract

According to the structure of the reutamycin, structural derivation is carried out on the basis of the reutamycin, and a series of novel compounds with certain physiological activity are provided and have a good inhibition effect on fusarium graminearum.

Description

Technical Field

[0001] The priority information of the present invention is as follows: priority number is 2023116800133, priority date is December 8, 2023, the name of the invention is rutamycin derivatives and uses thereof, and the disclosure thereof is incorporated herein by reference. The present invention relates to the field of compounds, and specifically to rutamycin derivatives and uses thereof. Background Art

[0002] Rutamycin (hereinafter referred to as RTM), also known as oligomycin D, is a macrolide antibiotic produced by Streptomyces spp., and its structural formula is as follows:

[0003] Summary of the invention

[0004] According to the structure of rutamycin, the present invention performs structural derivation on the basis of the structure and provides a series of new compounds with certain physiological activities.

[0005] Specifically, the compound represented by the following formula I or its pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate:

[0006]

[0007] R1 is selected from -OH, -N3, -OC(=O)-benzene ring-(C0~C3 alkyl), -OS(=O)(=O)-benzene ring-Cl, -OC(=O)-benzene ring-O-(C0~C3 alkyl), -OC(=O)-benzene ring-benzene ring, -OC(=O)-benzene ring-N(CH3)(CH3), -OC(=O)-C(=O)-O-(C0~C3 alkyl), -OC(=O)-benzene ring-CF3, -OC(=O)-benzene ring-CCl3, -OC(=O)-(C0~C3 alkyl)-benzene ring, -OC(=O)-CH=CH-benzene ring, -OC(=O)-benzene ring-NO2, -OC(=O)-(C0~C3 alkyl), -OS(=O)(=O)-benzene ring-(C0-C4 alkyl), -OS(=O)(=O)-(C0~C3 alkyl).

[0008] R2 and R3 are selected from H, and a double bond is formed between the C to which R2 is connected and the C to which R3 is connected.

[0009] R4 is selected from -OH, -OC(=O)-benzene ring-(C0~C3 alkyl), -OC(=O)-benzene ring-benzene ring, -OC(=O)-C(=O)-O-(C0~C3 alkyl), -OC(=O)-benzene ring-CF3, -OC(=O)-benzene ring-CCl3, N3, -OC(=O)-C(=O)-O-(C0~C3 alkyl), -OS(=O)(=O)-(C0~C3 alkyl).

[0010] R5 is selected from =O or =N-NH2.

[0011] R6 is selected from -OH, -N3, -OC(=O)-phenyl ring-(C0~C3 alkyl), -OC(=O)-C(=O)-O-(C0~C3 alkyl).

[0012] R7 is selected from -OH, -OC(=O)-C(=O)-O-(C0-C3 alkyl);

[0013] R8, R9, R 10 With R 11 is selected from H, the C to which R8 is connected forms a double bond with the C to which R9 is connected, and R 10 Connected C and R 11 The C connected to R8 forms a double bond; or the C connected to R9 is connected to R8 through O to form a three-membered cyclic ether, R 10 Connected C and R 11 The connected C forms a double bond; or the C connected to R9 and R 10 The connected C forms a double bond, and the C connected to R8 forms a double bond with R 11 The connected C connection; or R9 connected to C and R 10 The connected C forms a double bond, and the C connected to R8 forms a double bond with R 11 The connected C connection; or R9 connected to C and R 10 The connected C forms a double bond, and the C connected to R8 forms a double bond with R 11 The connected C connection; or R9 connected to C and R 10 The connected C forms a double bond, and the C connected to R8 forms a double bond with R 11 The connected C connect.

[0014] Furthermore, the above structure does not include rutamycin.

[0015] The present application also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate in preventing and controlling wheat fusarium.

[0016] In order to more clearly describe the content of this application, the terms involved are defined as follows:

[0017] C1-Cn used in this application includes C1-C2, C1-C3...C1-Cn, n is an integer greater than one; the prefix of a substituent indicates the minimum and maximum number of carbon atoms in the substituent, for example, "C1-C6 alkyl" refers to a straight or branched alkyl containing one to six carbon atoms. In this application, "C0 alkyl" means that there is no group here.

[0018] The beneficial effects of the present invention are as follows: according to the structure of rutamycin, the present invention performs structural derivation on the basis of rutamycin and provides a series of new compounds with certain physiological activities, which have good inhibitory effects on wheat fusarium. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is the mass spectrum characteristic diagram of Example 1;

[0020] Figure 2 is the H NMR spectrum of Example 1;

[0021] Figure 3 is the NMR carbon spectrum of Example 1;

[0022] Figure 4 It is the mass spectrum characteristic diagram of Example 2;

[0023] Figure 5 is the H NMR spectrum of Example 2;

[0024] Figure 6 is the NMR carbon spectrum of Example 2;

[0025] Figure 7 It is the mass spectrum characteristic diagram of Example 3;

[0026] Figure 8 is the H NMR spectrum of Example 3;

[0027] Fig. 9 is the NMR carbon spectrum of Example 3;

[0028] Fig.10 It is the mass spectrum characteristic diagram of Example 4;

[0029] Fig.11 is the H NMR spectrum of Example 4;

[0030] Fig.12 is the NMR carbon spectrum of Example 4;

[0031] Fig.13 It is the mass spectrum characteristic diagram of Example 5;

[0032] Fig.14 is the H NMR spectrum of Example 5;

[0033] Fig.15 is the NMR carbon spectrum of Example 5;

[0034] Fig.16 It is the mass spectrum characteristic diagram of Example 6;

[0035] Fig.17 is the H NMR spectrum of Example 6;

[0036] Fig.18 is the NMR carbon spectrum of Example 6;

[0037] Fig.19 It is the mass spectrum characteristic diagram of Example 7;

[0038] Fig. 20 is the H NMR spectrum of Example 7;

[0039] Fig.21 is the NMR carbon spectrum of Example 7;

[0040] Fig. 22 It is the mass spectrum characteristic diagram of Example 8;

[0041] Fig.23 is the H NMR spectrum of Example 8;

[0042] Fig.24 is the NMR carbon spectrum of Example 8;

[0043] Fig.25 It is the mass spectrum characteristic diagram of Example 9;

[0044] Fig.26 is the H NMR spectrum of Example 9;

[0045] Fig. 27 is the NMR carbon spectrum of Example 9;

[0046] Fig.28 It is the mass spectrum characteristic diagram of Example 10;

[0047] Fig.29 is the H NMR spectrum of Example 10;

[0048] Fig.30 is the NMR carbon spectrum of Example 10;

[0049] Fig.31 is the mass spectrum characteristic diagram of Example 11;

[0050] Fig.32 is the H NMR spectrum of Example 11;

[0051] Fig.33 is the NMR carbon spectrum of Example 11;

[0052] Fig.34 is the mass spectrum characteristic diagram of Example 12;

[0053] Fig.35 is the H NMR spectrum of Example 12;

[0054] Fig.36 is the NMR carbon spectrum of Example 12;

[0055] Fig.37 is the mass spectrum characteristic diagram of Example 13;

[0056] Fig.38 is the H NMR spectrum of Example 13;

[0057] Fig.39 is the NMR carbon spectrum of Example 13;

[0058] Fig.40 It is the mass spectrum characteristic diagram of Example 14;

[0059] Fig.41 is the H NMR spectrum of Example 14;

[0060] Fig.42 is the NMR carbon spectrum of Example 14;

[0061] Fig.43 is the mass spectrum characteristic diagram of Example 15;

[0062] Fig.44 is the H NMR spectrum of Example 15;

[0063] Fig.45 is the NMR carbon spectrum of Example 15;

[0064] Fig.46 is the mass spectrum characteristic diagram of Example 16;

[0065] Fig.47 is the H NMR spectrum of Example 16;

[0066] Fig.48 is the NMR carbon spectrum of Example 16;

[0067] Fig.49 is the mass spectrum characteristic diagram of Example 17;

[0068] Fig.50 is the H NMR spectrum of Example 17;

[0069] Fig.51 is the NMR carbon spectrum of Example 17;

[0070] Fig.52 is the mass spectrum characteristic diagram of Example 18;

[0071] Fig.53 is the H NMR spectrum of Example 18;

[0072] Fig.54 is the NMR carbon spectrum of Example 18;

[0073] Fig.55 is the mass spectrum characteristic diagram of Example 19;

[0074] Fig.56 is the H NMR spectrum of Example 19;

[0075] Fig.57 is the NMR carbon spectrum of Example 19;

[0076] Fig.58 is the mass spectrum characteristic diagram of Example 20;

[0077] Fig.59 is the H NMR spectrum of Example 20;

[0078] Fig.60 is the NMR carbon spectrum of Example 20;

[0079] Fig.61 is the mass spectrum characteristic diagram of Example 21;

[0080] Fig.62 is the H NMR spectrum of Example 21;

[0081] Fig.63 is the NMR carbon spectrum of Example 21;

[0082] Fig.64 is the mass spectrum characteristic diagram of Example 22;

[0083] Fig.65 is the H NMR spectrum of Example 22;

[0084] Fig.66 is the NMR carbon spectrum of Example 22;

[0085] Fig.67 is the mass spectrum characteristic diagram of Example 23;

[0086] Fig.68 is the H NMR spectrum of Example 23;

[0087] Fig.69 is the NMR carbon spectrum of Example 23;

[0088] Fig.70 is the mass spectrum characteristic diagram of Example 24;

[0089] Fig.71 is the H NMR spectrum of Example 24;

[0090] Fig.72 is the NMR carbon spectrum of Example 24;

[0091] Fig.73 is the mass spectrum characteristic diagram of Example 25;

[0092] Fig.74 is the H NMR spectrum of Example 25;

[0093] Fig.75 This is the NMR carbon spectrum of Example 25. DETAILED DESCRIPTION

[0094] Example 1 Synthesis of Compound RTM-0215

[0095] Synthesis method: Dissolve rutamycin (400.0 mg, 0.515 mmol, 1.0 eq.) in dichloromethane (10 mL), activate at 0 ° C for 20 min, add benzoyl chloride (0.359 mL, 3.09 mmol, 6.0 eq.), and react at 25 ° C for 4 h. After the reaction, adjust the pH to acidic with 2NH4Cl, extract with water and dichloromethane (3*15 mL), wash the organic layer with saturated brine (3*5 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (dichloromethane / methanol=100 / 1) to obtain 374.4 mg (white solid), with a yield of 41.6%.

[0096]

[0097] RTM-0215 ​​Synthesis Route

[0098] Mass spectrometry test: RTM-0215 ​​molecular formula C 58 H 80 O 13 , molecular weight 983( Figure 1 ).

[0099] Nuclear magnetic hydrogen spectrum test: 1HNMR(400MHz,CDCl3)δ8.01–7.87(m,4H),7.54–7.44(m,2H),7.37(q,J=7.7Hz,4H),6.84(dd,J=15.7,9.7Hz,1H),5.92(dd,J=14.6,10.6Hz,1H),5.86–5.72(m,2H),5.62(dd,J=10.3,1.8Hz,1H),5.47–5.34(m,1H),5.34–5.19(m,2H),5.06(dd,J=14.9,9.6Hz,1H),4.03–3.91(m,1H),3.86(d,J=4.1Hz,1H),3.80–3.72(m,1H),3.66(s,1H),3.65–3.56(m,2H),3.21(s,1H),2.90(q,J=7.3Hz,1H),2.81–2.71(m,1H),2.27(dt,J=16.1,8.1Hz,1H),2.15(dd,J=16.1,9.2Hz,2H),2.04–1.92(m,1H),1.88-1.84(m,2H),1.79–1.48(m,10H),1.47–1.26(m,8H),1.13-1.06(m,9H),1.03–0.91(m,7H),0.90(d,J=6.9Hz,3H),0.87–0.76(m,2H),0.79(d,J=6.9Hz,3H),0.70-0.62(m,1H),0.54(t,J=7.3Hz,3H)( Figure 2 )。

[0100] 13C NMR test: 13 C NMR(101MHz,CDCl3)δ216.57,165.00,164.72,164.11,147.69,137.10,132.27,131.70,131.49,129.90,129.20,128.66,128.61,128.55,128.52,127.86,127.49,127.31,121.69,96.41,82.14,73.22,72.30,71.55,69.68,68.98,68.41,66.76,44.84,44.19,43.70,39.57,39.47,39.05,37.52,34.43,34.28,32.54,30.65,29.74,29.26,28.68,26.93,25.31,20.17,17.24,13.58,13.42,11.12,10.21,7.82,7.61,4.20( Figure 3 ).

[0101] Example 2 Synthesis of Compound RTM-XZW-0304

[0102] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.2 mmol, 2.0 eq.) in dichloromethane (5.0 mL), add o-chlorobenzenesulfonyl chloride (0.1 mmol, 1.0 eq), and react at room temperature for 4 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0103]

[0104] RTM-XZW-0304 synthesis route mass spectrometry test: RTM-XZW-0304 molecular formula C 50 H 75 O 13 ClS, molecular weight 951 ( Figure 4 ).

[0105] Nuclear magnetic hydrogen spectrum test: 1 H NMR (400MHz, CDCl3) δ7.90–7.80(m,1H),7.53–7.45(m,2H),7.38-7.30(m,1H),6.77(ddd,J=15.9,9.4H z,1H),6.03–5.80(m,3H),5.49–5.34(m,1H),5.25-5.19(m,3H),3.99–3.79(m,9H),2.82–2.76(m,1H),2 .70–2.63(m,1H),2.20–0.71(m,22H),1.88(d,J=6.8Hz,3H),1.13(d,J=6.8Hz,3H),1.06(s,3H),1.02( d,J=6.8Hz,3H),0.92(d,J=6.8Hz,3H),0.91(d,J=6.8Hz,3H),0.87(d,J=6.8Hz,3H),0.80–0.66(m,9H)( Figure 5 ).

[0106] NMR carbon spectrum test: 13C NMR (101MHz, CDCl3) δ214.55,164.17,147.92,137.28,134.70,133.45,131.84,131.51,130.98,129. 22,129.04,127.96,125.81,121.57,96.43,84.18,82.04,71.91,71.55,69.83,69.03,66.34,63.62, 52.41,44.73,44.27,43.90,41.53,40.18,39.02,37.48,34.49,34.20,32.48,30.32,29.59,28.87,28.68,27.24,25.50,23.74,20.00,17.10,13.66,13.50,12.47,11.15,11.06,10.27,7.78,7.69,4.25( Figure 6 ).

[0107] Example 3 Synthesis of Compound RTM-m-CPBA

[0108] Synthesis method: Weigh 200 mg of rutamycin (0.13 mmol, 1.00 eq.) and m-chloroperbenzoic acid (67.30 mg, 67.30 mmol, 1.50 eq.) and dissolve them in dichloromethane (5 mL), and react at -17 ° C for 6 h. After the reaction is completed, the reaction solution is washed with 30 mL of saturated sodium bicarbonate solution, and the reaction solution is extracted with 50 mL of dichloromethane and 20 mL of water. The organic phase is washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. After column chromatography, a white powder is obtained.

[0109]

[0110] RTM-m-CPBA Synthesis Route

[0111] Mass spectrometry test: RTM-m-CPBA molecular formula C 44 H 72 O 12 , molecular weight 792( Figure 7 ).

[0112] Nuclear magnetic hydrogen spectrum test: 1H NMR (400MHz, CDCl3) δ6.54 (dd, J=15.6, 10.3Hz, 1H), 5.77 (d, J=15.6Hz, 1H), 5 .52(dd,J=15.5,7.8Hz,1H),5.38–5.20(m,2H),4.23(d,J=7.6Hz,1H),4.06(d, J=2.5Hz,1H),4.03–3.87(m,2H),3.78(dd,J=16.8,7.6Hz,2H),3.69(d,J=10.1 Hz,1H),3.66–3.55(m,2H),3.35(s,1H),3.19(s,1H),2.63(q,J=7.1Hz,2H),2. 36-2.29(m,1H),2.09-2.03(m,4H),1.93-1.84(m,2H),1.80(d,J=4.9Hz,1H),1 .73–1.09(m,10H),1.27(d,J=7.3Hz,3H),1.18(d,J=7.3Hz,3H),1.12(d,J=7.3 Hz,3H),1.06(s,3H),1.01(d,J=6.4Hz,3H),1.00(d,J=6.4Hz,3H),0.98(d,J=6 .4Hz,3H),0.86(d,J=6.4Hz,3H),0.83(d,J=6.4Hz,3H),0.71(t,J=7.4Hz,3H)( Figure 8 ).

[0113] NMR carbon spectrum test: 13 C NMR (101MHz, CDCl3) δ163.81,148.22,138.48,124.95,121.73,96.39,81.95,8 0.57,72.51,72.18,71.75,69.40,68.75,66.54,63.76,45.16,45.03,42.48,41 .47,40.71,38.92,34.66,33.78,33.37,29.66,28.81,28.56,27.24,26.39,26.27,25.50,23.70,19.20,16.46,16.08,13.06,10.62,10.37,7.62,7.25,4.84( Fig. 9 ).

[0114] Example 4 Synthesis of Compound RTM-317

[0115] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.2 mmol, 2.0 eq.) in dichloromethane (5.0 mL), add m-methoxybenzoyl chloride (0.1 mmol, 1.0 eq.), and react at room temperature for 4 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0116]

[0117] RTM-317 Synthesis Route

[0118] Mass spectrometry test: RTM-317 molecular formula C 52 H 78 O 13 , molecular weight 910( Fig.10 ).

[0119] Nuclear magnetic hydrogen spectrum test: 1 HNMR (400MHz, CDCl3) δ7.59(d,J=7.7Hz,1H),7.50(s,1H),7.36(dd,J=8.1Hz,1H),7.12(dd,J=8.1,2.7Hz,1H),6.91(dd,J=15.7,9.8H z,1H),6.08–5.91(m,2H),5.86(d,J=15.7Hz,1H),5.68(dd,J=10.3,2.2Hz,1H),5.50(dq,J=14.7,4.1Hz,1H),5.34–5.23(m,2H),4.10 –3.97(m,3H),3.95(s,1H),3.86(s,3H),3.77–3.65(m,2H),2.95(q,J=7.2Hz,1H),2.87–2.79(m,1H),2.39–0.81(m,25H),1.25(d,J=6 .5Hz,3H),1.87(s,3H),1.16(d,J=6.5Hz,6H),1.06–0.99(m,9H),0.91(d,J=6.9Hz,3H),0.89(d,J=6.9Hz,3H),0.83(t,J=7.4Hz,3H)( Fig.11 ).

[0120] NMR carbon spectrum test: 13C NMR (101MHz, CDCl3) δ217.46,165.62,165.25,159.64,149.01,138.22,132.50,130.88,130.13,129. 56,129.07,122.60,122.05,119.35,114.62,97.50,83.20,74.30,73.31,72.55,70.83,70.17,67.38, 64.64,55.47,55.44,46.05,45.21,44.78,42.63,40.67,40.60,38.52,35.45,35.42,33.57,31.48,30.95,30.64,29.83,28.41,26.51,24.76,21.20,18.35,14.57,14.40,12.13,11.26,8.84,8.58,5.18( Fig.12 ).

[0121] Example 5 Synthesis of Compound RTM-XZW-0320

[0122] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.3 mmol, 3.0 eq.) in dichloromethane (5.0 mL), add biphenyl-4-carbonyl chloride (0.2 mmol, 2.0 eq.), and react at room temperature for 4 h. After the reaction is completed, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0123]

[0124] RTM-XZW-0320 synthesis route mass spectrometry test: RTM-XZW-0320 molecular formula C 70 H 88 O 13 , molecular weight 1136( Fig.13 ).

[0125] Nuclear magnetic hydrogen spectrum test: 1H NMR (400MHz, CDCl3) δ8.04(d,J=8.2Hz,2H),7.99(d,J=8.2Hz,2H),7.66-7.53( m,8H),7.46–7.37(m,4H),7.42–7.30(m,2H),6.94(dd,J=15.7,9.5Hz,1H),5.99 (dd,J=15.1,10.2Hz,1H),5.92–5.82(m,2H),5.71(dd,J=10.3,2.1Hz,1H),5.48 –5.22(m,4H),5.04(dd,J=14.9,9.5Hz,1H),4.06–3.96(m,1H),3.86(s,1H),3.7 8–3.76(m,1H),3.69–3.62(m,3H),3.22(s,1H),2.99(q,J=7.2Hz,1H),2.85(qd ,J=6.8,2.1Hz,1H),2.31–2.24(m,1H),2.17–0.80(m,20H),1.33(d,J=7.7Hz,3H ),1.1(d,J=7.7Hz,9H),0.98(d,J=7.7Hz,3H),0.95(d,J=7.3Hz,3H),0.94(d,J= 7.3Hz,3H),0.91(d,J=7.3Hz,3H),0.81(d,J=7.3Hz,3H),0.55(t,J=7.3Hz,3H)( Fig.14 ).

[0126] NMR carbon spectrum test: 13 C NMR (101MHz, CDCl3) δ216.65,164.85,164.58,164.09,147.67,145.10,144.51,139.03,138.97,137.12,131.47,129 .18,129.15,129.04,128.63,127.93,127.89,127.79,127.19,127.06,126.30,126.23,125.99,121.69,96.40,82.1 3,73.19,72.28,71.53,69.66,69.00,68.42,66.75,44.92,44.16,43.73,39.56,39.48,39.09,37.50,34.44,34.27,32.51,30.66,29.79,29.28,28.69,26.95,25.30,20.20,20.14,17.28,13.58,13.47,11.20,10.21,7.85,7.61,4.19( Fig.15 ).

[0127] Example 6 Synthesis of Compound RTM-XZW-0318 Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.2 mmol, 2.0 eq.) in dichloromethane (5.0 mL), add 4-dimethylaminobenzoyl chloride (0.1 mmol, 1.0 eq), and react at room temperature for 4 h. After the reaction is completed, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0128]

[0129] RTM-XZW-0318 synthesis route mass spectrometry test: RTM-XZW-0318 molecular formula C 53 H 81 O 12 , molecular weight 923( Fig.16 ).

[0130] Nuclear magnetic hydrogen spectrum test: 1 H NMR (400MHz, CDCl3) δ7.82–7.74(m,2H),6.87(dd,J=15.6,9.9Hz,1H),6.60–6.56(m,2H),5.98(ddd,J=14.7,10.4,1.6Hz,1H),5.87(dd,J=1 4.9,10.5Hz,1H),5.77(d,J=15.6Hz,1H),5.61(dd,J=10.3,2.3Hz,1H),5.49–5.37(m,1H),5.27–5.17(m,2H),4.04–3.90(m,3H),3.88(s,1H ),3.76(s,2H),3.63(d,J=10.0Hz,1H),3.27(s,1H),2.97(s,6H),2.92–2.84(m,1H),2.72(qd,J=6.9,2.2Hz,1H),2.29–0.80(m,24H),1.17( d,J=6.2Hz,3H),1.11(s,3H),1.07(d,J=6.2Hz,6H),0.97–0.90(m,9H),0.85(d,J=6.7Hz,3H),0.85(d,J=6.7Hz,3H),0.76(t,J=7.4Hz,3H)( Fig.17 ).

[0131] NMR carbon spectrum test: 13C NMR (101MHz, CDCl3) δ216.76,164.79,164.24,162.35,153.00,152.49,148.15,137.21,131.41,130 .39,129.03,128.04,121.49,115.11,114.59,96.47,82.12,72.21,72.07,71.52,69.72,69.23,66. 24,63.54,45.22,44.36,43.45,41.60,39.83,39.80,39.06,37.47,34.42,34.38,32.53,30.55,30.07,29.60,28.79,27.43,25.47,23.77,20.17,17.46,13.55,13.44,11.17,10.25,7.81,7.62,4.17( Fig.18 ).

[0132] Example 7 Synthesis of Compound RTM-LHY-0366

[0133] Synthesis method: Weigh oligomycin D (200 mg, 0.26 mmol, 1.00 eq.) and N,N-dimethylaminopyridine (190.59 mg, 1.56 mmol, 6.00 eq.) and dissolve in dichloromethane (5 mL), stir at 0 ° C for 30 min, slowly add ethyl oxalyl chloride (191.12 mg, 1.56 mmol, 6.00 eq.) and move to room temperature to react for 6 h. After TLC monitoring, the solvent was removed under reduced pressure. After column chromatography, 90.00 mg of the product (white solid, yield 45%) was obtained.

[0134]

[0135] RTM-LHY-0366 synthesis route mass spectrometry test: RTM-LHY-0366 molecular formula C 52 H 80 O 17 , molecular weight 976( Fig.19 ).

[0136] H NMR test: 1H NMR (400MHz, Chloroform-d) δ6.84–6.65 (m, 1H), 6.02–5.89 (m, 2H), 5.89–5.73 (m, 1H), 5.50–5.34 (m, 2H), 5.22-5.04 (m, 3H), 4.35–4.18 (m, 4H), 4.04–3.86 (m, 1H), 3.83 (dd, J=11.9, 4.5Hz, 1H), 3.73–3.61 (m, 2H), 3.57 ( s,3H),3.20(d,J=7.4Hz,1H),2.77-2.27(m,1H),2.17-2.06(m,18H),1.34-1.26(m,13H),1.14-1.07(m,6H), 1.04(d,J=6.9Hz,3H),1.00(d,J=6.8Hz,3H),0.96–0.93(m,6H),0.87(d,J=6.9Hz,3H),0.75(t,J=5.9Hz,6H)( Fig. 20 ). Nuclear magnetic carbon spectrum test: 13C NMR (101MHz, CDCl3) δ216.00, 208.56, 163.97, 156.95, 156.42, 156.27, 147.58, 136.94, 131.44, 129.35, 128.04, 121.62, 96.47, 82.11, 72.03, 71.48, 69.53, 69.09, 67.11, 62.44, 62.0 6,44.77,44.34,43.48,39.26,39.07,38.58,37.46,34.38,34.12,32.51,29.46,29.05,28.63,27.16,25.19,20.01,19.75,17.05,13.57,13.29,12.91,11.19,10.06,7.86,7.45,4.02( Fig.21 ).

[0137] Example 8 Synthesis of Compound RTM-XZW-0366-2

[0138] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.2 mmol, 2.0 eq.) in dichloromethane (5.0 mL), add o-methylbenzoyl chloride (0.1 mmol, 1.0 eq.), and react at room temperature for 4 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0139]

[0140] RTM-XZW-0366-2 synthesis route mass spectrometry test: RTM-XZW-0366-2 molecular formula C 52 H 78 O 12 , molecular weight 895( Fig. 22 ).

[0141] H NMR test: 1H NMR (400MHz, DMSO) δ7.78 (dd, J = 8.2, 1.5Hz, 1H), 7.49 (td, J = 7.5, 1.5Hz, 1H), 7.38–7.31 (m, 2H), 6.85 (dd, J = 15.7, 9.0Hz, 1H), 6.12–5.92 (m, 2H), 5.88 (d, J = 15.6Hz, 1H) ,5.54(dd,J=9.8,2.0Hz,1H),5.43(ddd,J=14.8,10.6,4.2Hz,1H),5.25–5.13(m,3H ),4.45–4.36(m,2H),4.27(d,J=5.2Hz,1H),3.99–3.90(m,2H),3.84–3.75(m,2H),3. 75–3.69(m,1H),3.58(dd,J=7.5,1.4Hz,1H),2.83(tt,J=6.9,3.8Hz,1H),2.79–2.6 9(m,1H),2.48(s,2H),2.38(q,J=7.9Hz,1H),2.04–1.90(m,4H),1.76(q,J=6.8,5.9H z,1H),1.68–1.64(m,1H),1.63–1.56(m,2H),1.55–1.49(m,2H),1.44–1.17(m,9H), 1.10(t,J=6.7Hz,6H),1.05–0.93(m,15H),0.91–0.84(m,6H),0.81(t,J=7.3Hz,3H)( Fig.23 ).

[0142] Nuclear magnetic carbon spectrum test: 13C NMR (101MHz, DMSO) δ214.24, 166.69, 164.86, 150.54, 139.59, 136.70, 132.76, 132.52, 132.13, 131.33, 131.19, 130.33, 129.59, 128.76, 128.73, 128.64, 126.69, 126.55, 122.07, 97.04, 83.27, 74.43, 72.85, 71.99, 7 0.44,68.92,67.56,63.08,45.40,45.25,44.91,42.97,41.43,38.59,35.56,33.88,33.85,30.83,30.62,30.30,29.70,28.59,26.62,25.36,24.37,22.58,21.40,17.77,15.50,14.43,12.42,11.63,9.65,9.49,5.72( Fig.24 ).

[0143] Example 9 Synthesis of Compound RTM-XZW-0401-1

[0144] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.3 mmol, 3.0 eq.) in dichloromethane (5.0 mL), add trifluoromethylbenzoyl chloride (0.2 mmol, 2.0 eq.), and react at room temperature for 4 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0145]

[0146] RTM-XZW-0401-1 synthesis route mass spectrometry test: RTM-XZW-0401-1 molecular formula C60H78O13F6, molecular weight 1120 ( Fig.25 ). Nuclear magnetic hydrogen spectrum test: 11H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 7.2, 2.0 Hz, 1H), 7.81 (dd, J = 7.3, 1.8 Hz, 1H), 7.75 (dd, J = 7.3, 1.9 Hz, 2H), 7.63 - 7.51 (m, 4H), 6.89 (dd, J = 15.7, 9.6 Hz, 1H), 6.07 – 5.82 (m, 3H), 5.69 (dd, J = 10.5, 2.1 Hz, 1H), 5.55 – 5.43 (m, 1H), 5.28 – 5.16 (m, 3H), 3.96 - 3.88 (m, 1H), 3.93 (d, J = 1.6 Hz, 1H), 3.86 3.76 (m, 1H), 3.74 – 3.67 (m, 2H), 3.29 (s, 1H), 3.00 (q, J = 7.3 Hz, 1H), 2.87 (qd, J = 6.9, 2.2 Hz, 1H), 2.29 – 0.08 (m, 23H), 1.35 (d, J = 6.9 Hz, 3H), 1.10 (s, 3H), 1.07 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H), 0.79 (d, J = 6.9 Hz, 3H), 0.59 (t, J = 7.4 Hz, 3H)( Fig.26 ).

[0147] 13C NMR test: 13 13C NMR (101 MHz, CDCl3) δ 216.91, 165.06, 164.46, 164.12, 147.86, 137.25, 131.51, 130.91, 130.71, 130.30, 130.10, 129.73, 129.56, 129.14, 129.03, 127.83, 125.68, 121.57, 96.58, 82.08, 73.88, 72.16, 71.55, 70.33, 69.69, 69.17, 66.97, 44.76, 44.14, 43.71, 39.26, 39.20, 38.57, 37.53, 34.16, 34.05, 32.49, 30.68, 29.45, 29.06, 28.68, 28.53, 26.84, 25.32, 20.06, 19.49, 17.08, 13.52, 13.10, 11.10, 10.09, 7.80, 7.53, 4.21( Fig. 27 ).

[0148] Example 10 Synthesis of Compound RTM-XZW-0415

[0149] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.2 mmol, 2.0 eq.) in dichloromethane (5.0 mL), add m-methoxybenzoyl chloride (0.1 mmol, 1.0 eq.), and react at room temperature for 4 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0150]

[0151] RTM-XZW-0415 synthesis route mass spectrometry test: RTM-XZW-0415 molecular formula C 53 H 78 O 12 , molecular weight is 908( Fig.28 ).

[0152] Nuclear magnetic hydrogen spectrum test: 1 HNMR (400MHz, CDCl3) δ7.23-7.19(m,2H),7.15-7.10(m,3H),6.75(dd,J=15.7,9. 8Hz,1H),5.97(dd,J=14.1,11.0Hz,1H),5.87(dd,J=14.8,10.4Hz,1H),5.77(d,J= 15.7Hz,1H),5.49–5.36(m,1H),5.31(dd,J=10.3,2.0Hz,1H),5.28–5.14(m,2H), 4.05–3.97(m,1H),3.94(d,J=10.4Hz,1H),3.85(s,1H),3.82–3.71(m,2H),3.66(s ,1H),3.60(d,J=10.1Hz,1H),3.14(s,1H),2.91-2.80(m,2H),2.76(q,J=7.3Hz,1 H),2.70–2.60(m,1H),2.61–2.47(m,2H),2.32–1.94(m,4H),1.87(d,J=1.8Hz,3H) ,1.75–1.10(m,16H),1.17(d,J=6.2Hz,3H),1.10(d,J=6.6Hz,3H),1.07(s,3H),0 .96(d,J=6.8Hz,3H),0.94-0.90(m,6H),0.86(d,J=7.0Hz,3H),0.79-0.74(m,9H)( Fig.29 ).

[0153] NMR carbon spectrum test: 13 C NMR (101MHz, CDCl3) δ217.35,172.17,165.18,148.93,140.23,138.21,132.48,130.11,129.04 ,128.48,128.22,126.30,122.55,97.46,83.11,73.52,73.25,72.54,70.78,70.15,67.39,64.6 3,45.99,45.02,44.87,42.67,40.46,40.22,38.52,35.49,35.36,33.56,31.44,30.87,30.72,30.66,29.87,28.38,26.55,24.77,21.08,18.29,14.55,14.18,12.12,11.26,8.70,8.47,5.10( Fig.30 ).

[0154] Example 11 Synthesis of Compound RTM-XZW-0419

[0155] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.2 mmol, 2.0 eq.) in dichloromethane (5.0 mL), add m-methoxybenzoyl chloride (0.1 mmol, 1.0 eq.), and react at room temperature for 4 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0156]

[0157] RTM-XZW-0419 synthesis route mass spectrometry test: RTM-XZW-0419 molecular formula C 53 H 78 O 12 , molecular weight 906( Fig.31 ).

[0158] Nuclear magnetic hydrogen spectrum test: 1H NMR(400MHz, CDCl3)δ7.59(d,J=16.0Hz,1H),7.52–7.42(m,2H),7.37–7.25(m,3H),6.82 (dd,J=15.7,9.8Hz,1H),6.33(d,J=16.0Hz,1H),5.98(dd,J=14.2,11.0Hz,1H),5.88(dd, J=14.8,10.4Hz,1H),5.79(d,J=15.7Hz,1H),5.49(dd,J=10.3,2.0Hz,1H),5.47–5.37(m ,1H),5.26-5.17(m,2H),4.06-3.82(m,4H),3.77-3.74(m,1H),3.73(s,1H),3.67(d,J=10 .0Hz,1H),3.22(s,1H),2.85(q,J=7.3Hz,1H),2.72(dq,J=6.7,3.4Hz,1H),2.33–2.23(m ,1H),2.23–2.09(m,2H),2.03(tt,J=13.2,4.1Hz,1H),1.91-1.86(m,2H),1.85–1.76(m,1 H),1.74–0.90(m,16H),1.17(d,J=6.2Hz,3H),1.11(d,J=6.5Hz,6H),1.05(d,J=6.8Hz,3 H),0.98-0.92(m,9H),0.85(d,J=7.0Hz,3H),0.81(d,J=6.9Hz,3H),0.78(t,J=7.0Hz,3H( Fig.32 ).

[0159] NMR carbon spectrum test: 13 C NMR (101MHz, CDCl3) δ216.65,165.07,164.21,148.00,144.69,137.24,133.18,131.48,129.52,1 29.10,128.05,127.89,127.23,121.58,116.24,96.48,82.16,72.71,72.28,71.56,69.79,69.17, 66.36,63.61,45.06,44.11,43.77,41.65,39.59,37.52,34.47,34.40,32.57,30.48,29.95,29.65,28.84,27.39,25.91,25.52,23.77,20.15,17.35,13.56,13.39,11.13,10.26,7.74,7.57,4.14( Fig.33 ).

[0160] Example 12 Synthesis of Compound RTM-LHY-0328

[0161] Synthesis method: Weigh 200 mg, 0.26 mmol, 1.00 eq. of rutamycin, triphenylphosphine (410.00 mg, 1.56 mmol, 6.00 eq.) and p-nitrobenzoic acid (260.71 mg, 1.56 mmol, 6.00 eq.) and dissolve them in tetrahydrofuran (5 mL). Stir at 0 ° C for 30 min under argon protection, slowly add diisopropyl azodicarboxylate (315.43 mg, 1.56 mmol, 6.00 eq.) and move to room temperature to react for 6 h. After TLC monitoring, remove the solvent under reduced pressure. After column chromatography, a white powder is obtained.

[0162]

[0163] RTM-LHY-0328 synthesis route mass spectrometry test: RTM-LHY-0328 molecular formula C 51 H 75 NO 14 , molecular weight 925( Fig.34 ).

[0164] Nuclear magnetic hydrogen spectrum test: 11H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.9 Hz, 2H), 8.27–8.19 (m, 2H), 6.63 (dd, J = 15.6, 9.8 Hz, 1H), 6.05 (dd, J = 14.3, 10.8 Hz, 1H), 5.96 (dd, J = 14.7, 10.4 Hz, 1H), 5.82 (d, J = 15.7 Hz, 1H), 5.50 (ddd, J = 14.6, 10.5, 4.0 Hz, 1H), 5.38–5.15 (m, 3H), 4.03–3.92 (m, 2H), 3.84 (t, J = 5.5 Hz, 1H), 3.78 (d, J = 10.1 Hz, 1H), 3.71 (d, J = 8.9 Hz, 1H), 3.67–3.56 (m, 1H), 3.48 (d, J = 1.9 Hz, 1H), 3.35 (s, 1H), 2.81 (dt, J = 9.6, 5.2 Hz, 1H), 2.78–2.72 (m, 1H), 2.53 (d, J = 4.1 Hz, 1H), 2.41 (td, J = 9.8, 6.4 Hz, 1H), 2.22 (d, J = 13.6 Hz, 1H), 2.17–1.86 (m, 5H), 1.63 - 0.9 (m, 15H), 1.45 (d, J = 6.2 Hz, 3H), 1.20 (d, J = 6.5 Hz, 3H), 1.17 (s, 3H), 1.12 (d, J = 6.7 Hz, 3H), 1.11 (d, J = 7.2 Hz, 3H), 1.07 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H), 0.81 (d, J = 6.9 Hz, 3H), 0.76 (t, J = 7.4 Hz, 3H)( Fig.35 ).

[0165] 13C NMR (101 MHz, CDCl3) δ 164.73, 164.15, 150.50, 148.58, 137.12, 136.11, 132.33, 130.69, 129.73, 123.55, 122.64, 97.49, 83.03, 77.22, 73.07, 72.64, 72.37, 70.90, 70.56, 69.93, 68.36, 46.78, 45.81, 45.62, 41.87, 39.98, 39.66, 38.50, 35.50, 35.24, 33.55, 31.56, 30.55, 29.91, 29.68, 28.33, 26.27, 21.06, 20.68, 17.71, 14.49, 13.90, 11.99, 11.09, 9.52, 8.34, 5.25( Fig.36 ).

[0166] Example 13 Synthesis of Compound RTM-W-XZW-0474-1

[0167] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and N-phenylmaleimide (1 mmol, 10.0 eq.) in toluene (5.0 mL) and react at 105°C for 24 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0168]

[0169] RTM-W-XZW-0474-1 synthesis route mass spectrometry test: RTM-W-XZW-0474-1 molecular formula C 48 H 75 O 13 N, molecular weight 873 ( Fig.37 ).

[0170] Nuclear magnetic hydrogen spectrum test: 1 H NMR (400MHz, CDCl3) δ8.45 (s, 1H), 6.79 (dd, J = 15.6, 6.9Hz, 1H), 5.85-5.8 1(m,2H),5.65-5.6-(m,1H),5.33(dt,J=10.7,5.2Hz,1H),4.15–4.02(m,2H ),4.04–3.90(m,2H),3.83(t,J=5.8Hz,1H),3.63(d,J=9.8Hz,1H),3.55-3 .49(m,1H),3.44(s,2H),3.38(s,1H),3.36–3.29(m,1H),3.16–3.08(m,1H) ,2.64(t,J=7.3Hz,1H),2.59–2.49(m,1H),2.32(d,J=5.9Hz,3H),2.21–1. 91(m,7H),1.90–0.81(m,15H),1.18(s,3H),1.17(d,J=7.2Hz,3H),1.15(d, J=7.2Hz,3H),1.10(d,J=7.7Hz,6H),1.08(d,J=7.2Hz,3H),1.01(d,J=6.5H z,3H),0.86(d,J=6.9Hz,3H),0.82(d,J=6.9Hz,3H),0.78(t,J=7.4Hz,3H)( Fig.38 ).

[0171] Nuclear magnetic carbon spectrum test: 13C NMR (101MHz, CDCl3) δ177.44, 176.52, 165.06, 147.94, 132.42, 131.06, 120.95, 96.78, 82.02, 72.68, 70.54, 70.07, 69.72, 66.38, 63.15, 47.30, 44.53, 42.10, 42.01, 41.16, 40.82,39.08,37.60,35.49,34.45,33.39,33.07,32.09,29.71,28.78,28.68,25.59,25.39,24.75,23.94,21.49,19.99,14.70,13.79,13.45,10.15,9.37,8.75,7.79,3.80( Fig.39 ).

[0172] Example 14 Synthesis of Compound RTM-W-XZW-0511-1

[0173] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and N-phenylmaleimide (1 mmol, 10.0 eq.) in toluene (5.0 mL) and react at 105°C for 24 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0174]

[0175] RTM-W-XZW-0511-1 synthesis route mass spectrometry test: RTM-W-XZW-0511-1 molecular formula C 49 H 77 O 13 N, molecular weight 887( Fig.40 ).

[0176] Nuclear magnetic hydrogen spectrum test: 1H NMR (400MHz, CDCl3) δ6.80 (dd, J=15.6, 6.6Hz, 1H), 5.83 (dd, J=15.6, 1.2Hz, 1H) ,5.77(dd,J=7.7,4.5Hz,1H),5.57(dd,J=6.0,2.9Hz,1H),5.39–5.28(m,1H),4.1 7-4.11(m,2H),3.99-3.91(m,2H),3.86(t,J=6.4Hz,1H),3.62(d,J=9.6Hz,1H), 3.51(dd,J=9.6,6.9Hz,1H),3.45–3.37(m,2H),3.33–3.26(m,2H),3.12–3.03(m, 1H),2.79(s,3H),2.64(q,J=7.2Hz,1H),2.53(q,J=7.2Hz,1H),2.46–2.23(m,3H ),2.22–0.9(m,22H),1.18(d,J=6.2,Hz,3H),1.17(d,J=6.2,Hz,3H),1.17(s,3H) ,1.16(d,J=7.2,Hz,3H),1.11(d,J=7.2,Hz,3H),1.10(d,J=6.7Hz,3H),1.08(d,J =6.9Hz,3H),0.86(d,J=6.9Hz,3H),0.83(d,J=6.9Hz,3H),0.77(t,J=7.3Hz,3H)( Fig.41 ).

[0177] NMR carbon spectrum test: 13 C NMR (101MHz, CDCl3) δ222.90,220.00,178.18,177.42,166.09,148.91,133.35,131.99,121.9 0,97.86,82.97,73.68,71.62,71.50,71.15,70.61,67.38,63.94,48.39,45.49,42.05,41.81, 41.79,41.75,40.14,38.50,36.65,35.49,34.51,33.75,33.13,30.78,29.84,29.69,26.64,26.45,25.99,25.03,24.45,22.40,20.98,15.56,14.71,14.50,11.10,10.38,9.45,8.76,4.74( Fig.42 ).

[0178] Example 15 Synthesis of Compound RTM-W-XZW-0526-1

[0179] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and N-benzylmaleimide (1 mmol, 10.0 eq.) in toluene (5.0 mL) and react at 105°C for 24 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0180]

[0181] RTM-W-XZW-0526-1 synthesis route mass spectrometry test: RTM-W-XZW-0526-1 molecular formula C 55 H 81 O 13 N, molecular weight 963 ( Fig.43 ). Nuclear magnetic hydrogen spectrum test: 1 H NMR (400MHz, CDCl3) δ7.25(s,5H),6.86(dd,J=15.6,6.3Hz,1H),5.89(d,J=15.6Hz,1H),5.80(d,J=7.9Hz,1H),5.62(d,J=7.7Hz,1H),5.46–5.32(m,1 H),4.53(s,2H),4.23(d,J=4.6Hz,1H),4.18(d,J=10.7Hz,1H),3.99(d,J=9 .1Hz,2H),3.91(s,1H),3.68(d,J=9.4Hz,1H),3.62–3.51(m,1H),3.47(d,J =2.4Hz,2H),3.39-3.36(m,1H),3.29(s,1H),3.22–3.12(m,1H),2.69(q,J =7.2Hz,1H),2.59(q,J=6.9Hz,1H),2.54–2.29(m,4H),2.18-1.11(m,18H), 1.24(s,12H),1.18(d,J=6.8Hz,3H),1.15(d,J=7.6Hz,3H),1.10(d,J=2.7H z,6H),0.93(d,J=6.5Hz,3H),0.89(d,J=6.6Hz,3H),0.83(t,J=6.9Hz,3H)( Fig.44 ). NMR carbon spectrum test: 13C NMR (101MHz, CDCl3) δ177.79,177.02,166.03,148.86,135.73,133.37,132.02,128.56,128.21,12 7.74,121.92,97.82,83.00,77.22,73.72,71.55,71.49,71.11,70.61,67.31,63.89,48.38,45.48 ,42.21,42.09,41.76,41.71,40.31,38.50,36.55,35.47,34.45,33.89,33.25,30.76,29.80,29.68,26.65,26.46,25.99,25.04,22.40,20.95,15.57,14.79,14.52,11.11,10.36,9.48,8.78,4.76( Fig.45 ).

[0182] Example 16 Synthesis of Compound RTM-WC-LHY-0410

[0183] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.2 mmol, 2.0 eq.) in dichloromethane (5.0 mL), add m-methoxybenzoyl chloride (0.1 mmol, 1.0 eq.), and react at room temperature for 4 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0184]

[0185] RTM-WC-LHY-0410 synthesis route mass spectrometry test: RTM-WC-LHY-0410 molecular formula C 44 H 68 N 12 O7, molecular weight 876 ( Fig.46 ).

[0186] Nuclear magnetic hydrogen spectrum test: 1HNMR(400MHz, CDCl3)δ6.66(dd,J=15.6,8.0Hz,1H),6.03–5.85(m,2H),5.80(d ,J=15.6Hz,1H),5.64(dd,J=14.2,7.3Hz,1H),5.28(dd,J=14.5,8.8Hz,1H),5. 11(dt,J=12.0,4.8Hz,1H),3.88(dd,J=9.9,8.6Hz,1H),3.83–3.73(m,3H),3.5 5(d,J=8.4Hz,1H),3.46(dd,J=14.2,6.2Hz,1H),3.08-3.01(m,2H),2.63(q,J=7 .5Hz,1H),2.35(dd,J=16.0,7.5Hz,1H),2.19–1.90(m,7H),1.85-1.74(m,1H), 1.75–1.29(m,19H),1.26(d,J=6.5Hz,3H),1.18(d,J=7.5Hz,3H),1.14(d,J=6. 0Hz,3H),1.12(d,J=6.8Hz,3H),1.06(d,J=7.0Hz,3H),0.97(s,3H),0.84(d,J= 7.0Hz,3H),0.80(t,J=5.7Hz,3H),0.76(d,J=6.9Hz,3H),0.68(d,J=6.9Hz,3H)( Fig.47 ).

[0187] Nuclear magnetic hydrogen spectrum test: 13 C NMR(101MHz,Chloroform-d)δ164.39,147.74,134.90,130.59,130.00,121.13,96.52,84.86,82.12,72.03,70.24,67.20,53.63,48.91,48.51,44.9 3,42.48,38.40,37.64,37.06,34.52,33.10,32.65,28.81,28.11,27.20, 25.23,19.13,16.87,15.66,12.55,12.42,11.01,10.68,9.89,6.97,3.55( Fig.48 ).

[0188] Example 17 Synthesis of Compound RTM-W-XZW-0458

[0189] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.2 mmol, 2.0 eq.) in dichloromethane (5.0 mL), add benzoyl chloride (0.1 mmol, 1.0 eq.), and react at room temperature for 4 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0190]

[0191] RTM-W-XZW-0458 synthesis route mass spectrometry test: RTM-W-XZW-0458 molecular formula C 51 H 76 O 12 , molecular weight 880( Fig.49 ).

[0192] Nuclear magnetic hydrogen spectrum test: 1 H NMR (400MHz, CDCl3) δ8.02(d,J=7.2Hz,2H),7.60(t,J=7.4Hz,1H),7.47(t,J=7.7Hz,2H ),6.94(dd,J=15.7,9.9Hz,1H),6.07(dd,J=14.5,11.0Hz,1H),5.97(dd,J=14.8,10.5Hz ,1H),5.88(d,J=15.6Hz,1H),5.72(dd,J=10.3,1.9Hz,1H),5.60–5.46(m,1H),5.39–5. 23(m,2H),4.13–4.00(m,3H),3.97(s,1H),3.85(d,J=9.1Hz,1H),3.75(s,1H),3.71(d,J =10.0Hz,1H),3.32(s,1H),2.98(q,J=7.3Hz,1H),2.85(qd,J=7.3,2Hz,1H),2.42–2.17 (m,3H),2.15-2.05(m,3H),2.05-0.80(m,17H),1.26(d,J=6.4Hz,3H),1.21(s,3H),1.18 (d,J=3.3Hz,3H),1.17(d,J=2.9Hz,3H),1.06(d,J=7.1Hz,3H),1.04(d,J=5.8Hz,3H),1. 03(d,J=7.2Hz,3H),0.94(d,J=7.1Hz,3H),0.92(d,J=7.0Hz,3H),0.85(t,J=7.4Hz,3H)( Fig.50 ).

[0193] Nuclear magnetic carbon spectrum test: 13C NMR (101MHz, CDCl3) δ 217.55, 165.76, 165.24, 149.03, 138.28, 133.30, 132.49, 130.11, 129.69, 129.58, 129.08, 128.52, 122.59, 97.50, 83.20, 74.21, 73.31, 72.53, 70.81, 70.19, 67.3 6,64.62,46.09,45.21,44.76,42.64,40.66,40.61,38.53,35.42,33.57,31.51,30.98,30.65,29.84,28.42,26.52,24.78,21.19,18.37,14.58,14.41,12.15,11.27,8.85,8.59,5.20( Fig.51 ).

[0194] Example 18 Synthesis of Compound RTM-W-XZW-0539

[0195] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.2 mmol, 2.0 eq.) in dichloromethane (5.0 mL), add acetyl chloride (0.1 mmol, 1.0 eq.), and react at room temperature for 4 h. After the reaction is completed, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid ( Fig.69 ).

[0196]

[0197] RTM-W-XZW-0539 synthesis route mass spectrometry test: RTM-W-XZW-0539 molecular formula C 46 H 74 O 12 , molecular weight 818( Fig.52 ).

[0198] Nuclear magnetic hydrogen spectrum test: 1 H NMR(400MHz, CDCl3) δ6.81(dd,J=15.7,9.8Hz,1H),6.04(dd,J=14.2,11.0Hz,1H),5.94(dd,J=14.8,10.4 Hz,1H),5.83(d,J=15.7Hz,1H),5.56-5.48(m,1H),5.38(dd,J=10.3,1.9Hz,1H),5.29-5.23(m,2H),4.09–

[0199] 4.03(m,1H),4.01(d,J=10.4Hz,1H),3.94-3.88(m,1H),3.91–3.79(m,2H),3.78(d,J=1.4 Hz,1H),3.70(d,J=10.1Hz,1H),3.27(s,1H),2.84(q,J=7.5Hz,1H),2.73(qd,J=6.9,2.0H z,1H),2.39–2.04(m,5H),2.03(s,3H),2.02-0.80(m,18H),1.24(d,J=6.8Hz,3H),1.17(d ,J=6.8Hz,3H),1.15(s,3H),1.05(d,J=6.8Hz,3H),1.01(d,J=6.7Hz,3H),1.00(d,J=6.7)( Fig.53 ).

[0200] NMR carbon spectrum test: 13 C NMR (101MHz, CDCl3) δ217.80,170.45,165.16,148.89,138.20,132.47,130.11,129.05 ,122.54,97.46,83.11,73.61,73.26,72.53,70.77,70.15,67.36,64.60,46.06,44.99, 44.82,42.64,40.43,40.20,38.50,35.44,35.35,33.56,31.47,30.92,30.64,29.83,28.39,26.51,24.77,21.10,20.70,18.24,14.55,14.32,12.13,11.26,8.65,8.48,5.09( Fig.54 ).

[0201] Example 19 Synthesis of Compound RTM-W-XZW-0578-2

[0202] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.2 mmol, 2.0 eq.) in dichloromethane (5.0 mL), add phenylacetyl chloride (0.2 mmol, 2.0 eq.), and react at room temperature for 4 h. After the reaction is completed, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0203]

[0204] RTM-W-XZW-0578-2 synthesis route mass spectrometry test: RTM-W-XZW-0578-2 molecular formula C 69 H 94 O 13 , molecular weight 1130( Fig.55 ).

[0205] Nuclear magnetic hydrogen spectrum test: 1 H NMR (400MHz, CDCl3) δ7.36–6.94(m,15H),6.69(dd,J=15.7,9.8Hz,1H),6.00–5.80(m,2H),5.73(d,J=15.7Hz,1H),5.48–5.36(m,1H),5.33(d, J=10.2Hz,1H),5.22-5.14(m,3H),5.01–4.81(m,1H),4.70(d,J=1.7Hz, 1H),3.82(s,1H),3.80–3.54(m,7H),3.53–3.44(m,3H),3.35(dd,J=14. 6,14.6Hz,1H),3.15(s,1H),2.73(q,J=7.1Hz,1H),2.68–2.55(m,1H), 2.32–0.80(m,19H),1.20(d,J=6.6Hz,6H),1.06(s,3H),1.03(d,J=6.6H z,3H),0.94(d,J=6.6Hz,3H),0.92(d,J=6.6Hz,3H),0.89(d,J=7.3Hz,3H),0.76(d,J=7.2Hz,3H),0.74(d,J=7.3Hz,3H),0.71(t,J=7.3Hz,3H)( Fig.56 ).

[0206] NMR carbon spectrum test: 13C NMR (101MHz, CDCl3) δ216.54,199.93,172.95,169.87,166.82,164.14,147.84,136.92,135.55,132.55,132.36,131.42,130.40 ,129.80,129.25,128.59,128.54,128.35,128.12,127.95,127.80,127.62,127.53,127.37,127.21,126.98,126.22,126.17,126 .05,125.97,125.63,121.48,96.56,82.06,72.81,72.13,71.54,69.55,69.21,47.38,44.80,43.99,43.82,40.28,39.39,38.27,37.50,34.21,32.51,30.42,29.19,28.68,27.31,20.10,19.57,17.12,13.53,13.04,11.20,11.15,9.91,9.79,7.64,7.49,4.05( Fig.57 ).

[0207] Example 20 Synthesis of Compound RTM-W-XZW-0621-1

[0208] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and N-cyclohexane maleimide (1 mmol, 10.0 eq.) in toluene (5.0 mL) and react at 105 ° C for 24 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0209]

[0210] RTM-W-XZW-0621-1 synthesis route mass spectrometry test: RTM-W-XZW-0621-1 molecular formula C 54 H 85 O 13 N, molecular weight 955( Fig.58 ).

[0211] Nuclear magnetic hydrogen spectrum test: 11H NMR (400 MHz, CDCl3) δ 6.83 (dd, J = 15.6, 6.2 Hz, 1H), 5.84 (dd, J = 15.6, 1.4 Hz, 1H), 5.74 (dt, J = 5.9, 3.0 Hz, 1H), 5.63–5.51 (m, 1H), 5.45–5.30 (m, 1H), 4.19 (d, J = 5.7 Hz, 1H), 4.16 (d, J = 11.2 Hz, 1H), 3.98 (s, 1H), 3.92 (d, J = 9.9 Hz, 1H), 3.88 (t, J = 7.1 Hz, 1H), 3.78 (tt, J = 8.6, 3.7 Hz, 1H), 3.61 (d, J = 9.5 Hz, 1H), 3.55–3.44 (m, 1H), 3.44 - 3.40 (m, 2H), 3.24 (dd, J = 8.2, 5.8 Hz, 1H), 3.19 (s, 1H), 3.02 (dd, J = 8.2, 5.9 Hz, 1H), 2.90 (s, 1H), 2.65 (q, J = 7.2 Hz, 1H), 2.52 (q, J = 6.8 Hz, 1H), 2.41 - 2.26 (m, 3H), 2.15 - 19.3 (m, 8H), 1.89–1.80 (m, 23H),

[0212] 1.19 - 1.17 (m, 9H), 1.12 (d, J = 6.9 Hz, 3H), 1.11 (d, J = 6.9 Hz, 3H), 1.09 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H), 0.74 (t, J = 7.4 Hz, 3H)( Fig.59 )。

[0213] 13C NMR test: 13 13C NMR (101 MHz, CDCl3) δ 177.30, 176.45, 165.14, 147.88, 132.11, 130.70, 120.77, 96.89, 81.98, 72.74, 70.66, 70.45, 70.25, 69.41, 66.29, 62.67, 50.73, 47.51, 44.40, 41.01, 40.73, 40.03, 39.30, 37.30, 35.64, 34.48, 33.37, 32.43, 32.25, 29.81, 28.81, 28.68, 27.88, 27.77, 25.65, 25.15, 24.83, 24.05, 21.22, 19.88, 14.31, 13.67, 13.61, 10.08, 9.41, 7.97, 7.79, 3.64( Fig.60 ).

[0214] Example 21 Synthesis of Compound RTM-W-XZW-0656

[0215] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.2 mmol, 2.0 eq.) in dichloromethane (5.0 mL), add benzenesulfonyl chloride (0.1 mmol, 1.0 eq.), and react at room temperature for 4 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0216]

[0217] RTM-W-XZW-0656 synthesis route mass spectrometry test: RTM-W-XZW-0656 molecular formula C 50 H 76 O 13 S, molecular weight 916 ( Fig.61 ).

[0218] Nuclear magnetic hydrogen spectrum test: 1 H NMR (400MHz, CDCl3) δ7.82–7.75(m,2H),7.57(dd,J=7.5,7.5Hz,1H),7.46(dd,J=7.7,7.5Hz,2H),6.79(dd,J=15.7,9.5Hz,1H),6.05–

[0219] 5.83(m,2H),5.80(d,J=15.7Hz,1H),5.52–5.36(m,1H),5.29–5.15(m,3H),4.02-3.94(m,2H),3.91–3.84(m,1 H),3.81(d,J=0.9Hz,1H),3.80–3.73(m,1H),2.88(q,J=7.3Hz,1H),2.71(qd,J=6.9,1.6Hz,1H),2.3-0.80(m,2 6),1.18(d,J=6.7Hz,3H),1.13(d,J=6.9Hz,3H),1.05(s,3H),0.97(d,J=6.9Hz,3H),0.95(d,J=6.9Hz,3H),0. 92(d,J=5.9Hz,3H),0.88(d,J=7.0Hz,3H),0.85(d,J=4.1Hz,3H),0.82(d,J=6.7Hz,3H),0.77(6,J=6.7Hz,3H)( Fig.62 ).

[0220] NMR carbon spectrum test: 13 C NMR (101MHz, CDCl3) δ215.01,164.27,148.09,137.33,135.94,132.80,131.56,129.08,128.1 6,128.03,126.77,126.53,121.54,96.50,82.07,81.79,72.01,71.55,69.85,69.07,66.38,6 3.64,44.68,44.22,43.97,41.58,40.17,39.12,37.53,34.49,34.20,32.51,30.35,29.64,29.52,28.87,27.21,25.55,23.74,19.99,17.15,13.81,13.50,11.15,10.27,7.91,7.60,4.29( Fig.63 ).

[0221] Example 22 Synthesis of Compound RTM-W-XZW-0657

[0222] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.2 mmol, 2.0 eq.) in dichloromethane (5.0 mL), add p-toluenesulfonyl chloride (0.1 mmol, 1.0 eq), and react at room temperature for 4 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0223]

[0224] RTM-W-XZW-0657 synthesis route mass spectrometry test: RTM-W-XZW-0657 molecular formula C 51 H 78 O 13 S, molecular weight 930 ( Fig.64 ).

[0225] Nuclear magnetic hydrogen spectrum test: 1H NMR (400MHz, CDCl3) δ7.67(d,J=8.0Hz,2H),7.25(d,J=8.0Hz,2H),6.80(dd,J=15.7,9.5Hz,1H),6.00–5.85(m,2H),5.80 (d,J=15.7Hz,1H),5.46–5.39(m,1H),5.28–5.19(m,3H),4.00–3.75(m,6H),2.89–2.85(m,1H),2.72–2.67(m,1H),2.36(s ,3H),2.33–0.80(m,27H),1.18(d,J=6.6Hz,3H),1.13(d,J=6.6Hz,3H),1.06(s,3H),0.96(d,J=6.6Hz,3H),0.95(d,J=6.6 Hz,3H),0.93(d,J=6.6Hz,3H),0.88(d,J=6.6Hz,3H),0.86(d,J=6.6Hz,3H),0.81(d,J=6.6Hz,3H),0.76(T,J=6.6Hz,3H)( Fig.65 ).

[0226] NMR carbon spectrum test: 13 C NMR (101MHz, CDCl3) δ214.98,164.29,148.12,143.82,137.31,132.99,131.55,129.09,128. 63,128.03,126.80,121.52,96.50,82.07,81.50,72.01,71.55,69.85,69.08,66.38,63.63,4 4.69,44.22,43.93,41.57,40.19,39.12,37.54,34.48,34.20,32.51,30.36,29.64,29.53,28.86,27.22,25.55,23.74,20.66,20.00,17.14,13.86,13.51,11.15,10.27,7.92,7.61,4.28( Fig.66 ).

[0227] Example 23 Synthesis of Compound RTM-W-XZW-0677

[0228] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.2 mmol, 2.0 eq.) in dichloromethane (5.0 mL), add p-tert-butylbenzenesulfonyl chloride (0.1 mmol, 1.0 eq), and react at room temperature for 4 h. After the reaction, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0229]

[0230] RTM-W-XZW-0677 synthesis route mass spectrometry test: RTM-W-XZW-0677 molecular formula C 54 H 84 O 13 S, molecular weight 972 ( Fig.67 ).

[0231] H NMR test: 1H NMR (400MHz, CDCl3) δ7.73–7.70 (m, 2H), 7.49–7.43 (m, 2H), 6.79 (dd, J=15.9, 9.4, Hz, 1H), 6.03–5.72 (m, 3H), 5.49–5.37 (m, 1H), 5.24–5.18 (m, 2H), 4.08–3.80 (m, 6H), 2.78-2.69 (m, 1H), 2.76-2.72 (m, 1H), 2.25-0.80 (m, 28H), 1. 27(s,9H),1.18(d,J=6.6Hz,3H),1.12(d,J=6.5Hz,3H),1.06(s,3H),0.97(d,J=6.5Hz,3H),0.95(d,J=6.5Hz,3H) ,0.94(d,J=6.5Hz,3H),0.92(d,J=6.5Hz,3H).0.86(d,J=6.5Hz,3H),0.84(d,J=6.5Hz,3H),0.77(t,J=7.3Hz,3H)( Fig.68 ).

[0232] Nuclear magnetic carbon spectrum test: 13C NMR (101MHz, CDCl3) δ215.05, 164.29, 156.81, 148.11, 137.36, 132.79, 131.57, 129.06, 128.01, 126.72, 126.69, 125.01, 124.98, 121.52, 96.51, 82.09, 81.22, 72.01, 71.53, 69.87, 69.08, 66.37, 63.65, 44.66,44.21,43.87,41.55,40.22,39.13,37.56,34.44,34.27,34.18,32.50,30.37,30.09,30.00,29.64,29.50,28.88,27.19,25.55,23.72,19.99,17.14,13.91,13.51,11.14,10.27,7.94,7.60,4.28( Fig.69 ).

[0233] Example 24 Synthesis of Compound RTM-LHY-0368

[0234] Synthesis method: Weigh oligomycin D (200 mg, 0.26 mmol, 1.00 eq.) and N,N-dimethylaminopyridine (190.59 mg, 1.56 mmol, 6.00 eq.) and dissolve in dichloromethane (5 mL), stir at 0 ° C for 30 min, slowly add monomethyl oxalyl chloride (191.12 mg, 1.56 mmol, 6.00 eq.) and move to room temperature to react for 6 h. After TLC monitoring, the solvent was removed under reduced pressure. After column chromatography, 90.00 mg of the product (white solid, yield 45%) was obtained.

[0235]

[0236] RTM-LHY-0368 synthesis route mass spectrometry test: RTM-LHY-0368 molecular formula C 50 H 76 O 17 , molecular weight 948( Fig.70 ).

[0237] Nuclear magnetic hydrogen spectrum test: 1H NMR (400MHz, CDCl3) δ6.77(dd,J=15.7,9.4Hz,1H),6.14(dd,J=14.9,10.5Hz,1H),6.00–5.86(m,2H),5.54(dd,J=6.4,2.2Hz ,1H),5.47–5.29(m,4H),5.24(s,1H),5.23–5.13(m,2H),4.37-4.29(m,9H),3.97–3.82(m,1H),3.83–3.72(m,1H),3.64-3.5 9(m,1H),3.27(s,1H),3.11–2.92(m,2H),2.79-2.71(m,1H),2.20–0.80(m,31H),1.31(s,3H),1.16(d,J=7.1Hz,3H),1.10(d ,J=6.7Hz,3H),1.03(d,J=7.0Hz,6H),0.99(d,J=7.0Hz,3H),0.94(d,J=7.0Hz,3H),0.91(d,J=6.9Hz,3H),0.87–0.79(m,6H)( Fig.71 ).

[0238] NMR carbon spectrum test: 13 C NMR (101MHz, CDCl3) δ215.59,209.61,164.62,157.98,157.75,157.64,157.54,157.40,157.08,156.67,156. 50,146.92,137.77,133.87,130.50,128.61,124.08,97.34,83.02,80.61,76.78,72.76,70.79,69.64,67.81 ,63.36,63.28,63.15,63.02,45.32,43.97,43.59,40.95,39.55,39.19,35.64,35.27,33.20,31.03,30.09,29.97,29.61,28.14,26.29,22.47,20.70,16.70,16.18,13.92,13.89,12.91,11.88,11.10,10.78,9.58,5.24( Fig.72 ).

[0239] Example 25 Synthesis of Compound RTM-XZW-0302

[0240] Synthesis method: Dissolve rutamycin (77.7 mg, 0.1 mmol, 1.0 eq.) and DMAP (0.1 mmol, 1.0 eq.) in dichloromethane (5.0 mL), add ethylsulfonyl chloride (0.2 mmol, 2.0 eq.), and react at room temperature for 4 h. After the reaction is completed, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a white solid.

[0241]

[0242] RTM-XZW-0302 synthesis route mass spectrometry test: RTM-XZW-0302 molecular formula C 48 H 80 O 15 S2, molecular weight 960 ( Fig.73 ).

[0243] Nuclear magnetic hydrogen spectrum test: 1 HNMR(400MHz, CDCl3)δ6.70(dd,J=15.7,9.5Hz,1H),6.01–5.83(m,3H),5.76(d,J=15.7Hz,1H),5.47-5 .40(m,1H),5.28–5.09(m,4H),4.84–4.80(m,1H),3.89–3.44(m,7H),3.09–3.04(m,6H),2.82–2.76(m,1 H),2.72–2.67(m,1H),2.29–0.80(m,18H),1.42(d,J=6.2Hz,3H),1.37-1.34(m,9H),1.11(d,J=6.6Hz,6 H),1.08(s,3H),1.02(d,J=6.9Hz,3H),0.95(d,J=6.7Hz,3H),0.86(d,J=7.0Hz,3H),0.80–0.74(m,6H)( Fig.74 ).

[0244] Nuclear magnetic carbon spectrum test: 13C NMR (101MHz, CDCl3) δ216.08, 164.21, 147.77, 137.40, 131.67, 129.03, 127.89, 121.61, 96.61, 82.12, 80.22, 72.03, 71.67, 69.77, 69.17, 67.21, 45.51, 45.34, 44.23, 44.19, 44 .13,40.03,39.88,39.09,37.57,34.36,33.87,32.53,30.27,28.96,28.69,28.62,26.77,25.19,21.12,20.03,17.10,14.04,13.50,11.19,10.04,7.76,7.47,7.23,7.10,3.99( Fig.75 ).

[0245] Example 26 Synthesis of Compound RTM-0211

[0246] To synthesize the compound RTM-0211, the raw material RTM is dissolved in tetrahydrofuran, and p-nitrobenzoic acid, triphenylphosphine and ethyl azodicarboxylate are added to react. After the first step is completed, the resulting product is dissolved in tetrahydrofuran and methanol solution, potassium carbonate is added, and hydrolysis is performed to obtain the target product RTM-0211. The configuration of the hydroxyl groups at positions 5, 9, 12, 13, and 33 of RTM can be reversed to obtain the target compound RTM-0211, with a yield of 53%. The nuclear magnetic resonance (NMR) hydrogen spectrum of RTM-A-24 shows that its structure is different from that of RTM, and the proton peaks with chemical shifts between 1.0-3.0 have obvious differences. The high-resolution mass spectrum shows that the m / z of RTM-0211 is 776.5075, which is consistent with RTM, indicating that RTM-0211 is the product of the reversal of the configuration of the hydroxyl group of RTM.

[0247]

[0248] RTM-0211 Synthesis Route

[0249] Example 27 Synthesis of Compound RTM-0212

[0250] To synthesize the compound RTM-0212, the raw material RTM is dissolved in ethanol, hydrochloric acid and hydrazine are added, and the reaction is carried out. The carbonyl group at position 7 of RTM can undergo an oxime reaction to obtain the target compound RTM-0212. The nuclear magnetic resonance (NMR) hydrogen spectrum of RTM-0212 shows that its structure is different from that of RTM, and the hydrogen with a chemical shift between 1.0 and 3.0 has a relatively obvious difference. The mass spectrum shows that the molecular weight of RTM-0212 is 790, indicating that the product has the same structural characteristics as RTM-0212.

[0251] Example 28 Test on the inhibition rate of RTM and its derivatives against wheat fusarium

[0252] The inhibitory rate of 20 mg / L RTM and its derivatives against wheat fusarium was determined by the pathogen mycelium growth method (Table 1).

[0253] Table 1 Inhibition rate of 20 mg / L RTM derivatives on wheat fusarium

[0254]

[0255] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound as shown in the following formula I or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

2. The compound according to claim 1 or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, characterized in that: R1 is selected from -OH, -N3, -OC(=O)-benzene-(C0~C3 alkyl), -OS(=O)(=O)-benzene-Cl, -OC(=O)-benzene-O-(C0~C3 alkyl), -OC(=O)-benzene-benzene, -OC(=O)-benzene-N(CH3)(CH3), -OC(=O)-C(=O)-O-(C0~C3 alkyl), -OC(=O)-benzene ring-CF3, -OC(=O)-benzene ring-CCl3, -OC(=O)-(C0~C3 alkyl)-benzene ring, -OC(=O)-CH=CH-benzene ring, -OC(=O)-benzene ring-NO2, -OC(=O)-(C0~C3 alkyl), -OS(=O)(=O)-phenyl ring-(C0-C4 alkyl), -OS(=O)(=O)-(C0-C3 alkyl).

3. The compound according to claim 1 or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, characterized in that: R2 and R3 are selected from H, and a double bond is formed between the C to which R2 is connected and the C to which R3 is connected.

4. The compound according to claim 1 or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, characterized in that: R4 is selected from -OH, -OC(=O)-benzene ring-(C0-C3 alkyl), -OC(=O)-benzene ring-benzene ring, -OC(=O)-C(=O)-O-(C0~C3 alkyl), -OC(=O)-benzene ring-CF3, -OC(=O)-benzene ring-CCl3, N3, -OC(=O)-C(=O)-O-(C0~C3 alkyl), -OS(=O)(=O)-(C0~C3 alkyl).

5. The compound according to claim 1 or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, characterized in that: R5 is selected from =O or =N-NH2.

6. The compound according to claim 1 or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, characterized in that: R6 is selected from -OH, -N3, -OC(=O)-phenyl ring-(C0~C3 alkyl), -OC(=O)-C(=O)-O-(C0~C3 alkyl).

7. The compound according to claim 1 or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, characterized in that: R7 is selected from -OH, -OC(=O)-C(=O)-O-(C0~C3 alkyl).

8. The compound according to claim 1 or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, characterized in that: R8, R9, R 10 With R 11 is selected from H, the C to which R8 is connected forms a double bond with the C to which R9 is connected, and R 10 Connected C and R 11 The C connected to R8 forms a double bond; or the C connected to R9 is connected to R8 through O to form a three-membered cyclic ether, R 10 Connected C and R 11 The connected C forms a double bond; or the C connected to R9 and R 10 The connected C forms a double bond, and the C connected to R8 forms a double bond with R 11 The connected C connection; or R9 connected to C and R 10 The connected C forms a double bond, and the C connected to R8 forms a double bond with R 11 The connected C connection; or R9 connected to C and R 10 The connected C forms a double bond, and the C connected to R8 forms a double bond with R 11 The connected C connection; or R9 connected to C and R 10 The connected C forms a double bond, and the C connected to R8 forms a double bond with R 11 The connected C connect.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which can be used for preventing and controlling wheat fusarium head blight in the agricultural field, characterized in that: The structural formula of the compound used to prevent and treat wheat scab is selected from one of the following:

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