Camptothecin compound, antibody conjugate thereof, preparation method and application thereof

Abstract

The invention discloses a camptothecin compound, an antibody conjugate of the camptothecin compound, a preparation method of the antibody conjugate and application of the antibody conjugate. The invention provides a camptothecin compound or a pharmaceutically acceptable salt thereof. The camptothecin compound is a compound shown as a formula I or a compound shown as a formula II. The compound and the antibody drug conjugate prepared from the compound have a good inhibition effect on cancer cells such as pancreatic cancer cells, breast adenocarcinoma cells, gastric cancer cells, colon cancer cells or breast cancer cells.

Description

Technical Field

[0001] This invention specifically relates to camptothecin compounds and their antibody conjugates, their preparation methods, and their uses. Background Technology

[0002] Camptothecin is a naturally occurring alkaloid compound, specifically a pentacyclic quinoline alkaloid. It is primarily studied as an anticancer drug, often used as a lead compound for new antitumor drugs, leading to the development of a series of drugs with good therapeutic effects against cancer. As an effective antitumor drug, camptothecin warrants further development by researchers in the hope of obtaining an even more effective anticancer agent. Summary of the Invention

[0003] The technical problem this invention aims to solve is that the structures of existing camptothecin-based anticancer drugs are relatively simple. Therefore, this invention provides a camptothecin-based compound and its antibody-drug conjugate, its preparation method, and its uses. The compound of this invention and the antibody-drug conjugate prepared therefrom exhibit good inhibitory effects on cancer cells such as pancreatic cancer cells, breast adenocarcinoma cells, gastric cancer cells, colon cancer cells, or breast cancer cells.

[0004] This invention provides a camptothecin-type compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the camptothecin-type compound is a compound as shown in Formula I or Formula II:

[0005]

[0006] R 1 and R 2 Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 alkoxy; or, R 1 and R 2 Independently connected to form C 1-10 Alkylene or C 1-10 Heteroalkyl;

[0007] R 3 and R 4 Independently H or D; or R 3 and R 4 Connection forms C 1-10 Alkylene or C 1-10 Heteroalkyl;

[0008] The various C 1-10 The heteroatom types of the heteroalkyl group are independently selected from one, two, or three of N, O, and S; the number of heteroatoms is independently one, two, or three;

[0009] m and n are independently 0, 1 or 2;

[0010] M is independent of C 1-6 Alkylene.

[0011] In a preferred embodiment, certain groups in the camptothecin compound or its pharmaceutically acceptable salt have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment").

[0012] In one scheme, the R 1 and R 2 In, the C 1-6 Alkyl groups are independently C 1-4 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and methyl, for example.

[0013] In one scheme, the R 1 and R 2 In, the C 1-6 Alkyl groups are independently C 1-4 Alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, and methoxy, for example.

[0014] In one scheme, the R 1 and R 2 In this context, the halogen is independently fluorine, chlorine, bromine, or iodine, such as fluorine.

[0015] In one scheme, the various Cs 1-10 The alkylene group is a straight-chain alkylene group; each of the C... 1-10 Alkylenes can independently be C 1-4 Alkylene; for example

[0016] In one scheme, the various Cs 1-10 The heteroalkylene group is a straight-chain heteroalkylene group; each of the C... 1-10 Heteroalkyl groups can independently be C 1-4 Heteroalkyl, such as C 3-4 Heteroalkyl; each of the C 1-10 The heteroatom in the heteroalkylene group may be O, and the number of heteroatoms may independently be one or two, for example, two; each C 1-10 Heteroalkyl groups can be

[0017] In one scheme, in M, the C 1-6 The alkylene group is a straight-chain alkylene group; the C 1-6 Alkylene can be C 1-4 Alkylene, for example For example

[0018] In one particular scheme, R 1 Independently H or halogen, such as halogen.

[0019] In one particular scheme, R 2 Independent of H, halogen, C 1-4 Alkyl or C 1-4 Alkyl groups; for example, R 2 Halogen, C 1-4 Alkyl or C 1-4 Alkyl groups; for example, R 2 C 1-4 alkyl.

[0020] In one particular scheme, R 1 and R 2 Independently connected to form C 1-10 Heteroalkylene; for example, R 1 and R 2 Independently connected to form C 1-4 Heteroalkyl; the C 1-4 The heteroatom in the heteroalkyl group is O, and the number of heteroatoms is 1 or 2.

[0021] In one particular scheme, R 3 and R 4 Connection forms C 1-10 Alkylene; for example, R 3 and R 4 Connection forms C 1-4 Alkylene.

[0022] In a certain scheme, m and n are independently 0 or 1, for example, m and n are both 0 or both 1.

[0023] In a certain scheme, M is independently C. 1-4 Alkylene.

[0024] In one particular scheme, R 1 Independently, it can be H or F, for example, F.

[0025] In one particular scheme, R 2 It can be H, F, methyl, or methoxy, for example, methyl.

[0026] In one particular scheme, R 3 and R 4 For H.

[0027] In one particular scheme, R 1 and R 2 Independently connected to form For example

[0028] In one particular scheme, R 3 and R 4 Connection formation

[0029] In one possible solution, M is...

[0030] In one embodiment, the compound represented by Formula I is a compound represented by Formula IA and / or Formula IB:

[0031]

[0032] In one embodiment, when m ≠ n, the compound represented by formula II is a compound represented by formula II-A and / or II-B:

[0033]

[0034] In one particular scheme, R 1 Independently H or halogen;

[0035] R 2 Independent of H, halogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0036] Or, R 1 and R 2 Independently connected to form C 1-4 Heteroalkyl; the C 1-4 The heteroatom in the heteroalkylene group is O, and the number of heteroatoms is independently 1 or 2;

[0037] R 3 and R 4 For H; or R 3 and R 4 Connection forms C 1-4 Alkylene;

[0038] m and n are independently 0 or 1;

[0039] M is independent of C 1-4 Alkylene.

[0040] In one embodiment, the compound is a compound as shown in Formula I:

[0041] Among them, R 1 It is a halogen;

[0042] R 2 Halogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0043] Or, R 1and R 2 Connection forms C 1-4 Heteroalkyl; the C 1-4 The heteroatom in the heteroalkylene group is O, and the number of heteroatoms is 1 or 2;

[0044] R 3 and R 4 For H; or R 3 and R 4 Connection forms C 1-4 Alkylene;

[0045] M is C 1-4 Alkylene.

[0046] This invention provides a compound, wherein the compound is any one of the following compounds:

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054] Preferably, the camptothecin-like compound is any of the following compounds:

[0055] The compound that elutes after chromatographic conditions Z are as follows: The chromatographic conditions Z are: InfinityLab Poroshell 120EC-C18 column (4.5*100mm, 2.7μm); mobile phase consisting of mobile phases A and B, where mobile phase A is an aqueous solution of trifluoroacetic acid and mobile phase B is a trifluoroacetic acid-acetonitrile solution, wherein the volume percentage of trifluoroacetic acid in mobile phases A and B is independently 0.05%; elution conditions are: mobile phases A and B eluted at a volume ratio of 95:5 for 0.1 min, followed by an increase in the volume percentage of mobile phase B from 5% to 95% within 6.9 min; flow rate of 1.5 mL / min; and / or... 1The compound was analyzed by ¹H NMR (400 MHz, DMSO-d6) with δ values ​​of 9.36 (s, 1H), 8.62 (d, J = 8.5 Hz, 1H), 8.23 ​​(d, J = 8.4 Hz, 1H), 7.92 (t, J = 7.6 Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 7.36 (s, 1H), 6.55 (s, 1H), 5.40 (d, J = 33.8 Hz, 4H), 4.89 (t, J = 5.4 Hz, 1H), 4.38 (t, J = 5.1 Hz, 2H), 3.81 (q, J = 5.2 Hz, 2H), 1.88 (p, J = 7.0 Hz, 2H), and 0.89 (t, J = 7.3 Hz, 3H). Preferably, the retention time of the later-eluting compound was 6.097 min.

[0056] The compound that elutes first under the following chromatographic conditions Z; said chromatographic conditions Z are: InfinityLab Poroshell 120EC-C18 column 4.5*100mm 2.7μm; mobile phase A is an aqueous solution of trifluoroacetic acid, and mobile phase B is a trifluoroacetic acid acetonitrile solution, wherein the volume percentage of trifluoroacetic acid in mobile phase A and mobile phase B is independently 0.05%; elution conditions are: mobile phase A and mobile phase B eluted at a volume ratio of 95:5 for 0.1 min, and then the volume percentage of mobile phase B increased from 5% to 95% within 6.9 min; flow rate is 1.5 mL / min; and / or, 1 The compound exhibits H NMR (400 MHz, DMSO-d6) values ​​of δ 7.87 (d, J = 10.7 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 6.53 (d, J = 4.5 Hz, 1H), 5.43 (s, 2H), 5.31 (d, J = 9.0 Hz, 2H), 4.75 (t, J = 5.4 Hz, 1H), 4.25 (t, J = 5.0 Hz, 2H), 3.71–3.64 (m, 2H), 2.90 (t, J = 6.5 Hz, 2H), 2.40 (d, J = 10.9 Hz, 3H), 1.87 (p, J = 6.9 Hz, 2H), and 0.88 (t, J = 7.3 Hz, 4H); preferably, the retention time of the first eluting compound is 4.868 min.

[0057] Compounds eluting under the following chromatographic conditions Z; wherein chromatographic conditions Z are: InfinityLab Poroshell 120EC-C18 column 4.5*100mm 2.7μm; mobile phase A is an aqueous solution of trifluoroacetic acid, and mobile phase B is a trifluoroacetic acid acetonitrile solution, wherein the volume percentage of trifluoroacetic acid in mobile phase A and mobile phase B is independently 0.05%; elution conditions are: mobile phase A and mobile phase B eluted at a volume ratio of 95:5 for 0.1 min, and then the volume percentage of mobile phase B increased from 5% to 95% within 6.9 min; flow rate is 1.5 mL / min; and / or, 1 The compound exhibits H NMR (400 MHz, DMSO-d6) values ​​of δ 7.82 (d, J = 10.9 Hz, 1H), 7.33 (s, 1H), 6.53 (s, 1H), 5.43 (d, J = 1.4 Hz, 2H), 5.29 (s, 2H), 4.89 (t, J = 5.5 Hz, 1H), 4.38 (t, J = 5.1 Hz, 2H), 3.82 (q, J = 5.2 Hz, 2H), 3.22 (d, J = 7.0 Hz, 2H), 3.13 (t, J = 6.6 Hz, 2H), 2.41 (d, J = 1.9 Hz, 3H), 1.87 (hept, J = 7.1 Hz, 2H), and 0.89 (t, J = 7.3 Hz, 3H); preferably, the retention time of the later-eluting compound is 4.990 min.

[0058] The compound that elutes first under the following chromatographic conditions Z; said chromatographic conditions Z are: InfinityLab Poroshell 120EC-C18 column, 4.5*100mm, 2.7μm; mobile phase A is an aqueous solution of trifluoroacetic acid, and mobile phase B is a trifluoroacetic acid-acetonitrile solution, wherein the volume percentage of trifluoroacetic acid in mobile phase A and mobile phase B is independently 0.05%; elution conditions are: mobile phase A and mobile phase B elute at a volume ratio of 95:5 for 0.1 min, and then the volume percentage of mobile phase B increases from 5% to 95% within 6.9 min; flow rate is 1.5 mL / min; and / or, 1H NMR (400MHz, DMSO-d6) is δ8.37(d,J=13.1Hz,1H),8.35–8.23(m,1H),8.08(ddd,J=18.7,11 .6,8.6Hz,1H),7.34(d,J=4.6Hz,1H),7.13(d,J=22.6Hz,1H),6.57(s,1H),5.43(s,1H),5. The compounds have 25 (s, 1H), 5.16 (s, 1H), 4.73 (d, J = 5.1 Hz, 1H), 4.24–4.16 (m, 2H), 3.61 (d, J = 4.2 Hz, 2H), 1.96 (dtt, J = 75.4, 14.2, 6.9 Hz, 2H), and 0.94–0.79 (m, 3H); preferably, the retention time of the first eluting compound is 6.337 min.

[0059] Compounds eluting under the following chromatographic conditions Z; wherein chromatographic conditions Z are: InfinityLab Poroshell 120EC-C18 column, 4.5*100mm, 2.7μm; mobile phase A being an aqueous solution of trifluoroacetic acid, and mobile phase B being an acetonitrile solution of trifluoroacetic acid, wherein the volume percentage of trifluoroacetic acid in mobile phase A and mobile phase B is independently 0.05%; elution conditions being elution of mobile phase A and mobile phase B at a volume ratio of 95:5 for 0.1 min, followed by an increase in the volume percentage of mobile phase B from 5% to 95% within 6.9 min; flow rate being 1.5 mL / min; and / or, 1 The compound exhibits H NMR (400 MHz, DMSO-d6) values ​​of 9.30 (s, 1H), 8.73 (dd, J = 12.5, 8.6 Hz, 1H), 8.26 (dd, J = 11.2, 8.1 Hz, 1H), 7.33 (s, 1H), 6.55 (s, 1H), 5.43 (d, J = 2.1 Hz, 2H), 5.31 (s, 2H), 4.90 (s, 1H), 4.43–4.33 (m, 2H), 3.86–3.75 (m, 2H), 1.87 (p, J = 6.9 Hz, 2H), and 0.88 (t, J = 7.3 Hz, 3H); preferably, the retention time of the later-eluting compound is 6.652 min. The compound that elutes first under the following chromatographic conditions Z is: chromatographic column: InfinityLab Poroshell 120EC-C18 4.5*100mm 2.7μm; mobile phase A: trifluoroacetic acid aqueous solution, mobile phase B: trifluoroacetic acid acetonitrile solution, wherein the volume percentage of trifluoroacetic acid in mobile phase A and mobile phase B is independently 0.05%; elution conditions: elution of mobile phase A and mobile phase B at a volume ratio of 95:5 for 0.1 min, followed by an increase in the volume percentage of mobile phase B from 5% to 95% within 6.9 min; flow rate: 1.5 mL / min; and / or... 1 The compound has H NMR (400MHz, DMSO-d6) values ​​of δ 8.40 (s, 1H), 8.07–7.70 (m, 2H), 7.39–7.16 (m, 1H), 6.55 (d, J = 3.6 Hz, 1H), 5.49–5.10 (m, 4H), 4.81 (dt, J = 71.0, 5.4 Hz, 1H), 4.29 (dt, J = 73.5, 5.1 Hz, 2H), 3.71 (dq, J = 78.4, 5.2 Hz, 2H), 1.87 (hept, J = 7.0 Hz, 2H), and 0.87 (q, J = 5.9, 4.5 Hz, 3H); preferably, the retention time of the first eluting compound is 6.568 min. Compounds eluting under the following chromatographic conditions Z are: chromatographic column: InfinityLab Poroshell 120EC-C18 4.5*100mm 2.7μm; mobile phase A: trifluoroacetic acid aqueous solution, mobile phase B: trifluoroacetic acid acetonitrile solution, wherein the volume percentage of trifluoroacetic acid in mobile phase A and mobile phase B is independently 0.05%; elution conditions: elution of mobile phase A and mobile phase B at a volume ratio of 95:5 for 0.1 min, followed by an increase in the volume percentage of mobile phase B from 5% to 95% within 6.9 min; flow rate: 1.5 mL / min; and / or... 1 The compound exhibits H NMR (400 MHz, DMSO-d6) values ​​of 9.34 (s, 1H), 8.58 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 10.7 Hz, 1H), 7.32 (s, 1H), 6.55 (s, 1H), 5.43 (d, J = 1.9 Hz, 2H), 5.28 (s, 2H), 4.90 (t, J = 5.4 Hz, 1H), 4.38 (dd, J = 5.8, 4.4 Hz, 2H), 3.80 (q, J = 5.2 Hz, 2H), 1.97–1.78 (m, J = 7.2 Hz, 2H), and 0.89 (t, J = 7.3 Hz, 3H); preferably, the retention time of the later-eluting compound is 6.896 min.

[0060] The compound that elutes first under the following chromatographic conditions Z; said chromatographic conditions Z are: InfinityLab Poroshell 120EC-C18 column 4.5*100mm 2.7μm; mobile phase A is an aqueous solution of trifluoroacetic acid, and mobile phase B is a trifluoroacetic acid acetonitrile solution, wherein the volume percentage of trifluoroacetic acid in mobile phase A and mobile phase B is independently 0.05%; elution conditions are: mobile phase A and mobile phase B eluted at a volume ratio of 95:5 for 0.1 min, and then the volume percentage of mobile phase B increased from 5% to 95% within 6.9 min; flow rate is 1.5 mL / min; and / or, 1 H NMR (400MHz, DMSO-d6) is δ8.44(s,1H),8.04(t,J=11.9Hz,1H),7.48(d,J=9.1Hz,1H),7.30 (d,J=3.8Hz,1H),6.53(d,J=3.6Hz,1H),5.42(s,2H),5.28(d,J=30.6Hz,2H),4.81(dt,J= The compounds having 65.8 (5.3 Hz, 1H), 4.30 (dt, J = 65.0, 5.1 Hz, 2H), 4.08 (d, J = 8.6 Hz, 3H), 3.71 (dq, J = 77.2, 5.2 Hz, 2H), 1.86 (p, J = 7.1 Hz, 2H), and 0.91–0.79 (m, 3H) eluents; preferably, the retention time of the first eluent compound is 6.211 min.

[0061] Compounds eluting under the following chromatographic conditions Z; wherein chromatographic conditions Z are: InfinityLab Poroshell 120EC-C18 column 4.5*100mm 2.7μm; mobile phase A is an aqueous solution of trifluoroacetic acid, and mobile phase B is a trifluoroacetic acid acetonitrile solution, wherein the volume percentage of trifluoroacetic acid in mobile phase A and mobile phase B is independently 0.05%; elution conditions are: mobile phase A and mobile phase B eluted at a volume ratio of 95:5 for 0.1 min, and then the volume percentage of mobile phase B increased from 5% to 95% within 6.9 min; flow rate is 1.5 mL / min; and / or, 1The compound exhibits H NMR (400 MHz, pyridine-d5) values ​​of δ 9.32 (s, 1H), 8.21 (d, J = 11.8 Hz, 1H), 8.05 (s, 1H), 7.95 (d, J = 8.9 Hz, 1H), 5.97 (d, J = 16.1 Hz, 1H), 5.63 (d, J = 16.1 Hz, 1H), 5.54 (d, J = 6.2 Hz, 2H), 4.60 (dd, J = 5.8, 4.1 Hz, 2H), 4.25 (t, J = 4.9 Hz, 2H), 3.99 (s, 3H), 2.16 (q, J = 7.3 Hz, 2H), and 1.19 (t, J = 7.3 Hz, 3H); preferably, the retention time of the later-eluting compound is 6.571 min.

[0062] The compound that elutes first under the following chromatographic conditions Z; said chromatographic conditions Z are: InfinityLab Poroshell 120EC-C18 column 4.5*100mm 2.7μm; mobile phase A is an aqueous solution of trifluoroacetic acid, and mobile phase B is a trifluoroacetic acid acetonitrile solution, wherein the volume percentage of trifluoroacetic acid in mobile phase A and mobile phase B is independently 0.05%; elution conditions are: mobile phase A and mobile phase B eluted at a volume ratio of 95:5 for 0.1 min, and then the volume percentage of mobile phase B increased from 5% to 95% within 6.9 min; flow rate is 1.5 mL / min; and / or, 1 ¹H NMR (400 MHz, DMSO-d⁶) values ​​were δ 9.32 +8.31 (s, 1H), 8.04 +7.40 (s, 1H), 7.60–7.47 (m, 1H), 7.31–7.19 (m, 1H), 6.56–6.44 (m, 1H), 6.30 (d, J = 15.0 Hz, 2H), 5.42 (s, 2H), and 5.32–5.16 (m, 2H). The compounds having 4.80 (dt, J = 70.7, 5.3 Hz, 1H), 4.27 (dt, J = 66.7, 5.1 Hz, 2H), 3.86–3.55 (m, 2H), 1.86 (hept, J = 7.0, 6.6 Hz, 2H), and 0.88 (t, J = 7.3 Hz, 3H) values; preferably, the retention time of the first eluting compound is 5.702 min.

[0063] Compounds eluting under the following chromatographic conditions Z; wherein chromatographic conditions Z are: InfinityLab Poroshell 120EC-C18 column 4.5*100mm 2.7μm; mobile phase A is an aqueous solution of trifluoroacetic acid, and mobile phase B is a trifluoroacetic acid acetonitrile solution, wherein the volume percentage of trifluoroacetic acid in mobile phase A and mobile phase B is independently 0.05%; elution conditions are: mobile phase A and mobile phase B eluted at a volume ratio of 95:5 for 0.1 min, and then the volume percentage of mobile phase B increased from 5% to 95% within 6.9 min; flow rate is 1.5 mL / min; and / or, 1 The compound exhibits H NMR (400 MHz, DMSO-d6) values ​​of 9.20 (s, 1H), 7.97 (s, 1H), 7.51 (s, 1H), 7.23 (s, 1H), 6.51 (s, 1H), 6.31 (d, J = 2.0 Hz, 2H), 5.41 (s, 2H), 5.19 (s, 2H), 4.89 (t, J = 5.4 Hz, 1H), 4.35 (t, J = 5.1 Hz, 2H), 3.80 (q, J = 5.2 Hz, 2H), 1.96–1.78 (m, J = 7.2 Hz, 2H), and 0.89 (t, J = 7.3 Hz, 3H); preferably, the retention time of the later-eluting compound is 6.032 min.

[0064] The compound that elutes first under the following chromatographic conditions Z; said chromatographic conditions Z are: InfinityLab Poroshell 120EC-C18 column, 4.5*100mm, 2.7μm; mobile phase A is an aqueous solution of trifluoroacetic acid, and mobile phase B is a trifluoroacetic acid-acetonitrile solution, wherein the volume percentage of trifluoroacetic acid in mobile phase A and mobile phase B is independently 0.05%; elution conditions are: mobile phase A and mobile phase B elute at a volume ratio of 95:5 for 0.1 min, and then the volume percentage of mobile phase B increases from 5% to 95% within 6.9 min; flow rate is 1.5 mL / min; and / or, 1 The compound exhibits H NMR (400 MHz, DMSO-d6) values ​​of 9.19 (s, 1H), 8.01 (s, 1H), 7.68–7.52 (m, 1H), 7.27 (d, J = 4.0 Hz, 1H), 6.49 (s, 1H), 5.41 (s, 2H), 5.20 (d, J = 14.5 Hz, 2H), 4.43 (s, 4H), 4.39–4.30 (m, 2H), 3.80 (d, J = 5.2 Hz, 2H), 1.96–1.77 (m, 2H), and 0.89 (td, J = 7.4, 3.2 Hz, 3H); preferably, the retention time of the first eluting compound is 5.778 min.

[0065] Compounds eluting under the following chromatographic conditions Z; wherein chromatographic conditions Z are: InfinityLab Poroshell 120EC-C18 column, 4.5*100mm, 2.7μm; mobile phase A being an aqueous solution of trifluoroacetic acid, and mobile phase B being an acetonitrile solution of trifluoroacetic acid, wherein the volume percentage of trifluoroacetic acid in mobile phase A and mobile phase B is independently 0.05%; elution conditions being elution of mobile phase A and mobile phase B at a volume ratio of 95:5 for 0.1 min, followed by an increase in the volume percentage of mobile phase B from 5% to 95% within 6.9 min; flow rate being 1.5 mL / min; and / or, 1 The compound exhibits H NMR (400 MHz, DMSO-d6) values ​​of 9.15 (s, 1H), 7.95 (s, 1H), 7.55 (s, 1H), 7.25 (s, 1H), 6.49 (s, 1H), 5.41 (s, 2H), 5.15 (d, J = 1.9 Hz, 2H), 4.45 (s, 4H), 4.35 (dd, J = 5.8, 4.4 Hz, 2H), 3.80 (t, J = 5.1 Hz, 2H), 2.01–1.73 (m, J = 7.3 Hz, 2H), and 0.90 (t, J = 7.3 Hz, 3H); preferably, the retention time of the later-eluting compound is 6.086 min.

[0066] This invention provides a compound or a pharmaceutically acceptable salt thereof: said compound is a compound of formula I-1 or formula II-1.

[0067]

[0068] Where L is the connector precursor;

[0069] M, m, n, R 1 R 2 R 3 and R 4 The definition is as described in any of the schemes of compounds represented by Formula I or Formula II.

[0070] In a preferred embodiment, certain groups in the compound of formula I-1 or II-1 or its pharmaceutically acceptable salt have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the invention (hereinafter referred to as "in a certain embodiment").

[0071] In this invention, the linker precursor refers to a group at one end that has been linked to the payload molecule in the drug conjugate, but at the other end has not yet been linked to an antibody group; after the other end of the linker precursor is linked to the antibody, the linker precursor forms a linker in the drug conjugate that links the antibody and the payload molecule; the linker may or may not be cleavable.

[0072] In one particular scheme, L is LD is a commonly used connector in the ADC field, and the linker precursor is linked to the antibody via LD; LD can link the antibody to L 1 (if it exists) or L 2 L 1 For single keys or connecting units; L 2 It is a single amino acid residue or a short peptide composed of 2-10 amino acid residues, wherein the amino acid is a natural amino acid or a non-natural amino acid; L 3 It is a spacer.

[0073] In one scheme, LD is Ring A is a 5-6 membered heteroolefin ring or a 5-6 membered heteroaromatic ring, wherein one or more carbon atoms in the 5-6 membered heteroolefin ring are replaced by C(O); the heteroatom types of the 5-6 membered heteroolefin ring and the 5-6 membered heteroaromatic ring are independently selected from one, two, or three of N, O, and S; the number of heteroatoms is independently one, two, or three; R 5 It is a leaveable group, such as -S(O)2-C 1-6 Alkyl group; p is 0 or 1.

[0074] In one of the schemes, L 1 Independently Each Z is independently C 1-6 Alkylene; each t is an independent integer from 1 to 16; preferably, L 1 Bit "1" is connected to ring A; bit "2" is connected to L. 2 connect.

[0075] In one of the schemes, L 2 Independently, it is a single amino acid residue, dipeptide residue, tripeptide residue, or tetrapeptide residue; preferably, the carbonyl group in said single amino acid residue, dipeptide residue, tripeptide residue, and tetrapeptide residue is related to L. 3 For connection; the NH and L in the individual amino acid residues, dipeptide residues, tripeptide residues and tetrapeptide residues 1 connect.

[0076] In one particular scheme, R 5 In the context, the -S(O)2-C 1-6 C in alkyl 1-6 Alkyl group is C1-4 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and methyl, for example.

[0077] In one embodiment, in ring A, the number of alkene bonds in the 5-6 membered heteroolefin ring is one or two, for example, one; the heteroatom in the 5-6 membered heteroolefin ring can be N, and the number of heteroatoms can be one or two, for example, one; for another example

[0078] In one embodiment, in ring A, the heteroatom type of the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms can be 1, 2 or 3, for example 2; another example is a pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring, and yet another example is a pyrimidine ring.

[0079] In one scheme, in Z, the C 1-6 The alkylene group is a straight-chain alkylene group; for example... For example

[0080] In one particular scheme, R 5 -S(O)2-C 1-4 Alkyl group; p = 1.

[0081] In one embodiment, ring A is independently a 5-6 membered heteroolefin ring or a 5-6 membered heteroaromatic ring, wherein the heteroatom in the 5-6 membered heteroolefin ring is N, and the number of heteroatoms is 1 or 2; one or more carbon atoms in the 5-6 membered heteroolefin ring are replaced by C(O); the heteroatom in the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms is 1, 2 or 3; preferably, ring A is independently a 5-6 membered heteroaromatic ring, wherein the heteroatom in the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms is 1, 2 or 3.

[0082] In a given scheme, t is independently 1, 2, 3, 4, 5, 6, 7, or 8, for example, 4.

[0083] In one of the schemes, L 1 Independently Among them, bit "1" is connected to ring A; bit "2" is connected to L. 2 connect.

[0084] In one of the schemes, L 2 Independently, it is a tetrapeptide residue; the tetrapeptide residue may be a tetrapeptide residue composed of glycine and phenylalanine; preferably, the carbonyl group in the tetrapeptide residue is related to L. 3 Linkage; the NH and L residues in the tetrapeptide 1 connect.

[0085] In one of the schemes, L3 Independently Among them NH and L 2 connect.

[0086] In one of the solutions, for

[0087] In one of the schemes, L 1 for Preferably, bit "1" is connected to ring A, and bit "2" is connected to L. 2 connect.

[0088] In one of the schemes, L 2 for NH -(Gly)2-Phe-Gly- C＝O For example, where the carbonyl end is associated with L 3 Connection; NH terminal and L 1 connect.

[0089] In one embodiment, the compound represented by formula I-1 or formula II-1,

[0090] LD is Ring A is a 5-6 membered heteroolefin ring or a 5-6 membered heteroaromatic ring, wherein one or more carbon atoms in the 5-6 membered heteroolefin ring are replaced by C(O); the heteroatom types of the 5-6 membered heteroolefin ring and the 5-6 membered heteroaromatic ring are independently selected from one, two, or three of N, O, and S; the number of heteroatoms is independently one, two, or three; R 5 -S(O)2-C 1-6 Alkyl group; p is 0 or 1;

[0091] L 1 Independently Each Z is independently C 1-6 Alkylene; L 1 Bit "1" is connected to ring A; bit "2" is connected to L. 2 connect;

[0092] t can be 1, 2, 3, 4, 5, 6, 7, or 8 independently;

[0093] L 2 Independently a tetrapeptide residue; the carbonyl group in the tetrapeptide residue and L 3 Linkage; the NH and L residues in the tetrapeptide 1 connect;

[0094] L 3 Independently Among them NH and L 2 connect;

[0095] R 1 Independently H or halogen;

[0096] R 2 Independent of H, halogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0097] Or, R 1 and R 2 Connection forms C 1-4 Heteroalkyl; the C 1-4 The heteroatom in the heteroalkylene group is O, and the number of heteroatoms is 1 or 2;

[0098] R 3 and R 4 For H; or R 3 and R 4 Connection forms C 1-4 Alkylene;

[0099] m and n are independently 0 or 1;

[0100] M is independent of C 1-4 Alkylene.

[0101] In one embodiment, the compound shown in Formula I-1 is a compound shown in Formula I-1A and / or a compound shown in Formula I-1B:

[0102]

[0103] In one embodiment, m ≠ n, and the compound shown in Formula II-1 is the compound shown in Formula II-1A and / or the compound shown in Formula II-1B:

[0104]

[0105] In one embodiment, the compound is any of the following compounds:

[0106]

[0107]

[0108]

[0109]

[0110]

[0111] This invention provides a drug conjugate, wherein the drug conjugate is a drug conjugate as shown in Formula I-2 or Formula II-2:

[0112] T stands for antibody;

[0113] G stands for connector;

[0114] d is a natural number from 1 to 8 and / or a decimal;

[0115] M, m, n, R 1 R 2 R 3 and R 4 The definition is as described in either scheme of the compound shown in Formula I or Formula II.

[0116] It should be noted that T is linked to G via a compound coupling method understood by those skilled in the art; for example, T is linked to ring B via S on it. Those skilled in the art will understand that one end of G is linked to the thiol group contained in T (antibody) after the disulfide bond is opened (e.g., the disulfide bond can be opened by reducing it with the reducing agent TCEP to generate a thiol group -SH). In other words, the -S- between G and T is not an additional external sulfur atom. The linker can be a degradable or non-degradable linker fragment; one end is linked to the compound shown in Formula I or Formula II; the other end is linked to antibody T.

[0117] In a preferred embodiment, certain groups in the drug conjugates shown as in Formula I-2 or II-3 have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment").

[0118] In one particular scheme, G is Wherein, ring B is the linker that connects to the antibody; L 1 L 2 and L 3 The definition is as described in either scheme of the compound shown in Formula I-1 or Formula II-1.

[0119] In one embodiment, ring B is independently a 5-6 membered heteroalkane ring or a 5-6 membered heteroaromatic ring, wherein one or more carbon atoms in the 5-6 membered heteroalkane ring are replaced by C(O); the heteroatom types of the 5-6 membered heteroalkane ring and the 5-6 membered heteroaromatic ring are independently selected from one, two or three of N, O and S; and the number of heteroatoms is independently one, two or three.

[0120] In one embodiment, in ring B, the heteroatom in the 5-6 membered heteroalkane ring can be N, and the number of heteroatoms can independently be 1 or 2, for example, 1; the two carbon atoms in the 5-6 membered heteroalkene ring are replaced by C(O); each 5-6 membered heteroalkane ring can be...

[0121] In one embodiment, in ring B, the heteroatom type of the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms can be 1, 2 or 3, for example 2; for example, pyridine ring, pyrazine ring or pyridazine ring, or pyrimidine ring.

[0122] In a preferred embodiment, T represents an anti-HER2 antibody, such as trastuzumab.

[0123] In a preferred embodiment, t is a natural number between 7 and 8 and / or a decimal; for example, 7.43, 7.68, 7.93, 7.95, or 8.

[0124] In a preferred embodiment, ring B is a 5-6 membered heteroalkane ring or a 5-6 membered heteroaromatic ring; one or more carbon atoms in the 5-6 membered heteroalkene ring are replaced by C(O); the heteroatom in the 5-6 membered heteroalkane ring is N, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms is 1, 2 or 3.

[0125] In a certain preferred solution, for Preferably, bit "1" is connected to T, and bit "2" is connected to L. 1 connect.

[0126] In a certain preferred solution,

[0127] T represents anti-HER2 antibody.

[0128] t is a natural number from 1 to 8 and / or a decimal;

[0129] Ring B is a 5-6 membered heteroalkane ring or a 5-6 membered heteroaromatic ring; one or more carbon atoms in the 5-6 membered heteroalkene ring are replaced by C(O); the heteroatom in the 5-6 membered heteroalkane ring is N, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms is 1, 2 or 3.

[0130] L 1 Independently Each Z is independently C 1-6 Alkylene; L 1 Bit "1" is connected to ring A; bit "2" is connected to L. 2 connect;

[0131] L 2 Independently composed of glycine and phenylalanine tetrapeptide residues; the carbonyl group in the tetrapeptide residues and L 3 For connection; the NH and L in the tetrapeptide residues 1 For connection;

[0132] L 3 Independently Among them NH and L 2 connect;

[0133] R 1 It is a halogen;

[0134] R 2 C 1-4 alkyl;

[0135] Or R 1 and R 2 Connection forms C 1-4 Heteroalkyl; the C 1-4 The heteroatom in the heteroalkylene group is of type O, and the number of heteroatoms is 1 or 2;

[0136] R 3 and R 4 For H.

[0137] In a preferred embodiment, the drug conjugate as shown in Formula I-2 is a drug conjugate as shown in Formula I-2A or I-2B:

[0138]

[0139] In a preferred embodiment, m ≠ n, and the drug conjugate shown in Formula II-2 is a drug conjugate shown in Formula II-2A or II-2B:

[0140]

[0141] In a preferred embodiment, the drug conjugate is any of the following compounds:

[0142]

[0143] Wherein, T is trastuzumab, and t is defined as described in any one of the present invention;

[0144] Preferably, the drug conjugate represented by Formula I-2 or Formula II-3 is any of the following compounds:

[0145]

[0146] T stands for trastuzumab.

[0147] The present invention also provides a pharmaceutical composition comprising:

[0148] (1) (Therapeuticly effective amount) of a compound of formula I or II or a pharmaceutically acceptable salt thereof, as described in any one of the present invention; a compound of formula I-1 or II-1 or a pharmaceutically acceptable salt thereof; or a drug conjugate of formula I-2 or II-2; and

[0149] (2) Pharmaceutical excipients.

[0150] The present invention also provides (therapeuticly effective amounts) of a compound of formula I or II as described in any one of the present invention, or a pharmaceutically acceptable salt thereof, a compound of formula I-1 or II-1, or a pharmaceutical conjugate of formula I-2 or II-2; or the use of the above pharmaceutical compositions in the preparation of a medicament for the prevention and / or treatment of cancer, wherein the cancer is pancreatic cancer, breast cancer, gastric cancer, colon cancer, or breast cancer.

[0151] This invention provides the use of a drug conjugate of formula I-2 or II-2 as described in any one of the present invention in the preparation of a medicament for the prevention and / or treatment of cancers associated with the trastuzumab target; wherein the cancers associated with the trastuzumab target are pancreatic cancer, breast adenocarcinoma, gastric cancer, colon cancer or breast cancer.

[0152] This invention provides a method for preparing a drug conjugate as shown in Formula I-2 or Formula II-2 according to any one of the present invention, comprising the following steps:

[0153] In a solvent, in the presence of a reducing agent, the antibody is coupled with the compound of Formula I-1 or a pharmaceutically acceptable salt thereof to obtain the compound of Formula I-2 or a pharmaceutically acceptable salt thereof.

[0154] Alternatively, in a solvent and in the presence of a reducing agent, the antibody is coupled with the compound of Formula II-1 or a pharmaceutically acceptable salt thereof to obtain the compound of Formula II-2 or a pharmaceutically acceptable salt thereof.

[0155]

[0156]

[0157] The solvent, the reducing agent, and the amounts of each raw material are conventional types and amounts used in this type of coupling reaction in the art. For example, the solvent is PBS buffer; the reducing agent may be a thiol reducing agent (TCEP).

[0158] Terminology Definition

[0159] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0160] In this specification, groups and their substituents may be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left.

[0161] In this invention, any combination of variables is permitted only if such a combination produces a stable compound.

[0162] In this invention, unless otherwise stated, when each atom in the carbon-nitrogen double bond of a compound is connected to two different substituents (the lone pair of electrons on the nitrogen atom is considered as one of the substituents it is connected to), if the nitrogen atom in the carbon-nitrogen double bond of the compound is connected to its substituent by a... If indicated, it represents the (Z) isomer, (E) isomer, or a mixture of the two isomers in any proportion; if the carbon-nitrogen double bonds in the compound are crossed, it indicates that the compound is a (Z) isomer, an (E) isomer, or a mixture of the two isomers in any proportion; The expression indicates that the compound is a mixture of (Z) type isomers and (E) type isomers in any proportion; for example, the following formula (B) indicates that the compound exists as a single isomer of formula (B-1) or formula (B-2) or as a mixture of two isomers of formula (B-1) and formula (B-2).

[0163]

[0164] The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for patient use. The term "patient" preferably refers to a mammal, and more preferably a human.

[0165] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of this invention with a relatively non-toxic, pharmaceutically acceptable acid or base.

[0166] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0167] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms (e.g., C1 to C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, and n-hexyl.

[0168] The term "alkoxy" refers to -O-alkyl, and the definition of alkyl is as described above.

[0169] The term "alkylene" refers to a substituent formed by eliminating two hydrogen atoms from a saturated straight-chain or branched alkane. The two eliminated hydrogen atoms can be on the same carbon atom or on different carbon atoms (e.g., the two eliminated hydrogen atoms are on the carbon atoms at the two ends). Thus, C1 alkylene (i.e., methylene) refers to -CH2-, and C2 alkylene (i.e., ethylene) refers to -CH2-CH2- or -CH(CH3)-.

[0170] C 3-10 Alkane rings refer to those with a specified number of carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 5-6 A saturated cyclic system consisting only of carbon atoms; preferably a monocyclic ring. 3-10 Alkane rings include, but are not limited to, cyclopentane rings and cyclohexane rings. C 3-10 The alkane ring is connected to the rest of the molecule by a single bond.

[0171] "3-10 membered heteroalkane rings" refer to saturated cyclic systems having a specified number of ring atoms (e.g., 5-6), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), preferably monocyclic. For example, a pyrrolidine ring. The 3-10 membered heteroalkane ring is connected to the rest of the molecule by a single bond.

[0172] "3-10 membered heteroene rings" refer to cyclic systems with a specified number of ring atoms (e.g., 5-6), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom type (one or more of N, O, and S), containing one or more double bonds but no ternary bonds, and lacking aromaticity, preferably monocyclic. An example is a nitrogen-containing heptene ring. The 3-10 membered heteroene ring is connected to the rest of the molecule by single bonds.

[0173] "5-10 heteroaromatic ring" refers to a heteroaromatic cyclic system having a specified number of ring atoms (e.g., 5-6), a specified number of heteroatoms (e.g., 1, 2, 3), and a specified type of heteroatom (one or more of N, O, and S), preferably a monocyclic ring; for example, a pyrimidine ring. The heteroaromatic ring is connected to the rest of the molecule by a single bond.

[0174] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. They are all substances contained in pharmaceutical preparations, excluding the active ingredient.

[0175] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0176] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0177] The term "therapeutic effective amount" refers to an amount of compound sufficient to effectively treat the disease or condition described herein when administered to a patient. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but may be adjusted as needed by those skilled in the art.

[0178] The term "patient" refers to any animal, preferably a mammal and human, that is about to or has already been administered the compound or composition according to embodiments of the invention.

[0179] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0180] The reagents and raw materials used in this invention are all commercially available.

[0181] The positive and progressive effects of this invention are that the compounds of this invention and the antibody-drug conjugates prepared therefrom have good inhibitory effects on cancer cells such as pancreatic cancer cells, breast adenocarcinoma cells, gastric cancer cells, colon cancer cells, or breast cancer cells. Detailed Implementation

[0182] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0183] In the following examples, the carbon-nitrogen double bonds in the compound are crossed. The symbol indicates that the compound is a mixture of (Z) isomers and (E) isomers in a specific ratio.

[0184] Example 1: Synthesis route of OD001

[0185]

[0186] Preparation process:

[0187] Step 1: Synthesis of Compound 1

[0188] CPT (1 g, 2.87 mmol) was dissolved in a mixture of methanol (50 mL) and water (60 mL). Sulfuric acid (50 mL, 18.4 M) was slowly added, followed by ferrous sulfate heptahydrate (798.08 mg, 2.87 mmol). Finally, hydrogen peroxide (10 mL, 2.87 mmol) was added dropwise at 0°C. After the addition was complete, the reaction mixture was stirred in an ice bath for 2 hours, then heated to room temperature and stirred for 22 hours. LC-MS showed that the reaction was complete. Water (80 mL) was added to the reaction mixture, and the precipitate was filtered and dried under vacuum to give compound 1 (874 mg, Yield: 80.46%).

[0189] LCMS(ESI): m / z, 379.2 [M+H] +

[0190] Step 2: Synthesis of Compound 2

[0191] Compound 1 (470 mg, 1.24 mmol) was dissolved in acetic acid (100 mL) and the reaction mixture was stirred overnight at 90°C under an oxygen atmosphere. LC-MS showed that the reaction was complete. The reaction mixture was evaporated to dryness, water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 5). The extract was washed with brine and dried over anhydrous sodium sulfate. The organic phases were combined and evaporated to dryness to give crude compound 2 (500 mg, yield: 107%).

[0192] LCMS(ESI): m / z, 377.2 [M+H] +

[0193] Step 3: Synthesis of compound OD001

[0194] Compound 2 (200 mg, 531.39 μmol) was dissolved in ethanol (15 mL), and compound 4 (122.88 mg, 106.85 μmol) and pyridine (1.5 mL, 18.55 mmol) were added. The reaction mixture was stirred at 90°C for 5 hours. LC-MS showed that the reaction was complete, yielding compound OD001. The reaction mixture was evaporated to dryness, first slurryed with methanol to obtain a crude product, and then OD001-P1 and solid OD001-P2 (OD001-P2: 71 mg, yield: 30.68%, purity: 96.9%) were prepared by high-performance liquid chromatography.

[0195] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatogram manufacturer is Shimadzu, model LC-20AP. The chromatographic column is a Phenomenex Luna C18 250*30mm*10um. The mobile phase is water (0.225% HCOOH)-acetonitrile, with an elution ratio of 20% to 50%.

[0196] The high-performance liquid chromatography (HPLC) analysis methods for OD001-P1 and OD001-P2 are as follows:

[0197]

[0198]

[0199] The retention time of OD001-P2 is 6.097 min.

[0200] LCMS(ESI): m / z, 436.2 [M+H] +

[0201] 1 H NMR (400MHz, DMSO-d6) δ9.36(s,1H),8.62(d,J=8.5Hz,1H),8.23(d,J=8.4Hz,1H),7.92(t,J=7.6Hz,1H),7.78(t,J=7.7Hz,1H),7.36(s,1H),6.55 (s,1H),5.40(d,J=33.8Hz,4H),4.89(t,J=5.4Hz,1H),4.38(t,J=5.1Hz,2H),3.81(q,J=5.2Hz,2H),1.88(p,J=7.0Hz,2H),0.89(t,J=7.3Hz,3H).

[0202] The retention time of OD001-P1 was 5.742 min.

[0203] Example 2: OD002 Synthesis Route

[0204]

[0205] Preparation process:

[0206] Step 1: Synthesis of Compound 2

[0207] Compound 1 (1 g, 1.00 eq) was dissolved in acetic acid (2 mL) and water (8 mL). The reaction solution was cooled to 0°C, and hydrochloric acid (10 mL, 12 M in water) was added, followed by the slow dropwise addition of sodium nitrite (257 mg, 3.72 mL, 3.72 mmol, 2 eq, 1 M in water). After the addition was complete, the reaction solution was stirred at room temperature for 3 hours. LCMS showed that the reaction was complete. The reaction solution was cooled to 0°C, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate. The solution was then extracted with ethyl acetate (3 x 300 mL), and the organic phase was washed with saturated brine (1 x 100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give compound 2 (400 mg, yield: 34.45%, purity: 70%). LCMS (ESI): m / z, 437.2 [M+H] + .

[0208] Step 2: Synthesis of Compound 3

[0209] Compound 2 (400 mg, 70%, 1.00 eq) was dissolved in dichloromethane (5 mL). DMP (360.96 mg, 98%, 1.30 eq) was added under ice bath conditions, and the reaction mixture was stirred at room temperature for 12 hours. LC-MS showed the reaction was complete. The reaction mixture was evaporated to dryness and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10:1) to give compound 3 (200 mg, crude).

[0210] LCMS(ESI): m / z, 435.2 [M+H] +

[0211] Step 3: Synthesis of compound OD002

[0212] Compound 3 (200 mg, crude, 1.00 eq) and compound 4 (103.20 mg, 98%, 3.00 eq) were dissolved in acetic acid (3 mL), and sodium acetate (3.62 mg, 0.10 eq) was added. The reaction mixture was stirred at 100°C for 30 minutes under nitrogen atmosphere. LC-MS showed the reaction was complete, yielding compound OD002. The reaction mixture was concentrated and dissolved in N,N-dimethylformamide (3 mL). High-performance liquid chromatography (HPLC) yielded two cis-trans isomers: (27.93 mg, yield: 11.24%, purity: 98.67%, OD002-P1 (containing 15% OD002-P2)) and (13.54 mg, yield: 5.45%, purity: 100%, OD002-P2).

[0213] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatogram was manufactured by Oriendo, model BRIX-2860. The column was a YMC-Triart Prep C18 150*30mm*10um. The mobile phase was water (0.225% FA)-acetonitrile, with an elution ratio of 30% to 60%.

[0214] The high-performance liquid chromatography analysis method is the same as OD001-P2:

[0215] The retention time of OD002-P1 was 4.868 min, and the retention time of OD002-P2 was 4.990 min.

[0216] OD002-P1 (including 15% P2): LCMS(ESI): m / z, 494.2 [M+H]+.

[0217] 1 H NMR (400MHz, DMSO-d6) δ7.87(d,J=10.7Hz,1H),7.33(d,J=2.5Hz,1H),6.53(d,J=4.5Hz,1H),5.43(s,2H),5.31(d,J=9.0Hz,2H),4.75(t,J=5. 4Hz,1H),4.25(t,J=5.0Hz,2H),3.71–3.64(m,2H),2.90(t,J=6.5Hz,2H),2.40(d,J=10.9Hz,3H),1.87(p,J=6.9Hz,2H),0.88(t,J=7.3Hz,4H).

[0218] OD002-P2: LCMS(ESI):m / z,494.2[M+H]+.

[0219] 1 H NMR (400MHz, DMSO-d6) δ7.82(d,J=10.9Hz,1H),7.33(s,1H),6.53(s,1H),5.43(d,J=1.4Hz,2H),5.29(s,2H),4.89(t,J=5.5Hz,1H),4.38(t,J=5.1 Hz, 2H), 3.82 (q, J = 5.2Hz, 2H), 3.22 (d, J = 7.0Hz, 2H), 3.13 (t, J = 6.6Hz, 2H), 2.41 (d, J = 1.9Hz, 3H), 1.87 (hept, J = 7.1Hz, 2H), 0.89 (t, J = 7.3Hz, 3H).

[0220] Example 3: OD003 Synthesis Route

[0221]

[0222] Preparation process: Step 1: Synthesis of compound 3

[0223] Compound 1 (2 g, 11.45 mol) and compound 2 (900 mg, 11.45 mol) were dissolved in ethanol (20 mL) and pyridine (6 mL). The reaction mixture was stirred at 90°C for 5 hours. LC-MS showed that the reaction was complete. The reaction mixture was evaporated to dryness to give crude compound 3 (2.64 g, yield: 100.14%).

[0224] LCMS(ESI): m / z, 131.2 [M+H-Boc] +

[0225] Step 2: Synthesis of Compound 4

[0226] Compound 3 (2.64 g, 11.47 mmol) was dissolved in methanol (80 mL), and HCl (24 g, 16 mL, 4 M in 1,4-Dioxane) was added. The reaction mixture was stirred at 25°C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was evaporated to dryness to give crude compound 4 (1.49 g, yield: 99.85%).

[0227] LCMS(ESI): m / z, 131.2 [M+H] +

[0228] Step 3: Synthesis of Compound 5

[0229] Compound 4 (1.49 g, 11.45 mmol) was dissolved in dichloromethane (30 mL), and imidazole (3.94 g, 57.24 mmol) and tert-butyldimethylchlorosilane (2.67 g, 17.17 mmol) were added. The reaction mixture was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was purified by silica gel column chromatography (eluent: methanol / dichloromethane 1:20 to 1:10) to give compound 5 (2.16 g, yield: 77.20%). LCMS (ESI): m / z, 245.3 [M+H] +

[0230] Step 4: Synthesis of compound OD003

[0231] Compound 5 (286.03 mg, 1.17 mmol) was dissolved in 1,4-dioxane (10 mL), followed by compound 6 (500 mg, 1.17 mmol), palladium acetate (26.81 mg, 117.03 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (138.19 mg, 234.06 μmol), and tripotassium phosphate (760.45 mg, 3.51 mmol). The reaction mixture was purged three times with nitrogen. Under a nitrogen atmosphere, the reaction mixture was stirred at 80°C for 16 hours. LCMS analysis confirmed the reaction was complete (the result indicated compound 7, LCMS (ESI): m / z, 591.3 [M+H]). + The reaction solution was purified by silica gel column chromatography (eluent: methanol / dichloromethane 1:20 to 1:5). The residue was purified by silica gel column chromatography (C18) (ISCO, R-330g SepaFlash Silica Flash Column, eluent of 5-30% water / CH3CN@100mL / min). (During the preparation process, compound 7 directly generated OD003) to obtain compound OD003 (60mg, yield: 10.76%, purity: 96.24%).

[0232] The preparative conditions for high-performance liquid chromatography (HPLC) were as follows: The preparative chromatograph was manufactured by Oriendo, model BRIX-2860 (R1, 4, 5, 6). The column was a Phenomenex Luna C18 250*50mm*10um. The mobile phase was water (0.225% HCOOH)-acetonitrile, with water elution ranging from 45% to 85%.

[0233] OD003 LCMS(ESI):m / z,477.1[M+H] +

[0234] 1 H NMR(400MHz,DMSO-d6)δ8.16(d,J=8.4Hz,1H),7.96(dd,J=8.4,1.3Hz,1H),7.7 3(ddd,J=8.3,6.8,1.2Hz,1H),7.48(ddd,J=8.4,6.8,1.4Hz,1H),7.24(s,1H), 6.49(s,1H),5.75–5.48(m,6H),5.42(s,2H),4.74(t,J=5.6Hz,1H),4.09(t,J= 5.2Hz, 2H), 3.64 (q, J = 5.4Hz, 2H), 1.86 (p, J = 6.9Hz, 2H), 0.87 (t, J = 7.3Hz, 3H).

[0235] Example 4: OD004 Synthesis Route

[0236]

[0237] Preparation process: Step 1: Synthesis of compound 2

[0238] Compound 1 (10 g, 28.71 mmol) was dissolved in acetic anhydride (300 mL) and pyridine (200 mL), and the reaction mixture was stirred at 25°C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was evaporated to dryness, and the residue was slurried with dichloromethane (50 mL total volume), filtered, and the filter cake was washed with dichloromethane (50 mL total volume). The residual solvent in the filter cake was evaporated to dryness, giving crude compound 2 (13 g, yield: 116%).

[0239] LCMS(ESI): m / z, 391.2 [M+H] +

[0240] Step 2: Synthesis of Compound 3

[0241] Compound 2 (13 g, 33.30 mmol) and m-chloroperoxybenzoic acid (20.28 g, 99.90 mmol) were dissolved in dichloromethane (600 mL), and the reaction mixture was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. Sodium sulfite (200 mL, 15%) was added to the reaction mixture at 0°C and stirred for 30 minutes. The mixture was then extracted with dichloromethane (500 mL x 3). The organic phase was dried, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1 to 10:1) to give crude compound 3 (13 g, yield: 96.07%). LCMS (ESI): m / z, 407.1 [M+H] + .

[0242] Step 3: Synthesis of Compound 4

[0243] Compound 3 (13.6 g, 33.47 mmol) was dissolved in N,N-dimethylformamide (260 mL), and oxaloyl bromide (8.19 g, 36.81 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 25°C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was washed with dichloromethane (500 mL x 3) and water (500 mL), the organic phase was dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1 to 10:1) to give crude compound 4 (7.67 g, yield: 48.84%). LC-MS (ESI): m / z, 471.0 [M+H] + .

[0244] Step 4: Synthesis of Compound 5

[0245] Compound 4 (4.89 g, 10.42 mmol) and sodium methoxide (2.87 mg, 52.10 mmol) were dissolved in methanol (50 mL). The reaction mixture was stirred at 25°C for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was adjusted to pH 2 with hydrochloric acid (1 M) and filtered. The filter cake was slurried with dichloromethane (50 mL total), filtered, and washed with dichloromethane (15 mL total). The residual solvent in the filter cake was evaporated to give compound 5 (2.9 g, yield: 43.43%). LC-MS (ESI): m / z, 426.9 [M+H] + .

[0246] Step 5: Synthesis of compound 6c

[0247] Compound 6a (3 g, 14.76 mmol) and compound 6b (1.16 g, 14.76 mmol) were dissolved in ethanol (90 mL) and pyridine (9 mL). The reaction mixture was stirred at 90°C for 5 hours. LC-MS showed that the reaction was complete. The reaction mixture was evaporated to dryness to give crude compound 6c (3.81 g, yield: 99.96%).

[0248] LCMS(ESI): m / z, 203.1 [M+H-56] +

[0249] Step 6: Synthesis of compound 6d

[0250] Compound 6c (3.81 g, 14.75 mmol) was dissolved in HCl (35 mL, 4 M 1,4-dioxane solution) / methanol (150 mL), and the reaction mixture was stirred at 25°C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was evaporated to dryness to give crude compound 6d (2.87 g, yield: 99.96%).

[0251] LCMS(ESI): m / z, 159.2 [M+H] +

[0252] Step 7: Synthesis of Compound 6

[0253] Compound 6d (2.87 g, 18.14 mmol) was dissolved in dichloromethane (30 mL), and imidazole (6.24 g, 90.71 mmol) and tert-butyldimethylchlorosilane (5.64 g, 36.28 mmol) were added. The reaction mixture was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was washed with dichloromethane (50 mL x 3) and water (50 mL), the organic phase was dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1 to 5:1) to give compound 6 (1.54 g, yield: 31.16%). LCMS (ESI): m / z, 273.3 [M+H] +

[0254] Step 8: Synthesis of Compound 7

[0255] Compound 5 (1.4 g, 3.28 mmol) was dissolved in dioxane (28 mL), and compound 6 (892.79 mg, 3.28 mmol), palladium acetate (375 mg, 1.64 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (773.88 mg, 1.31 mmol), and potassium phosphate (2.13 g, 9.83 mmol) were added. The reaction mixture was purged with nitrogen three times, and stirred at 100°C for 16 hours under nitrogen protection. LC-MS showed that the reaction was complete. The reaction mixture was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1 to 5:1) to give crude compound 7 (100 mg, yield: 4.93%).

[0256] LCMS(ESI): m / z, 619.2 [M+H] +

[0257] Step 9: Synthesis of compound OD004

[0258] Compound 7 (100 mg, 161.60 μmol) was dissolved in N,N-dimethylformamide (10 mL) and formic acid (5 mL), and the reaction mixture was stirred at 25°C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was purified by high-performance liquid chromatography to obtain compound OD004 (4.39 mg, yield: 1.80%).

[0259] The preparative conditions for high-performance liquid chromatography (HPLC) were as follows: The preparative chromatogram was manufactured by Oriendo, model BRIX-2860 (R6). The column was a Phenomenex Luna C18 250*50mm*10um. The mobile phase was water (0.225% HCOOH)-acetonitrile, with water elution ratios ranging from 45% to 85%.

[0260] LCMS(ESI): m / z, 505.2 [M+H] +

[0261] 1 H NMR (400MHz, DMSO-d6) δ8.28–8.15(m,1H),8.15–8.02(m,1H),7.82(ddd,J= 8.4,6.7,1.4Hz,1H),7.67(ddd,J=8.3,6.7,1.3Hz,1H),7.33(s,1H),5.53( s,2H),5.44(s,2H),4.04(t,J=5.3Hz,2H),3.63(t,J=5.3Hz,6H),2.86(s,2 H), 2.59 (t, J = 5.7Hz, 2H), 1.87 (hept, J = 7.0Hz, 2H), 0.87 (t, J = 7.5Hz, 3H).

[0262] Example 5: OD005 Synthesis Route

[0263]

[0264] Preparation process: Step 1: Synthesis of compound 2

[0265] Compound 1 (10.20 g, 98%, 53.44 mmol) was dissolved in tetrahydrofuran (300 mL). Lithium aluminum hydride (3.04 g, 32.06 mL, 80.15 mmol, 2.50 M in THF) was added under nitrogen protection at -10°C. The reaction mixture was stirred at 0°C for 1 hour, then at 25°C for 19 hours. LC-MS showed the reaction was complete. Under ice bath conditions, 3 mL of water was added dropwise, followed by 3 mL of 10% sodium hydroxide aqueous solution, and finally 9 mL of water. After stirring for 10 minutes, the mixture was filtered. The filter cake was washed with tetrahydrofuran (20 mL x 3), and the filtrate was concentrated to give compound 2 (6.90 g, yield: 81.14%).

[0266] LCMS(ESI): m / z, 141.9 [M-OH] +

[0267] Step 2: Synthesis of Compound 3

[0268] Compound 2 (1 g, 12.57 mmol) and manganese dioxide (11.26 g, 125.68 mmol) were dissolved in dichloromethane (100 mL), and the reaction mixture was stirred at 25°C for 20 hours. LC-MS showed that the reaction was complete. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane (10 mL x 3). The filtrate was concentrated to give crude compound 3 (0.92 g, yield: 90.14%).

[0269] Step 3: Synthesis of Compound 5

[0270] Compound 3 (500 mg, 3.18 mmol) was dissolved in toluene (80 mL), followed by the addition of compound 4 (800 mg, 3.18 mmol) and pyridine 4-methylbenzenesulfonic acid (816 mg, 122.39 mmol). The reaction mixture was stirred at 120°C for 16 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1, Rf = 0.7) to give compound 5 (330 mg, yield: 26.98%). LCMS (ESI): m / z, 385.1 [M+H]+

[0271] Step 4: Synthesis of Compound 6

[0272] Compound 5 (230 mg, 598.43 μmol) was dissolved in methanol (7 mL) and water (6 mL). Sulfuric acid (3.2 mL, 59.84 mmol, 95%) was slowly added dropwise at 0°C, followed by ferrous sulfate heptahydrate (168.05 mg, 598.43 μmol) and hydrogen peroxide (230 μL, 30%). The reaction mixture was stirred at 25°C for 24 hours. LC-MS indicated the reaction was complete. The reaction mixture was slowly poured into ice water (20 mL) and filtered. The filter cake was washed three times with water (20 mL), then slurried with dichloromethane / methanol (10 / 1, 10 mL) and filtered. The filter cake was washed three times with dichloromethane (10 mL). The filtrate was concentrated to give crude compound 6 (115 mg, yield: 46.38%, purity: 66%). LC-MS (ESI): m / z, 415.3 [M+H] +

[0273] Step 5: Synthesis of Compound 7

[0274] Compound 6 (360 mg, 868.79 μmol) was dissolved in dichloromethane (36 mL), and Dysmartin oxidant (1.88 g, 98%, 1.38 mL, 4.34 mmol) was added. The reaction was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. Dichloromethane (200 mL x 2) and water (100 mL) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 7 (670 mg, crude product). LCMS (ESI): m / z, 413.1 [M+H] +

[0275] Step 6: Synthesis of compound OD005

[0276] Compound 7 (630 mg, 1.53 mmol) and compound 8 (240 mg, 3.06 mmol) were dissolved in ethanol (18 mL) and pyridine (3 mL). The reaction mixture was stirred at 90°C for 2 hours. LC-MS showed that the reaction was complete. The solvent was removed under reduced pressure, and the residue was subjected to high-performance liquid chromatography to prepare two cis-trans isomers: compound OD005-P1 (7.11 mg, purity: 98.23%) and compound OD005-P2 (101.10 mg, purity: 92.08%).

[0277] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatogram was manufactured by Oriendo, model BRIX-2860(R5). The column was a Phenomenex Luna C18 250*50mm*10um. The mobile phase was water (0.225% HCOOH)-acetonitrile, with an elution ratio of 30% to 60%.

[0278] The high-performance liquid chromatography analysis method is the same as OD001-P2:

[0279] The retention time of OD005-P1 was 6.337 min, and the retention time of OD005-P2 was 6.652 min.

[0280] LCMS(ESI): m / z, 472.1 [M+H] +

[0281] OD005-P1: 1 H NMR(400MHz, DMSO-d6)δ8.37(d,J=13.1Hz,1H),8.35–8.23(m,1H),8.08(ddd,J= 18.7,11.6,8.6Hz,1H),7.34(d,J=4.6Hz,1H),7.13(d,J=22.6Hz,1H),6.57(s,1H ),5.43(s,1H),5.25(s,1H),5.16(s,1H),4.73(d,J=5.1Hz,1H),4.24–4.16(m,2H ),3.61(d,J=4.2Hz,2H),1.96(dtt,J=75.4,14.2,6.9Hz,2H),0.94–0.79(m,3H).

[0282] OD005-P2: 1H NMR(400MHz, DMSO-d6)δ9.30(s,1H),8.73(dd,J=12.5,8.6Hz,1H),8.26(dd,J=11.2,8.1Hz,1H),7.33(s,1H),6.55(s,1H),5.43 (d,J=2.1Hz,2H),5.31(s,2H),4.90(s,1H),4.43–4.33(m,2H),3.86–3.75(m,2H),1.87(p,J=6.9Hz,2H),0.88(t,J=7.3Hz,3H).

[0283] Example 6: OD006 Synthesis Route

[0284] Preparation process: Step 1: Synthesis of compound 2

[0285] Compound 1 (10 g, 48.03 mmol, 1.00 eq) and triethylamine (5.89 g, 57.64 mmol, 1.20 eq) were dissolved in dichloromethane (200 mL), and Boc anhydride (10.70 g, 48.03 mmol, 1.00 eq) was added at 0°C. The reaction mixture was stirred at 25°C under nitrogen protection for 12 hours. LC-MS showed the formation of the target product. The reaction mixture was diluted with dichloromethane (200 mL) and washed three times with water (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10:1) to obtain compound 2 (8.00 g, crude product).

[0286] LCMS(ESI):m / z,289.1 / 291.1[M-56+ACN] +

[0287] Step 2: Synthesis of Compound 4

[0288] Compound 2 (5.60 g, 18.41 mmol, 1.00 eq) and compound 3 (2.60 g, 18.41 mmol, 1.00 eq) were dissolved in 1,4-dioxane (100 mL) and water (20 mL). Sodium carbonate (3.94 g, 1.54 mL, 36.82 mmol, 2.00 eq) and Pd(dppf)Cl2 (687.33 mg, 920.57 μmol, 0.05 eq) were added. After purging the reaction solution with nitrogen three times, the mixture was stirred at 90°C for 12 hours under nitrogen protection. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered with diatomaceous earth, and the filter cake was washed with dichloromethane (3 x 50 mL). The organic phase was evaporated to dryness and then redissolved in dichloromethane (200 mL). The organic phase was washed with water (3 x 100 mL), dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10:1) to give compound 4 (2.70 g, yield: 58.36%, purity: 93%).

[0289] LCMS(ESI): m / z, 196.1 [M+H-56] +

[0290] Step 3: Synthesis of Compound 5

[0291] Compound 4 (2.70 g, 9.99 mmol, 1.00 eq) and sodium periodate (8.59 g, 39.97 mmol, 4.00 eq) were dissolved in tetrahydrofuran (40 mL) and water (10 mL). Potassium osmium tetroxide dihydrate (314.23 mg, 999.20 μmol, 0.10 eq) was added at 25°C. The reaction mixture was stirred for 2 hours under nitrogen protection at 25°C. LC-MS showed the reaction was complete. The reaction mixture was filtered directly, the tetrahydrofuran was evaporated to dryness, and then redissolved in dichloromethane (200 mL), washed three times with water (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10:1) to give compound 5 (1.80 g, yield: 66.15%, purity: 96.7%).

[0292] LCMS(ESI):m / z,195.2[M+ACN-100] +

[0293] Step 4: Synthesis of Compound 6

[0294] Compound 5 (500 mg, 1.91 mmol, 1.00 eq) was dissolved in methanol (8 mL), and oxalyl chloride (741.77 mg, 5.73 mmol, 3.00 eq) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was slowly poured into an ice-cold, saturated sodium bicarbonate solution (50 mL), and extracted three times with dichloromethane (50 mL) under ice bath protection. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness at low temperature to give compound 6 (300 mg, crude product).

[0295] LCMS(ESI): m / z, 154.2 [M+H] +

[0296] Step 5: Synthesis of Compound 8

[0297] Compound 6 (440 mg, 2.87 mmol, 1.00 eq) and compound 7 (763.91 mg, 99%, 2.87 mmol, 1.00 eq) were dissolved in toluene (10 mL), and p-toluenesulfonic acid (736.67 mg, 98%, 2.87 mmol, 1.00 eq) was added. The reaction mixture was stirred at 120°C for 12 hours under nitrogen protection. LC-MS showed the reaction was complete. The reaction mixture was evaporated to dryness, then slurried with dichloromethane (10 mL). The resulting solid was evaporated to dryness to give product 8 (500 mg, yield: 45.76%, purity: 98%).

[0298] LCMS(ESI): m / z, 381.2 [M+H] +

[0299] Step 6: Synthesis of Compound 9

[0300] Compound 8 (500 mg, 1.29 mmol, 1.00 eq) was dissolved in methanol (15 mL) and water (12.50 mL). Concentrated sulfuric acid (6.5 mL) was slowly added dropwise at 0°C, maintaining the reaction solution at 0°C. Ferrous sulfate heptahydrate (361.75 mg, 1.29 mmol, 1.00 eq) was then added. After the addition was complete, hydrogen peroxide (0.5 mL, 30%) was slowly added dropwise. The reaction solution was stirred at 0°C for 1 hour, then increased to 25°C and stirred for 11 hours. LC-MS showed the reaction was complete. The reaction solution was slowly poured into ice water (100 mL) and stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with water (10 mL x 3). The filter cake was then slurried with dichloromethane / methanol = 10 / 1 (10 mL), filtered, and the filter cake was collected and evaporated to dryness to obtain product 9 (380 mg, yield: 71.88%, purity: 95%).

[0301] LCMS(ESI): m / z, 411.2 [M+H] +

[0302] Step 7: Synthesis of Compound 10

[0303] Compound 9 (300 mg, 694.44 μmol, 1.00 eq) was dissolved in dichloromethane (15 mL), and Dysmartin oxidant (1.50 g, 3.47 mmol, 5.00 eq) was added. The reaction mixture was stirred at 25°C for 2 hours under nitrogen protection. LC-MS showed the reaction was complete. The reaction mixture was slowly poured into saturated sodium bicarbonate (200 mL), and then extracted three times with dichloromethane (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give product 10 (200 mg, crude product). LC-MS (ESI): m / z, 409.1 [M+H] +

[0304] Step 8: Synthesis of compound OD006

[0305] Compound 10 (200 mg, 489.73 μmol, 1.00 eq) and compound 11 (115.56 mg, 98%, 1.47 mmol, 3.00 eq) were dissolved in ethanol (9 mL) and pyridine (1.5 mL). The reaction mixture was stirred for 12 hours under nitrogen protection at 85°C. LC-MS showed that the reaction was complete, yielding compound OD006. The reaction mixture was directly filtered, and the filter cake was washed twice with methanol (5 mL). Compounds OD006-P1 (14.31 mg, yield: 6.25%, purity: 96.66%) and OD006-P2 (29.54 mg, yield: 12.90%, purity: 99.54%) were prepared by high-performance liquid chromatography.

[0306] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatogram was manufactured by Oriendo, model BRIX-2860. The column was a Phenomenex Luna C18 (150*25mm*10um). The mobile phase was water (0.225% FA)-acetonitrile, with an elution ratio of 20% to 50%.

[0307] The high-performance liquid chromatography analysis method is the same as OD001-P2:

[0308] The retention time of OD006-P1 was 6.568 min, and the retention time of OD006-P2 was 6.896 min.

[0309] OD006-P1:LCMS(ESI):m / z,468.2[M+H] +

[0310] 1H NMR (400MHz, DMSO-d6) δ8.40(s,1H),8.07–7.70(m,2H),7.39–7.16(m,1H),6.55(d,J=3.6Hz,1H),5.49–5.10(m,4H),4.81(dt,J=7 1.0,5.4Hz,1H),4.29(dt,J=73.5,5.1Hz,2H),3.71(dq,J=78.4,5.2Hz,2H),1.87(hept,J=7.0Hz,2H),0.87(q,J=5.9,4.5Hz,3H).

[0311] OD006-P2:LCMS(ESI):m / z,468.2[M+H] +

[0312] 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.58(d,J=8.0Hz,1H),7.92(d,J=10.7Hz,1H),7.32(s,1H),6.55(s,1H),5.43(d,J=1.9Hz,2H),5. 28(s,2H),4.90(t,J=5.4Hz,1H),4.38(dd,J=5.8,4.4Hz,2H),3.80(q,J=5.2Hz,2H),1.97–1.78(m,J=7.2Hz,2H),0.89(t,J=7.3Hz,3H).

[0313] 19 F NMR(377MHz,Pyridine-d5)δ-112.24.

[0314] Example 7: OD007 Synthesis Route

[0315]

[0316] Preparation process:

[0317] Step 1: Synthesis of Compound 2

[0318] Compound 1 (5 g, 97%, 22.04 mmol, 1.00 eq) was dissolved in dichloromethane (50 mL), and triethylamine (4.51 g, 44.08 mmol, 2.00 eq) was added. The reaction solution was cooled to 0°C, and acetyl chloride (2.10 g, 26.45 mmol, 1.20 eq) was slowly added under nitrogen protection. After the addition was complete, the reaction solution was stirred at 0°C for 1 hour under nitrogen protection. LCMS showed that the reaction was complete. The reaction solution was diluted with dichloromethane (200 mL) and washed with water (3 x 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2 (6.00 g, crude product). LCMS (ESI): m / z, 262.0 / 264.0 [M+H] +

[0319] Step 2: Synthesis of Compound 4

[0320] Compound 2 (5.50 g, 20.99 mmol, 1.00 eq) and compound 3 (2.96 g, 20.99 mmol, 1.00 eq) were dissolved in 1,4-dioxane (100 mL) and water (100 mL), followed by the addition of sodium carbonate (4.49 g, 41.97 mmol, 2.00 eq) and Pd(dppf)Cl2 (783.44 mg, 1.05 mmol, 0.05 eq). The reaction mixture was purged with nitrogen three times. Under nitrogen protection, the reaction mixture was stirred at 90°C for 12 hours. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with dichloromethane (3 x 50 mL). The organic phase was evaporated to dryness, then redissolved in dichloromethane (200 mL), washed with water (3 x 100 mL), dried, and evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10:1) to give compound 4 (3.50 g, yield: 78.12%, purity: 98%).

[0321] LCMS(ESI): m / z, 210.2 [M+H] +

[0322] Step 3: Synthesis of Compound 5

[0323] Compound 4 (3.50 g, 16.39 mmol, 1.00 eq) and sodium periodate (14.10 g, 65.58 mmol, 4.00 eq) were dissolved in tetrahydrofuran (80 mL) and water (20 mL). Potassium osmium tetroxide dihydrate (515.57 mg, 1.64 mmol, 0.10 eq) was added at 25°C. The reaction mixture was stirred for 2 hours under nitrogen protection at 25°C. LC-MS showed the reaction was complete. The reaction mixture was filtered directly, the tetrahydrofuran was evaporated to dryness, and then redissolved in dichloromethane (200 mL), washed three times with water (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10:1) to give compound 5 (2.80 g, yield: 80.87%, purity: 96%).

[0324] LCMS(ESI): m / z, 212.2 [M+H] +

[0325] Step 4: Synthesis of Compound 6

[0326] Compound 5 (1.50 g, 6.82 mmol, 1.00 eq) was dissolved in ethanol (10 mL) and hydrochloric acid (10 mL, 6 N in water). The reaction mixture was stirred at 90°C for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature and then slowly poured into an ice-cold, saturated sodium bicarbonate solution (50 mL) to adjust the pH to approximately 8. The mixture was extracted three times with dichloromethane (50 mL) under ice bath protection. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness at low temperature to give compound 6 (1.10 g, crude product). LC-MS (ESI): m / z, 170.2 [M+H] +

[0327] Step 5: Synthesis of Compound 8

[0328] Compound 6 (500 mg, 2.96 mmol, 1.00 eq) and compound 7 (85.97 mg, 2.96 mmol, 1.00 eq) were dissolved in toluene (10 mL), and p-toluenesulfonic acid (316.54 mg, 242 mmol, 2.00 eq) was added. After the addition was complete, the reaction mixture was stirred at 120°C under nitrogen protection for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated to obtain a crude product, which was then slurried with dichloromethane (10 mL). The filter cake was collected and evaporated to dryness to obtain compound 8 (700 mg, yield: 59.75%, purity: 98%).

[0329] LCMS(ESI): m / z, 397.1 [M+H] +

[0330] Step 6: Synthesis of Compound 9

[0331] Compound 8 (700 mg, 1.77 mmol, 1.00 eq) was dissolved in methanol (21 mL) and water (17.50 mL). Concentrated sulfuric acid (9.10 mL) was slowly added dropwise at 0°C, maintaining the reaction solution at 0°C, followed by the addition of ferrous sulfate heptahydrate (495.93 mg, 1.77 mmol, 1.00 eq). After the addition was complete, hydrogen peroxide (0.7 mL, 30%) was slowly added dropwise. The reaction solution was stirred at 0°C for 1 hour, then increased to 25°C and stirred for 11 hours. LC-MS showed the reaction was complete. The reaction solution was slowly poured into ice water (100 mL) and stirred for 10 minutes. The mixture was filtered, and the filter cake was washed three times with water (10 mL). The filter cake was slurried with dichloromethane / methanol = 10 / 1 (10 mL), collected, and evaporated to dryness to obtain compound 9 (500 mg, crude product).

[0332] LCMS(ESI): m / z, 427.1 [M+H] +

[0333] Step 7: Synthesis of Compound 10

[0334] Compound 9 (300 mg, 492.50 μmol, 1.00 eq) was dissolved in dichloromethane (10 mL), and Dysmartin oxidant (1.07 g, 2.46 mmol, 5.00 eq) was added. The reaction mixture was stirred for 2 hours under nitrogen protection at 25°C. LC-MS showed that the reaction was complete. The reaction mixture was slowly poured into saturated sodium bicarbonate (200 mL), and then extracted three times with dichloromethane (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 10 (300 mg, crude product). LC-MS (ESI): m / z, 425.1 [M+H] +

[0335] Step 8: Synthesis of compound OD007

[0336] Compound 10 (300 mg, 706.91 μmol, 1.00 eq) and compound 11 (166.80 mg, 98%, 2.12 mmol, 3.00 eq) were dissolved in ethanol (9 mL) and pyridine (2.25 mL). The reaction mixture was stirred at 85°C for 12 hours under nitrogen protection. LC-MS showed the reaction was complete. The reaction mixture was directly filtered, and the filter cake was washed twice with methanol (5 mL). Compounds OD007-P1 (10.15 mg, yield: 2.97%, purity: 93.19%) and OD007-P2 (156.51 mg, yield: 45.80%, purity: 95.76%) were prepared by high-performance liquid chromatography.

[0337] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatogram was manufactured by Oriendo, model BRIX-2860. The column was a Welch Xtimate C18 150*30mm*10um. The mobile phase was water (0.225% FA)-acetonitrile, with water elution ranging from 20% to 50%.

[0338] The high-performance liquid chromatography analysis method is the same as OD001.

[0339] The retention time of OD007-P1 was 6.211 min, and the retention time of OD007-P2 was 6.571 min.

[0340] OD007-P1:LCMS(ESI):m / z,484.2[M+H] +

[0341] 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.04(t,J=11.9Hz,1H),7.48(d,J=9.1Hz,1 H),7.30(d,J=3.8Hz,1H),6.53(d,J=3.6Hz,1H),5.42(s,2H),5.28(d,J=30.6Hz ,2H),4.81(dt,J=65.8,5.3Hz,1H),4.30(dt,J=65.0,5.1Hz,2H),4.08(d,J=8.6 Hz,3H),3.71(dq,J=77.2,5.2Hz,2H),1.86(p,J=7.1Hz,2H),0.91–0.79(m,3H).

[0342] OD007-P2:LCMS(ESI):m / z,484.2[M+H] +

[0343] 1 H NMR (400MHz, Pyridine-d5) δ9.32(s,1H),8.21(d,J=11.8Hz,1H),8.05(s,1H),7.95(d,J=8.9Hz,1H),5.97(d,J=16.1Hz,1H),5.63(d,J=16.1 Hz,1H),5.54(d,J=6.2Hz,2H),4.60(dd,J=5.8,4.1Hz,2H),4.25(t,J=4.9Hz,2H),3.99(s,3H),2.16(q,J=7.3Hz,2H),1.19(t,J=7.3Hz,3H).

[0344] 19F NMR(377MHz,Pyridine-d5)δ-126.91.

[0345] Example 8: OD008 Synthesis Route

[0346]

[0347] Preparation process:

[0348] Step 1: Synthesis of Compound 2

[0349] Compound 1 (1 g, 2.55 mmol, 1.00 eq) was dissolved in methanol (30 mL) and water (25 mL). Concentrated sulfuric acid (8.30 mL) was slowly added dropwise at 0°C, maintaining the reaction solution at 0°C. Ferrous sulfate heptahydrate (715.70 mg, 2.55 mmol, 1.00 eq) was then added. After the addition was complete, hydrogen peroxide (30%, 1 mL) was slowly added dropwise. The reaction solution was stirred at 0°C for 1 hour, then increased to 25°C and stirred for 11 hours. LC-MS showed the reaction was complete. The reaction solution was slowly poured into ice water (100 mL), stirred for 10 minutes, filtered, and the filter cake was washed three times with water (50 mL), filtered again, and the filter cake was slurried with dichloromethane / methanol = 10 / 1 (30 mL) to obtain compound 2 (700 mg, crude product).

[0350] LCMS(ESI): m / z, 423.2 [M+H] +

[0351] Step 2: Synthesis of Compound 3

[0352] Compound 2 (300 mg, 55%, 390.63 μmol, 1.00 eq) was dissolved in dichloromethane (15 mL), and Dysmartin oxidant (760.79 mg, 98%, 1.76 mmol, 4.50 eq) was added. The reaction mixture was stirred at 25°C for 4 hours under nitrogen protection. LC-MS showed the reaction was complete. The reaction mixture was slowly poured into saturated sodium bicarbonate (250 mL), and then extracted three times with dichloromethane (250 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 3 (300 mg, crude product).

[0353] LCMS(ESI): m / z, 421.1 [M+H] +

[0354] Step 3: Synthesis of compound OD008

[0355] Compound 3 (230 mg, 547.12 μmol, 1.00 eq) and compound 4 (129.10 mg, 1.64 mmol, 3.00 eq) were dissolved in ethanol (9 mL) and pyridine (1.5 mL). The reaction mixture was stirred for 12 hours under nitrogen protection at 90 °C. LC-MS showed that the reaction was complete, yielding compound OD008. The reaction mixture was directly filtered, and the filter cake was washed twice with methanol (5 mL). Compounds OD008-P1 (1.90 mg, yield: 0.72%, purity: 91.71%) and OD008-P2 (11.29 mg, yield: 4.30%, purity: 95.97%) were prepared by high-performance liquid chromatography.

[0356] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: OD008-P2 preparative chromatogram manufacturer: Oriendo, model BRIX-2860. The chromatographic column is a Welch Xtimate C18 150*30mm*10um. The mobile phase is water (0.1% TFA)-acetonitrile, with an elution ratio of 20% to 50%.

[0357] The high performance liquid chromatography analysis method is the same as OD001. The retention time of OD008-P1 is 5.702 min, and the retention time of OD008-P2 is 6.032 min.

[0358] OD008-P1:LCMS(ESI):m / z,480.1[M+H] +

[0359] 1 H NMR(400MHz,DMSO-d6)δ9.32+8.31(s,1H),8.04+7.40(s,1H),7.60–7.47(m, 1H),7.31–7.19(m,1H),6.56–6.44(m,1H),6.30(d,J=15.0Hz,2H),5.42(s,2H ),5.32–5.16(m,2H),4.80(dt,J=70.7,5.3Hz,1H),4.27(dt,J=66.7,5.1Hz, 2H),3.86–3.55(m,2H),1.86(hept,J=7.0,6.6Hz,2H),0.88(t,J=7.3Hz,3H).

[0360] OD008-P2:LCMS(ESI):m / z,480.1[M+H] +

[0361] 1H NMR (400MHz, DMSO-d6) δ9.20(s,1H),7.97(s,1H),7.51(s,1H),7.23(s,1H),6.51(s,1H),6.31(d,J=2.0Hz,2H),5.41(s,2H),5.1 9(s,2H),4.89(t,J=5.4Hz,1H),4.35(t,J=5.1Hz,2H),3.80(q,J=5.2Hz,2H),1.96–1.78(m,J=7.2Hz,2H),0.89(t,J=7.3Hz,3H).

[0362] Example 9: OD009 Synthesis Route

[0363]

[0364] Preparation process: Step 1: Synthesis of compound 2

[0365] Compound 1 (3 g, 13.06 mmol) and triethylamine (6.67 g, 65.29 mmol) were dissolved in tetrahydrofuran (30 mL). Isopropyl chloroformate (6.53 g, 52.23 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 3 hours. TLC showed that the starting material disappeared and a new spot with low polarity was formed. Then, lithium borohydride (1.20 g, 52.23 mmol) was added at 0 °C, and the reaction mixture was stirred at 0-25 °C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was quenched by adding water (30 mL) at 0 °C, and then extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether 1:3 to 1:1) to give compound 2 (2.60 g, yield: 94.29%). LCMS(ESI): m / z, 234.0 [M+Na] +

[0366] Step 2: Synthesis of Compound 3

[0367] Compound 2 (2.6 g, 12.31 mmol) and manganese dioxide (5.82 g, 61.56 mmol) were dissolved in dichloromethane (60 mL), and the reaction mixture was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with DCM (30 mL), and the organic phase was concentrated to give crude compound 3 (2.56 g, yield: 99.41%). LCMS (ESI): m / z, 210.1 [M+H] +

[0368] Step 3: Synthesis of Compound 4

[0369] Compound 3 (2.56 g, 12.24 mmol) was dissolved in ethanol (100 mL) / water (50 mL), and iron powder (3.43 g, 61.20 mmol) and ammonium chloride (6.68 g, 122.39 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with EtOH (30 mL). The filtrate was concentrated, and the residue was pulped (dichloromethane, total volume 20 mL). The filtrate was concentrated to give compound 4 (2 g, yield: 91.20%).

[0370] LCMS(ESI): m / z, 180.2 [M+H] +

[0371] Step 4: Synthesis of Compound 6

[0372] Compound 4 (1 g, 5.58 mmol) was dissolved in toluene (40 mL), and compound 5 (1.48 g, 5.58 mmol) and p-toluenesulfonic acid (970 mg, 5.58 mmol) were added. The reaction mixture was stirred at 120°C for 16 hours. LC-MS showed that the reaction was complete. The 40 mL toluene reaction mixture was directly evaporated to dryness, and the residue was slurried (dichloromethane / methanol 10:1, total volume 10 mL), filtered, and the filter cake was washed with dichloromethane / methanol (V:V = 10:1, total volume 20 mL). The residual solvent in the filter cake was evaporated to dryness to give compound 6 (1 g, yield: 44.09%). LC-MS (ESI): m / z, 407.1 [M+H] +

[0373] Step 5: Synthesis of Compound 7

[0374] Compound 6 (1 g, 2.46 mmol) was dissolved in methanol (150 mL) / water (125 mL). Sulfuric acid (13 mL, 18.4 M), ferrous sulfate heptahydrate (381 mg, 2.46 mmol), and hydrogen peroxide (5 mL, 30%) were slowly added dropwise at 0°C. The reaction mixture was stirred at 25°C for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was poured into water (20 mL) at 0°C, filtered, and the filter cake was slurried with methanol (10 mL), filtered again, washed with methanol (5 mL), and the residual solvent in the filter cake was evaporated to obtain crude compound 7 (1 g, yield: 93.12%, purity: 50%).

[0375] LCMS(ESI): m / z, 437.1 [M+H] +

[0376] Step 6: Synthesis of Compound 8

[0377] Compound 7 (500 mg, 1.15 mmol) was dissolved in dichloromethane (20 mL), and Dys-Martin oxidant (2.48 g, 5.73 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. LC-MS showed that the reaction was complete. Dichloromethane (20 mL x 3) and water (20 mL) were added to the reaction mixture for washing. The organic phase was dried, filtered, and evaporated to dryness to give crude compound 8 (500 mg, yield: 100.47%).

[0378] LCMS(ESI): m / z, 435.3 [M+H] +

[0379] Step 7: Synthesis of compound OD009

[0380] Compound 8 (500 mg, 1.15 mmol) and compound 9 (177 mg, 2.30 mmol) were dissolved in ethanol (28 mL) and pyridine (2.8 mL), and the reaction mixture was stirred at 90°C for 5 hours. LC-MS showed that the reaction was complete, yielding compound OD009. The reaction mixture was directly evaporated to dryness, and the residue was purified by high-performance liquid chromatography to give the cis-trans isomers OD009-P1 (30 mg, purity: 91.5%) and OD009-P2 (130 mg, purity: 96.26%).

[0381] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatograph is manufactured by Oriendo, model BRIX-2860(R5). The chromatographic column is a Phenomenex Luna C18 250*50mm*10um. The mobile phase is water (0.225% HCOOH)-acetonitrile, with water elution ratios ranging from 45% to 85%.

[0382] The high performance liquid chromatography analysis method is the same as OD001: the retention time of OD009-P1 is 5.778 min, and the retention time of OD009-P2 is 6.086 min.

[0383] LCMS(ESI): m / z, 494.2 [M+H] +

[0384] OD009-P1: 1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.01(s,1H),7.68–7.52(m,1H),7.27(d,J=4.0Hz,1H),6.49(s,1H),5.41(s,2H),5.2 0(d,J=14.5Hz,2H),4.43(s,4H),4.39–4.30(m,2H),3.80(d,J=5.2Hz,2H),1.96–1.77(m,2H),0.89(td,J=7.4,3.2Hz,3H).

[0385] OD009-P2: 1 H NMR (400MHz, DMSO-d6) δ9.15(s,1H),7.95(s,1H),7.55(s,1H),7.25(s,1H),6.49(s,1H),5.41(s,2H),5.15(d,J=1.9Hz, 2H), 4.45 (s, 4H), 4.35 (dd, J=5.8, 4.4Hz, 2H), 3.80 (t, J=5.1Hz, 2H), 2.01–1.73 (m, J=7.3Hz, 2H), 0.90 (t, J=7.3Hz, 3H).

[0386] Example 10: Synthesis route of OD010

[0387]

[0388] Preparation process:

[0389] Step 1: Synthesis of Compound 2

[0390] Compound 1 (10 g, 52.25 mmol) was dissolved in methanol (300 mL) and tetrahydrofuran (200 mL). Palladium on carbon (5 g, 46.98 mmol, 10%) was added, and the reaction mixture was purged with hydrogen three times. The reaction solution was stirred at 25°C for 16 hours (hydrogen atmosphere). LCMS showed that the reaction was complete. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with methanol (100 mL). The filtrate was evaporated to dryness to give compound 2 (8 g, yield: 94.52%). LCMS (ESI): m / z, 166.2 [M+H] +

[0391] Step 2: Synthesis of Compound 4

[0392] Compound 2 (4.50 g, 27.25 mmol) was dissolved in toluene (45 mL), followed by the addition of compound 3 (7.17 g, 27.25 mmol) and pyridine 4-methylbenzenesulfonic acid (6.99 g, 27.25 mmol). The reaction mixture was stirred at 120 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was evaporated to dryness and then slurried (dichloromethane / methanol 10:1, total volume 20 mL). The mixture was filtered, and the filter cake was washed with (dichloromethane / methanol 10:1, total volume 5 mL). The residual solvent in the filter cake was evaporated to dryness, yielding compound 4 (6.68 g, yield: 62.53%).

[0393] LCMS(ESI): m / z, 393.2 [M+H] +

[0394] Step 3: Synthesis of Compound 5

[0395] Compound 4 (6.68 g, 17.04 mmol) was dissolved in acetic anhydride (480 mL) and pyridine (320 mL), and the reaction mixture was stirred at 25°C for 48 hours. LC-MS showed that the reaction was complete. The reaction mixture was evaporated to dryness and then slurried (ethyl acetate / dichloromethane 1:1, total volume 50 mL), filtered, and the filter cake was washed with (ethyl acetate / dichloromethane 1:1, total volume 10 mL). The residual solvent in the filter cake was evaporated to dryness, giving compound 5 (6.80 g, yield: 91.88%). LC-MS (ESI): m / z, 435.2 [M+H] +

[0396] Step 4: Synthesis of Compound 6

[0397] Compound 5 (6.80 g, 15.65 mmol) and m-chloroperoxybenzoic acid (9.53 g, 46.96 mmol) were dissolved in dichloromethane (280 mL), and the reaction mixture was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. Sodium thiosulfate solution (10%) was slowly added to the reaction mixture at 0°C until starch-potassium iodide paper no longer turned blue. After stirring at 0°C for 30 minutes, water (200 mL) was added, and the mixture was extracted with dichloromethane (200 mL x 3). The organic phase was dried, filtered, concentrated, and the resulting residue was pulped (dichloromethane, total amount 50 mL) and filtered. The filter cake was washed with (dichloromethane, total amount 10 mL), and the residual solvent in the filter cake was evaporated to give compound 6 (10.40 g, yield: 147.51%).

[0398] LCMS(ESI): m / z, 451.1 [M+H] +

[0399] Step 5: Synthesis of Compound 7

[0400] Compound 6 (6.5 g, 14.43 mmol) was dissolved in N,N-dimethylformamide (200 mL), and oxaloyl bromide (4.77 g, 21.65 mmol) was slowly added dropwise at 0°C. The reaction mixture was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. Water (50 mL) was added to the reaction mixture at 0°C, and the mixture was extracted with dichloromethane (100 mL x 3). The organic phase was dried, filtered, concentrated, and the residue was purified by silica gel chromatography (eluent: dichloromethane / methanol 20:1 to 5:1) to give compound 7 (5 g, yield: 67.50%). LCMS (ESI): m / z, 512.9 [M+H] +

[0401] Step 6: Synthesis of Compound 8

[0402] Compound 7 (4.5 g, 8.77 mmol) and sodium methoxide (4.74 g, 26.30 mmol) were dissolved in methanol (135 mL), and the reaction mixture was stirred at 35°C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was adjusted to pH 1-2 with hydrochloric acid (1 M), filtered, and the filter cake was slurried with methanol (30 mL). After filtration, the filter cake was washed with methanol (5 mL), and the residual solvent in the filter cake was evaporated to obtain compound 8 (2.50 g, yield: 60.51%). LC-MS (ESI): m / z, 472.9 [M+H] +

[0403] Step 7: Synthesis of Compound 10

[0404] Compound 8 (600 mg, 1.27 mmol) was dissolved in 1,4-dioxane (36 mL), and compound 9 (311.18 mg, 1.27 mmol), palladium acetate (58.34 mg, 254.64 μmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (300.69 mg, 509.27 μmol), and potassium phosphate (827.32 mg, 3.82 mmol) were added. The mixture was purged with nitrogen three times, and the reaction solution was stirred at 100 °C for 16 hours (under nitrogen atmosphere). LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was evaporated to dryness, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1 to 5:1) to give compound 10 (100 mg, yield: 12.37%).

[0405] LCMS(ESI): m / z, 635.3 [M+H] +

[0406] Step 8: Synthesis of compound OD010

[0407] Compound 10 (100 mg, 157.54 μmol) was dissolved in tetrahydrofuran (1 mL), and triethylamine hydrofluoric acid salt (26.18 mg, 157.54 μmol) was added. The reaction mixture was stirred at 25°C for 4 hours. LCMS showed that the reaction was complete. The reaction mixture was then subjected to high performance liquid chromatography to prepare compound OD010 (4.27 mg, yield: 5.21%, purity: 97.51%).

[0408] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatogram manufacturer is Shimadzu, model LC-20AP. The chromatographic column is a YMC-Triart Prep C18 250*50mm*7um. The mobile phase is water (0.225% HCOOH)-acetonitrile, with water elution ratios ranging from 10% to 40%.

[0409] LCMS(ESI): m / z, 521.2 [M+H] +

[0410] 1 H NMR (400MHz, DMSO-d6) δ7.70(d,J=4.3Hz,2H),7.29(s,1H),7.14(p,J=4.7Hz,1H),5.44(s,2H),5.28(s,2H),4.21(t,J=4.9Hz,2H), 3.90(t,J=4.9Hz,2H), 3.42(ddd,J=10.6,7.7,4.4Hz,2H), 1.96–1.79(m,J=7.2Hz,2H), 1.33(t,J=7.3Hz,3H), 0.88(t,J=7.3Hz,3H).

[0411] Example 11: Synthesis method of LOD series

[0412] LOD001 Synthesis Route

[0413] Preparation process: Step 1: Synthesis of compound 1

[0414] Compound OD001 (1 g, 2.30 mmol), compound 3 (863.26 mg, 2.30 mmol), and p-toluenesulfonic acid (399.46 mg, 2.30 mmol) were dissolved in tetrahydrofuran (40 mL). The reaction mixture was stirred at 35°C for 2 hours. The reaction was confirmed by LC-MS. The reaction mixture was purified by silica gel column chromatography (C18) (ISCO, R-330 g SepaFlash Silica Flash Column, Eluent of 5-30% water / CH3CN @ 100 mL / min) to give compound 1 (740 mg, yield: 43.32%).

[0415] LCMS(ESI): m / z, 744.4 [M+H]+

[0416] Step 2: Synthesis of Compound 2

[0417] Compound 1 (500 mg, 672.25 μmol) was dissolved in 50 mL of N,N-dimethylformamide. Ammonia solution (1.08 mL, 3.36 mmol, 3.10 M in THF) was slowly added dropwise at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction was confirmed to be complete by LC-MS. The reaction mixture was evaporated to dryness at low temperature to give crude compound 2 (350 mg, yield: 99.83%). LC-MS (ESI): m / z, 522.2 [M+H] +

[0418] Step 3: Synthesis of compound LOD001

[0419] Compound 2 (350 mg, 671.10 μmol), compound 4 (330.30 mg, 671.10 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (312.47 mg, 805.32 μmol), and N,N-diisopropylethylamine (173.47 mg, 1.34 mmol) were dissolved in N,N-dimethylformamide (50 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction was confirmed by LCMS. The reaction mixture was then subjected to high-performance liquid chromatography (HPLC) to obtain compound LOD001 (92 mg, yield: 13.71%).

[0420] The preparative conditions for high-performance liquid chromatography (HPLC) were as follows: The preparative chromatograph was manufactured by Oriendo, model BRIX-2860 (R1, 4, 5, 6). The column was a Phenomenex Luna C18 250*50mm*10um. The mobile phase was water (0.225% HCOOH)-acetonitrile, with water elution ranging from 45% to 85%.

[0421] LCMS(ESI): m / z, 976.2 [M+H] +

[0422] 1H NMR(400MHz,DMSO-d6)δ9.35(d,J=15.0Hz,1H),8.62(d,J=8.5Hz,1H),8.53(t,J=6.7Hz,1H),8.23–8.15(m,4H),8.07(d,J=6.2Hz,1H),7.94(t,J=7.8Hz,1H),7.78(t,J=7.4Hz,1H),7.35(d,J=15.5Hz,1H),7.22(d,J=18.5Hz,5H),6.56(d,J=6.3Hz,1H),6.51(d,J=5.5Hz,1H),5.33(d,J=13.8Hz,2H),4.62(d,J=6.9Hz,2H),4.48(d,J=11.0Hz,2H),4.05–3.96(m,1H),3.83–3.57(m,9H),3.11(d,J=6.2Hz,1H),2.86–2.80(m,1H),2.20–2.13(m,2H),1.85(dd,J=14.0,7.0Hz,2H),1.53(t,J=7.6Hz,4H),1.37–1.17(m,4H),0.93–0.81(m,5H).

[0423] 1 H NMR(400MHz,Pyridine-d5)

[0424] 1H NMR (400MHz, Pyridine-d5) δ9.55(t,J=5.6Hz,1H),9.45–9.28(m,2H),9.23(q,J=6.7,5.4Hz,2H),9.13(d,J=7.1Hz,1H),8.54–8.40(m,2H),8.12 (d,J=2.1Hz,1H),7.90–7.80(m,1H),7.68(dt,J=25.5,7.7Hz,1H),7.39(t,J=7.3Hz,2H),7.27(d,J=7.4Hz,5H),6.79(s,1H),5.94(dd,J=16.2,2 .7Hz,1H),5.77–5.47(m,3H),5.14(d,J=6.8Hz,3H),4.58–4.40(m,3H), 4.35–4.20(m,4H),4.22–4.01(m,3H),3.60(dd,J=13.8,5.7Hz,1H),3.45 (td,J=7.1,2.7Hz,2H),3.42–3.31(m,1H),2.38–2.26(m,2H),2.25–2.04 (m,2H),1.71(p,J=7.5Hz,2H),1.51(q,J=7.8Hz,2H),1.34–1.12(m,5H).

[0425] Example 12: Synthesis route of LOD002

[0426]

[0427] Preparation process: Step 1: Synthesis of compound 3

[0428] Compound 1 (5 g, 28.79 mmol, 1.00 eq), N,N-diisopropylethylamine (9.40 g, 12.02 mL, 2.50 eq), and compound 2 (5.93 g, 28.79 mmol, 1.00 eq) were dissolved in N,N-dimethylformamide (100 mL). The reaction solution was cooled to 0°C, and HATU (16.93 g, 43.19 mmol, 1.50 eq) was slowly added. After the addition was complete, the reaction solution was stirred at 25°C for 2 hours under nitrogen protection. LC-MS showed that the reaction was complete. The reaction solution was diluted with ethyl acetate (250 mL) and washed with water (3 x 250 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1 to 1:1) to obtain the compound product (6.00 g, crude product). LCMS(ESI): m / z, 312.2 [M+H] +

[0429] Step 2: Synthesis of Compound 4

[0430] Compound 3 (5.56 g, 90%, 16.06 mmol, 1.00 eq) was dissolved in tetrahydrofuran (60 mL). Lithium hydroxide monohydrate (40 mL, 2 M in H2O) was added to the reaction solution at 0°C. The reaction solution was stirred for 12 hours under nitrogen protection at 25°C. LC-MS showed the reaction was complete. The reaction solution was cooled to 0°C, and the pH was adjusted to 3 with hydrochloric acid (1 M in H2O), at which point a solid precipitated. The mixture was filtered, the filter cake was washed with water (3 x 10 mL), collected, and evaporated to dryness to give compound 4 (3.10 g, crude product). LC-MS (ESI): m / z, 284.2 [M+H] +

[0431] Step 3: Synthesis of Compound 5

[0432] Compound 4 (3.10 g, 10.94 mmol, 1.00 eq) and N-hydroxysuccinimide (2.57 g, 21.88 mmol, 2.00 eq) were dissolved in N,N-dimethylformamide (50 mL). The reaction solution was cooled to 0°C, and N,N'-diisopropylcarbodiimide (2.82 g, 21.88 mmol, 2.00 eq) was added. The reaction solution was stirred at 25°C under nitrogen protection for 12 hours. LCMS showed that the reaction was complete. The reaction solution was diluted with ethyl acetate (200 mL) and washed with water (3 x 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 5 (4.80 g, crude product). LCMS (ESI): m / z, 381.2 [M+H] +

[0433] Step 4: Synthesis of Compound 6

[0434] Compound 5 (4.80 g, 12.62 mmol, 1.00 eq) was dissolved in water (40 mL) and tetrahydrofuran (40 mL), and potassium peroxide monosulfonate (21.87 g, 97%, 126.18 mmol, 10.00 eq) was added. The reaction mixture was stirred for 12 hours under nitrogen protection at 25°C. LC-MS showed that the reaction was complete. The tetrahydrofuran in the reaction mixture was evaporated to dryness, and the crude product was dissolved in water (250 mL) and extracted with dichloromethane (3 x 250 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude reaction solution was purified by silica gel column chromatography (C18) (ISCO, Welch Ultimate C18 250*30mm*10um, eluent of 0-40% water / CH3CN@40mL / min) to give compound 6 (2.20 g, yield: 42.28%, purity: 95%). LCMS (ESI): m / z, 413.2 [M+H] +

[0435] Step 5: Synthesis of Compound 8

[0436] Compound 6 (526.32 mg, 1.21 mmol, 1.00 eq) and compound 7 (345.51 mg, 1.21 mmol, 1.00 eq) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (316.54 mg, 2.42 mmol, 2.00 eq) was added. After the addition was complete, the reaction mixture was stirred at 25°C under nitrogen protection for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was purified by silica gel column chromatography (C18) (ISCO, R-220 g SepaFlash Silica Flash Column, Eluent of 5-25% water / CH3CN @ 80 mL / min) to give compound 8 (310 mg, yield: 44.34%, purity: 70%).

[0437] LCMS(ESI): m / z, 577.2 [M+H] +

[0438] Step 6: Synthesis of compound LOD002

[0439] Compound 8 (35 mg, 60.70 μmol, 1.00 eq) and compound 9 (compound 2 from Example 11, 31.66 mg, 60.70 μmol, 1.00 eq) were dissolved in N,N-dimethylformamide (2 mL). The reaction solution was cooled to 0°C, and N,N-diisopropylethylamine (15.85 mg, 121.40 μmol, 2.00 eq) and HATU (28.55 mg, 72.84 μmol, 1.20 eq) were added. The reaction solution was stirred at 25°C under nitrogen protection for 1 hour. LCMS showed that the reaction was complete. Compound LOD002 trifluoroacetate (20.54 mg, yield: 28.05%, purity: 99%) was prepared by high-performance liquid chromatography.

[0440] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatogram was manufactured by Oriendo, model BRIX-2860. The column was a YMC-Triart Prep C18 150*30mm*10um. The mobile phase was water (0.225% TFA)-acetonitrile, with an elution ratio of 20% to 50%.

[0441] LCMS(ESI): m / z, 1102.4 [M+Na] +

[0442] 1 H NMR(400MHz, DMSO-d6)δ9.45–9.38(m,2H),9.01(dd,J=6.6,4.5Hz,1H),8.81–8.60(m,2H),8.37(td,J=5.9,2.9Hz,1H),8.30(t,J=7.9Hz,1H),8.21–8 .10(m,2H),8.13–7.93(m,2H),7.84(q,J=7.0Hz,1H),7.45(d,J=14.2Hz,1 H),7.34–7.17(m,5H),6.60(s,1H),5.49–5.30(m,4H),4.71(dd,J=9.1,6.7 Hz,2H),4.54(h,J=4.3Hz,2H),4.37–4.30(m,1H),3.90–3.53(m,9H),3.50 (s,3H),3.34(q,J=6.6Hz,2H),3.10(dt,J=13.9,3.4Hz,1H),2.84(ddd,J=1 4.5,9.6,5.2Hz,1H),2.20(t,J=7.4Hz,2H),2.01–1.85(m,2H),1.58(dq,J =14.5,7.3,6.1Hz,4H),1.37(p,J=7.8Hz,2H),0.95(td,J=7.4,1.8Hz,3H).

[0443] 19 F NMR(377MHz,DMSO-d6)δ-74.15.

[0444] Example 13: Synthesis route of LOD003

[0445] Preparation process:

[0446] Step 1: Synthesis of Compound 2

[0447] OD002 (1.40 g, 2.84 mmol, 1 eq) was dissolved in dichloromethane (70 mL), compound 6 (1.07 g, 2.84 mmol, 1.0 eq) was added, followed by trifluoroacetic acid (1.4 mL, 18.85 mmol, 6.64 eq). The reaction mixture was stirred at 35°C for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was evaporated to dryness, and the residue was subjected to high-performance liquid chromatography (HPLC) (Shimadzu LC-20AP preparative chromatograph; YMC-Triart Prep C18 250*50 mm*7 μm column; mobile phase: water (0.225% HCOOH)-acetonitrile; elution ratio of water from 30% to 60%) to prepare compound 2 (560 mg, yield: 24.62%).

[0448] LCMS(ESI): m / z, 802.2. [M+H] +

[0449] Step 2: Synthesis of Compound 3

[0450] Compound 2 (430 mg, 536.27 μmol, 1 eq) was dissolved in N,N dimethylformamide (5 mL), and ethylenediamine (558.02 μL, 5.36 mmol, 10 eq) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was then evaporated to dryness to give compound 3 (310 mg, crude).

[0451] LCMS(ESI): m / z, 580.2. [M+H] +

[0452] Step 3: Synthesis of Compound 5

[0453] Compound 3 (310 mg, 534.86 μmol, 1 eq) was dissolved in N,N-dimethylformamide (3 mL), and compound 4 (273.73 mg, 98%, 534.86 μmol, 1 eq) and N,N-diisopropylethylamine (178.58 μL, 1.07 mmol, 2 eq) were added. HATU (244.05 mg, 641.83 μmol, 1.2 eq) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was prepared by high-performance liquid chromatography (Shimadzu LC-20AP, YMC-Triart PrepC18 250*50 mm*7 μm column, mobile phase water (0.225% HCOOH)-acetonitrile, elution ratio of water from 30% to 60%) to obtain compound 5 (340 mg, yield: 59.79%).

[0454] LCMS(ESI): m / z, 1063.3. [M+H] +

[0455] Step 4: Synthesis of Compound 6

[0456] Compound 5 (110 mg, 103.47 μmol, 1 eq) was dissolved in N,N dimethylformamide (2 mL), followed by the addition of ethylenediamine (106.59 μL, 1.03 mmol, 10 eq). The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was then evaporated to dryness to give compound 6 (87 mg, crude product). LC-MS (ESI): m / z, 841.3. [M+H] +

[0457] Step 5: Synthesis of compound LOD003

[0458] Compound 6 (87 mg, 103.46 μmol, 1 eq) was dissolved in NN dimethylformamide (2 mL), followed by compound 7 (36.84 mg, 103.46 μmol, 1 eq) and NN diisopropylpropylamine (27.01 mg, 206.93 μmol, 2 eq). HATU (47.21 mg, 124.16 μmol, 1.2 eq) was added at 0°C. The reaction mixture was stirred at 25°C for 1 hour. LC-MS showed the reaction was complete. The reaction solution was prepared by high-performance liquid chromatography (HPLC) (Shimadzu LC-20AP chromatograph, YMC-Triart PrepC18 250*50mm*7um column; mobile phase: water (0.225% HCOOH)-acetonitrile, elution ratio of water from 30% to 60%), yielding compound LOD003 (48.90 mg, yield: 40.46%, purity: 95%).

[0459] LCMS(ESI): m / z, 1168.5. [M+H] +

[0460] 1 H NMR(400MHz, DMSO-d6)δ8.60(t,J=6.7Hz,1H),8.31(t,J=5.8Hz,1H),8.21–8. 09(m,2H),8.01(t,J=5.7Hz,1H),7.87–7.79(m,1H),7.33(d,J=1.0Hz,1H),7.2 7–7.19(m,1H),7.23–7.11(m,3H),7.02(s,2H),6.54(s,1H),5.43(s,2H),5.3 2(s,1H),4.67(d,J=6.6Hz,2H),4.46(q,J=7.7,6.1Hz,3H),3.83(dd,J=5.7,3. 8Hz,2H),3.80–3.65(m,5H),3.58(d,J=6.3Hz,2H),3.56(d,J=1.8Hz,1H),3.5 6–3.45(m,4H),3.50–3.39(m,11H),3.31(s,1H),3.21(d,J=7.0Hz,2H),3.11(t ,J=7.0Hz,2H),3.01(dd,J=13.8,4.4Hz,1H),2.76(dd,J=13.8,9.7Hz,1H),2. 42–2.33(m,5H),2.16(s,3H),1.87(hept,J=7.1Hz,2H),0.88(t,J=7.3Hz,3H).

[0461] Example 14: Synthesis route of LOD004

[0462]

[0463] Preparation process: Step 1: Synthesis of compound 2

[0464] Compound 1 (1.02 g, 5.88 mmol) was dissolved in dichloromethane (50 mL), and N-hydroxysuccinimide (828.05 mg, 7.05 mmol) and N,N'-dicyclohexylcarbodiimide (2.45 g, 11.75 mmol) were added. The reaction mixture was stirred at 25°C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was washed with water (200 mL). The organic phase was dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.4) to give compound 2 (1.55 g, Crude, yield: 98.70%).

[0465] LCMS(ESI): m / z, 268.1 [M+H] +

[0466] Step 2: Synthesis of Compound 4

[0467] Compound 2 (1.16 g, 4.35 mmol) and compound 3 (1.21 g, 4.35 mmol) were dissolved in N,N-dimethylformamide (50 mL). N,N-diisopropylethylamine (1.14 g, 99%, 1.45 mL, 8.70 mmol) was added at 0°C, and the reaction mixture was stirred at 25°C for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was filtered, and the filtrate was purified by high-performance liquid chromatography to give compound 4 (1.25 g, yield: 63.33%, purity: 92%).

[0468] LCMS(ESI): m / z, 418.2[M+H]+

[0469] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatograph is manufactured by Oriendo, model BRIX-2860(R5). The chromatographic column is a Phenomenex Luna C18 250*50mm*10um. The mobile phase is water (0.225% CF3COOH)-acetonitrile, with an elution ratio of water ranging from 5% to 25%.

[0470] Step 3: Synthesis of Compound 5

[0471] Compound 4 (673.91 mg, 92%, 1.49 mmol) was dissolved in water (15 mL) and tetrahydrofuran (15 mL), and Oxone (10.19 g, 98%, 59.40 mmol) was added. The reaction mixture was stirred at 35°C for 24 hours. LC-MS showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated to remove tetrahydrofuran. The mixture was extracted with water (30 mL) and dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, combined, and concentrated to give compound 5 (180 mg, yield: 26.97%).

[0472] LCMS(ESI): m / z, 450.1 [M+H]+

[0473] Step 4: Synthesis of compound LOD004

[0474] Compound 5 (41.69 mg, 92.76 μmol) and N,N-diisopropylethylamine (20.18 mg, 154.60 μmol) were dissolved in N,N-dimethylformamide (30 mL). Compound 6 (same as Compound 6 in Example 13, 65 mg, 77.30 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (35.99 mg, 92.76 μmol) were added at 0°C and stirred at 25°C for 1 hour. LCMS showed that the reaction was complete. The reaction solution was prepared by reversed-phase high-performance liquid chromatography to obtain compound LOD004 (22.25 mg, yield: 22.62%, purity: 99.2%).

[0475] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatograph is manufactured by Oriendo, model BRIX-2860(R5). The chromatographic column is a Phenomenex Luna C18 250*50mm*10um. The mobile phase is water (0.225% CF3COOH)-acetonitrile, with an elution ratio of 30% to 60%.

[0476] LCMS(ESI): m / z, 1294.2 [M+Na] +

[0477] 1 H NMR (400MHz, DMSO-d6) δ9.35(s,2H),9.11(t,J=5.4Hz,1H),8.58(t,J=6.6Hz,1H),8.29(t,J=5.7Hz ,1H),8.19–8.05(m,2H),8.00(t,J=5.7Hz,1H),7.78(dd,J=10.2,6.2Hz,1H),7.32(s,1H),7.27–7.1 0(m,5H),6.53(s,1H),5.42(s,2H),5.28(s,2H),4.67(d,J=6.6Hz,2H),4.46(s,3H),3.88–3.63(m,7 H),3.62–3.48(m,9H),3.48–3.39(m,13H),3.24–3.05(m,5H),3.01(dd,J=13.7,4.3Hz,1H),2.76(dd J=138 98Hz 1H)237(s 5H)187(dp J=141 70Hz 2H)088(t J=73Hz 3H)

[0478] Example 15: Synthesis route of LOD005

[0479] Preparation process: Step 1: Synthesis of compound 2

[0480] OD008 (300 mg, 625.72 μmol, 1 eq) was dissolved in dichloromethane (15 mL), compound 1 (235.21 mg, 625.72 μmol, 1 eq) was added, followed by trifluoroacetic acid (200 μL, 2.69 mmol, 4.30 eq). The reaction mixture was stirred at 35°C for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was then evaporated to dryness, and the residue was subjected to high-performance liquid chromatography (HPLC) (preparative chromatograph manufacturer: Oriendo, model R-120g; column: Lab311-ISCO-R4; mobile phase: water (0.225% HCOOH)-acetonitrile; elution ratio: water from 5% to 55%) to prepare compound 2 (145 mg, yield: 29.42%).

[0481] LCMS(ESI): m / z, 788.2. [M+H] +

[0482] Step 2: Synthesis of Compound 3

[0483] Compound 10 (225 mg, 285.61 μmol, 1 eq) was dissolved in N,N dimethylformamide (5 mL), and diethylamine (294.22 μL, 2.86 mmol, 10 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was directly evaporated to dryness to give crude compound 3 (161 mg, crude product), which was used directly in the next step. LCMS (ESI): m / z, 566.2. [M+H] +

[0484] Step 3: Synthesis of Compound 5

[0485] Compound 3 (161 mg, 284.68 μmol, 1 eq) was dissolved in N,N-dimethylformamide (5 mL), and compound 4 (145.69 mg, 284.68 μmol, 1 eq), N,N-diisopropylethylamine (94.10 μL, 569.37 μmol, 2 eq) and HATU (132.55 mg, 341.62 μmol, 1.2 eq) were added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was prepared by high-performance liquid chromatography (preparative chromatograph manufacturer: Oriendo, model R1; column: Welch Xtimate C18 250*30 mm*10 μm; mobile phase: water (0.225% HCOOH)-acetonitrile; elution ratio of water from 30% to 60%), yielding compound 5 (194 mg, yield: 64.96%).

[0486] LCMS(ESI): m / z, 1049.3. [M+H] +

[0487] Step 4: Synthesis of Compound 6

[0488] Compound 5 (194 mg, 184.93 μmol, 1 eq) was dissolved in N,N dimethylformamide (3 mL), followed by the addition of diethylamine (192.43 μL, 1.85 mmol, 10 eq). The reaction mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was directly evaporated to dryness to give crude compound 6 (152 mg, crude product), which was used directly in the next step without purification. LCMS (ESI): m / z, 827.3. [M+H] +

[0489] Step 5: Synthesis of compound LOD005

[0490] Compound 6 (152 mg, 183.84 μmol, 1 eq) was dissolved in NN dimethylformamide (3 ml), followed by compound 7 (65.45 mg, 183.84 μmol, 1 eq), NN diisopropylpropylamine (48 mg, 367.67 μmol, 2 eq), and HATU (83.88 mg, 220.60 μmol, 1.2 eq). The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed the reaction was complete. Compound LOD005 (53.58 mg, yield: 25.25%, purity: 92%) was obtained by high-performance liquid chromatography (preparative chromatograph manufacturer: Oriendo, model R7; column: Welch Xtimate C18 150*30mm*10um; mobile phase: water (0.225% HCOOH)-acetonitrile; elution ratio: water from 20% to 50%).

[0491] LCMS(ESI): m / z, 1155.1.[M+H]+

[0492] 1H NMR(400MHz, DMSO-d6)δ9.24(s,1H),8.60(dt,J=18.7,6.7Hz,1H),8.36–8.26(m,1H),8.12(tt,J=14.1,6.9Hz,2H),8.0 3–7.92(m,2H),7.54(s,1H),7.32–7.11(m,6H),7.01(s,1H),6.49(s,1H),6.34–6.27(m,2H),5.41(s,2H),5.26(s,1H), 4.66(d,J=6.7Hz,2H),4.46(ddd,J=16.5,6.3,3.4Hz,2H),3.83–3.63(m,11H),3.63–3.41(m,16H),3.03(dd,J=13.8,4. 5Hz, 1H), 2.77 (ddd, J=14.6, 9.8, 5.2Hz, 1H), 2.38 (t, J=6.5Hz, 2H), 1.94–1.77 (m, J=7.0Hz, 2H), 0.88 (t, J=7.3Hz, 3H).

[0493] Example 16: Synthesis route of LOD006

[0494]

[0495] Preparation process:

[0496] Step 1: Synthesis of compound LOD006

[0497] Compound 1 (57.08 mg, 126.99 μmol, 1 eq) was dissolved in NN dimethylformamide (2 ml), followed by compound 2 (same as compound 6 in Example 15, 105 mg, 126.99 μmol, 1 eq), and then NN diisopropylpropylamine (33.16 mg, 253.99 μmol, 2 eq). HATU (59.13 mg, 152.39 μmol, 1.2 eq) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction solution was prepared by high performance liquid chromatography (preparative chromatograph manufacturer: Oriendo, model R6; column: Synergi Max-RP 200*30mm*10um; mobile phase: water (0.225% HCOOH)-acetonitrile; elution ratio of water from 20% to 50%), yielding compound LOD006 (61.9 mg, yield: 38.74%, purity: 95%).

[0498] LCMS(ESI): m / z, 1259.5 [M+H] +

[0499] 1 H NMR(400MHz, DMSO-d6)δ9.24(s,1H),8.60(dt,J=18.7,6.7Hz,1H),8.36–8.26(m,1H),8.12(tt,J=14.1,6.9Hz,2H),8.0 3–7.92(m,2H),7.54(s,1H),7.32–7.11(m,6H),7.01(s,1H),6.49(s,1H),6.34–6.27(m,2H),5.41(s,2H),5.26(s,1H), 4.66(d,J=6.7Hz,2H),4.46(ddd,J=16.5,6.3,3.4Hz,2H),3.83–3.63(m,11H),3.63–3.41(m,16H),3.03(dd,J=13.8,4. 5Hz, 1H), 2.77 (ddd, J=14.6, 9.8, 5.2Hz, 1H), 2.38 (t, J=6.5Hz, 2H), 1.94–1.77 (m, J=7.0Hz, 2H), 0.88 (t, J=7.3Hz, 3H).

[0500] Example 17: Synthesis Route of LOD007

[0501]

[0502] Preparation process:

[0503] Step 1: Synthesis of Compound 3

[0504] OD005 (650 mg, 54%, 744.56 μmol) and compound 2 (559.76 mg, 1.49 mmol) were dissolved in N,N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL), and p-toluenesulfonic acid (129.51 mg, 744.56 μmol) was added. The reaction mixture was stirred at 80°C for 3 hours. LC-MS showed that the reaction had reached its limit. Compound 3 (155 mg, yield: 26.70%) was prepared by high-performance liquid chromatography. LC-MS (ESI): m / z, 780.2 [M+H] +

[0505] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatograph is manufactured by Oriendo, model BRIX-2860(R5). The chromatographic column is a Phenomenex Luna C18 250*50mm*10um. The mobile phase is water (0.1% CF3COOH)-acetonitrile, with an elution ratio of 30% to 60%.

[0506] Step 2: Synthesis of Compound 4

[0507] Compound 3 (430 mg, 551.46 μmol) was dissolved in N,N-dimethylformamide (10 mL), and diethylamine (407.41 mg, 5.51 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was then processed by high-performance liquid chromatography to obtain compound 4 (60 mg, yield: 19.52%). LCMS (ESI): m / z, 558.3 ​​[M+H] +

[0508] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatogram was manufactured by Oriendo, model BRIX-2860(R5). The column was a Phenomenex Luna C18 250*50mm*10um. The mobile phase was water (0.1% CF3COOH)-acetonitrile, with an elution ratio of water ranging from 10% to 40%.

[0509] Step 3: Synthesis of Compound 6

[0510] Compound 4 (60 mg, 107.62 μmol) and compound 5 (55.08 mg, 107.62 μmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (28.10 mg, 215.24 μmol) was added at 0°C, followed by HATU (50.11 mg, 98%, 129.15 μmol). The reaction mixture was stirred at 25°C for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was further analyzed by high-performance liquid chromatography (HPLC) to obtain compound 6 (75 mg, yield: 66.96%). LC-MS (ESI): m / z, 1063.3 [M+Na] +

[0511] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatograph is manufactured by Oriendo, model BRIX-2860(R5). The chromatographic column is a Phenomenex Luna C18 250*50mm*10um. The mobile phase is water (0.1% CF3COOH)-acetonitrile, with an elution ratio of 40% to 70%.

[0512] Step 4: Synthesis of Compound 7

[0513] Compound 6 was dissolved in N,N-dimethylformamide (2 mL), and diethylamine (53.22 mg, 720.43 μmol) was added. The reaction mixture was stirred at 25°C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was concentrated using an oil pump to remove DMF and residual diethylamine, yielding crude compound 7 (59 mg, yield: 75.01%, purity: 75%), which was used directly in the next step. LCMS (ESI): m / z, 841.2 [M+Na]+

[0514] Step 5: Synthesis of compound LOD007

[0515] Compound 7 (60 mg, 75%, 54.96 μmol) and compound 8 (24.70 mg, 54.96 μmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (14.35 mg, 109.92 μmol) was added. HATU (25.59 mg, 65.95 μmol) was added at 0°C, and the reaction mixture was stirred at 25°C for 4 hours. LCMS showed that the reaction was complete. The reaction mixture was then prepared by high-performance liquid chromatography to give compound LOD007 (23.50 mg, yield: 34.20%, purity: 95.44%).

[0516] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatograph is manufactured by Oriendo, model BRIX-2860(R5). The chromatographic column is a Phenomenex Luna C18 250*50mm*10um. The mobile phase is water (0.1% CF3COOH)-acetonitrile, with an elution ratio of 30% to 60%.

[0517] LCMS(ESI): m / z, 1272.4 [M+Na]+

[0518] 1 H NMR (400MHz, DMSO-d6) δ9.35(d,J=7.3Hz,2H),9.12(s,1H),8.76(dd,J=12.5,8.5Hz,1H),8.58(s ,1H),8.38–8.22(m,2H),8.21–7.81(m,4H),7.37(d,J=13.2Hz,1H),7.30–6.99(m,5H),5.46(d,J= 21.5Hz,2H),5.37(s,2H),4.66(d,J=6.3Hz,2H),4.48(s,2H),4.28(s,2H),3.98–3.69(m,8H),3. 68–3.39(m,18H),3.10–2.94(m,2H),2.84–2.69(m,2H),2.37(t,J=6.4Hz,2H),1.92–1.78(m,2H).

[0519] Example 18: Synthesis Route of LOD008

[0520]

[0521] Preparation process:

[0522] Step 1: Synthesis of Compound 2

[0523] OD006 (1 g, 80%, 1.71 mmol, 1.00 eq) and compound 1 (643.32 mg, 1.71 mmol, 1.00 eq) were dissolved in dichloromethane (50 mL), and trifluoroacetic acid (606.06 μL) was slowly added dropwise at room temperature until the reaction solution was mostly clear. The reaction solution was stirred for 1 hour under nitrogen protection at 35°C. LCMS showed that the reaction was complete. The reaction solution was diluted with dichloromethane (50 mL), then evaporated to dryness, and this process was repeated twice to remove most of the trifluoroacetic acid, yielding the crude product. The crude product was purified by silica gel column chromatography (C18) (ISCO, R-330 g SepaFlash Silica Flash Column, Eluent of 5-40% water (0.225% FA) / CH3CN@80 mL / min), and after lyophilization, compound 2 (900 mg, yield: 67.79%, purity: 70%) was obtained.

[0524] LCMS(ESI): m / z, 776.3 [M+H] +

[0525] Step 2: Synthesis of Compound 3

[0526] Compound 2 (200 mg, 70%, 180.46 μmol, 1.00 eq) was dissolved in N,N-dimethylformamide (2 mL), and diethylamine (133.32 mg, 1.80 mmol, 10.00 eq) was added dropwise at 0°C. The reaction mixture was stirred for 1 hour under nitrogen protection at 0°C. LCMS showed that the reaction was complete. The reaction mixture was concentrated to give compound 3 (100 mg, crude product). LCMS (ESI): m / z, 554.2 [M+H] +

[0527] Step 3: Synthesis of Compound 5

[0528] Compound 3 (100 mg, 180.65 μmol, 1.00 eq) and compound 4 (92.45 mg, 98%, 180.65 μmol, 1.00 eq) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (47.17 mg, 361.30 μmol, 2.00 eq) and HATU (84.98 mg, 216.78 μmol, 1.20 eq) were added dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour under nitrogen protection. LCMS showed the reaction was complete. The reaction mixture was then purified by high-performance liquid chromatography to obtain compound 5 (120 mg, yield: 64.05%, purity: 90%). LCMS (ESI): m / z, 1037.4 [M+H] +

[0529] The preparative chromatography column was manufactured by Shimadzu, model LC-20AP. The column was a Synergi Max-RP 250*40mm*10um. The mobile phase was water (0.225% FA)-acetonitrile, with water elution ratios ranging from 40% to 70%.

[0530] Step 4: Synthesis of Compound 6

[0531] Compound 5 (120 mg, 115.71 μmol, 1.00 eq) was dissolved in N,N-dimethylformamide (2 mL), and diethylamine (84.63 mg, 1.16 mmol, 10.00 eq) was added dropwise at 0°C. The reaction mixture was stirred for 1 hour under nitrogen protection at 0°C. LC-MS showed that the reaction was complete. The reaction mixture was concentrated to give compound 6 (90 mg, crude product). LC-MS (ESI): m / z, 837.3 [M+Na] +

[0532] Step 5: Synthesis of compound LOD008

[0533] Compound 6 (90 mg, 110.45 μmol, 1.00 eq) and compound 7 (58.41 mg, 85%, 110.45 μmol, 1.00 eq) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (28.84 mg, 99%, 36.88 μL, 220.90 μmol, 2.00 eq) and HATU (51.96 mg, 132.54 μmol, 1.20 eq) were added dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 minutes under nitrogen protection. LC-MS showed the reaction was complete. The reaction mixture was then subjected to high-performance liquid chromatography (HPLC) to prepare compound LOD008 (30.75 mg, yield: 22.34%, purity: 97.74%). The chromatograph used was Shimadzu LC-20AP. The chromatographic column was a YMC-Triart Prep C18 150*30mm*10um. The mobile phase was water (0.225% FA)-acetonitrile, with water elution ratios ranging from 20% to 50%.

[0534] LCMS(ESI): m / z, 1246.3 [M+H] +

[0535] 1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),9.35(s,2H),9.11(s,1H),8.65–8.54(m,2H),8.30(s,1H),8.19–8.0 6(m,2H),8.03–7.91(m,2H),7.33(s,1H),7.21(t,J=4.7Hz,5H),6.53(s,1H),5.42(s,2H),5.33(s,2H),4 .65(d,J=6.7Hz,2H),4.47(s,3H),3.86–3.62(m,7H),3.62–3.40(m,23H),3.28–3.25(m,2H),3.02(d,J=1 1.0Hz,1H),2.77(dd,J=13.8,9.7Hz,1H),2.37(t,J=6.6Hz,2H),1.93–1.78(m,2H),0.87(t,J=7.2Hz,3H).

[0536] 19 F NMR(377MHz,DMSO-d6)δ-112.28.

[0537] Example 20: Synthesis Route of LOD009

[0538]

[0539] Preparation process:

[0540] Step 1: Synthesis of Compound 2. OD007 (450 mg, 930.81 μmol, 1.00 eq) and Compound 1 (419.87 mg, 1.12 mmol, 1.20 eq) were dissolved in dichloromethane (8 mL), and trifluoroacetic acid (0.2 mL) was slowly added dropwise at room temperature until the reaction solution was mostly clear. The reaction solution was stirred for 3 hours under nitrogen protection at 35°C. LCMS showed that the reaction was complete. The reaction solution was diluted with dichloromethane (10 mL), then evaporated to dryness, and this process was repeated twice to obtain the crude product. The crude product was prepared by high performance liquid chromatography to obtain Compound 2 (260 mg, crude product).

[0541] LCMS(ESI): m / z, 792.3 [M+H] +

[0542] The preparative chromatography column was manufactured by Chengda, model BRIX-2860. The column was a YMC-Triart Prep C18 150*30mm*10um. The mobile phase was water (0.225% FA)-acetonitrile, with water elution ratios ranging from 40% to 70%.

[0543] Step 2: Synthesis of Compound 3

[0544] Compound 2 (260 mg, 328.37 μmol, 1.00 eq) was dissolved in N,N-dimethylformamide (3 mL), and diethylamine (242.60 mg, 3.28 mmol, 10.00 eq) was added dropwise at 0°C. The reaction mixture was stirred for 1 hour under nitrogen protection at 0°C. LCMS showed that the reaction was complete. The reaction mixture was concentrated to give compound 3 (180 mg, crude product). LCMS (ESI): m / z, 570.3 [M+H] +

[0545] Step 3: Synthesis of Compound 5

[0546] Compound 3 (180 mg, 316.04 μmol, 1.00 eq) and compound 4 (161.74 mg, 316.04 μmol, 1.00 eq) were dissolved in N,N-dimethylformamide (4 mL). N,N-diisopropylethylamine (82.51 mg, 632.08 μmol, 2.00 eq) was added dropwise at 0°C, followed by HATU (147.15 mg, 379.25 μmol, 1.20 eq). The reaction mixture was stirred at 0°C for 30 minutes under nitrogen protection. LC-MS showed the reaction was complete. Compound 5 (160 mg, crude product) was prepared by high-performance liquid chromatography.

[0547] LCMS(ESI): m / z, 1053.6 [M+H] +

[0548] The preparative chromatography column was manufactured by Chengda, model BRIX-2860. The column was a Synergi Max-RP 200*30mm*10um. The mobile phase was water (0.225% FA)-acetonitrile, with water elution ratios ranging from 40% to 70%.

[0549] Step 4: Synthesis of Compound 6

[0550] Compound 5 (160 mg, 151.94 μmol, 1.00 eq) was dissolved in N,N-dimethylformamide (3 mL), and diethylamine (112.25 mg, 1.52 mmol, 10.00 eq) was added dropwise at 0°C. The reaction mixture was stirred for 30 minutes under nitrogen protection at 0°C. LC-MS showed that the reaction was complete. The reaction mixture was concentrated to give compound 6 (120 mg, crude product). LC-MS (ESI): m / z, 853.4 [M+Na] +

[0551] Step 5: Synthesis of compound LOD009

[0552] Compound 6 (100 mg, 120.36 μmol, 1.00 eq) and compound 7 (54.10 mg, 120.36 μmol, 1.00 eq) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (31.43 mg, 240.72 μmol, 2.00 eq) and HATU (54.92 mg, 144.43 μmol, 1.20 eq) were added dropwise at 0°C. The reaction mixture was stirred for 30 minutes under nitrogen protection at 0°C. LC-MS showed the reaction was complete. Compound LOD009 (30.75 mg, yield: 22.34%, purity: 97.74%) was prepared by high-performance liquid chromatography (HPLC). The preparative chromatogram was manufactured by Shimadzu, model LC-20AP. The chromatographic column was a Synergi Max-RP250*40mm*10um. The mobile phase is water (0.1% TFA)-acetonitrile, with water elution ratios ranging from 20% to 50%.

[0553] LCMS(ESI): m / z, 1284.4 [M+Na] +

[0554] 1 H NMR(400MHz, DMSO-d6)δ9.45(s,1H),9.36(s,2H),9.11(d,J=5.8Hz,1H),8.66–8.56(m,1H),8.30(t,J=5.8Hz, 1H),8.19–7.96(m,5H),7.32(d,J=16.6Hz,1H),7.27–7.13(m,5H),6.53(s,1H),5.46–5.28(m,4H),4.66(d,J= 6.5Hz,2H),4.54–4.25(m,3H),4.08(d,J=7.2Hz,3H),3.84–3.65(m,7H),3.62–3.44(m,22H),3.02(dd,J=13.7 ,4.7Hz,1H),2.78(dd,J=13.9,9.7Hz,1H),2.37(t,J=6.5Hz,2H),1.86(h,J=7.0Hz,2H),0.88(t,J=7.2Hz,3H).

[0555] 19 F NMR(377MHz,DMSO-d6)δ-73.94,-127.25(TFA).

[0556] Example 21: Synthesis route of LOD010

[0557]

[0558] Preparation process:

[0559] Step 1: Synthesis of Compound 2

[0560] OD009 (500 mg, 1.01 mmol) was dissolved in dichloromethane (30 mL), and compound 1 (380.87 mg, 1.01 mmol) was added. Then, trifluoroacetic acid (0.45 mL, 6.06 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 35°C for 2 hours. The reaction was confirmed to be complete by LC-MS. The reaction mixture was purified by silica gel column chromatography (C18) (ISCO, R-330g SepaFlashSilica Flash Column, Eluent of 5-60% water / CH3CN@100 mL / min) to give compound 2 (400 mg, yield: 16.41%). LC-MS (ESI): m / z, 802.3 [M+H] +

[0561] Step 2: Synthesis of Compound 3

[0562] Compound 2 (350 mg, 436.51 μmol) was dissolved in 7 mL of N,N-dimethylformamide solution, and diethylamine (322.49 mg, 4.37 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction was confirmed to be complete by LC-MS. The reaction mixture was directly evaporated to dryness to give crude compound 3 (253 mg, yield: 100%). LC-MS (ESI): m / z, 580.3 [M+H] +

[0563] Step 3: Synthesis of Compound 5

[0564] Compound 3 (253 mg, 436.53 μmol) was dissolved in N,N-dimethylformamide (7 mL), and compound 4 (223.41 mg, 436.53 μmmol) and N,N-diisopropylethylamine (112.83 mg, 873.06 μmol) were added. 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (203.25 mg, 523.84 μmol) was added to the reaction solution at 0°C, and the reaction solution was stirred at 25°C for 1 hour. The reaction was confirmed by LCMS. The reaction solution was then analyzed by high-performance liquid chromatography to obtain compound 5 (180 mg, yield: 38.79%).

[0565] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatogram manufacturer is Shimadzu, model LC-20AP. The chromatographic column is a YMC-Triart Prep C18 250*50mm*7um. The mobile phase is water (0.225% HCOOH)-acetonitrile, with water elution ratios ranging from 30% to 60%.

[0566] LCMS(ESI): m / z, 1063.6 [M+H] +

[0567] Step 4: Synthesis of Compound 6

[0568] Compound 5 (150 mg, 141.10 μmol) was dissolved in 3 mL of N,N-dimethylformamide solution, and diethylamine (208.48 mg, 290.70 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. LCMS analysis confirmed the completion of the reaction. The reaction mixture was directly evaporated to dryness to give crude compound 6 (118 mg, yield: 100%). LCMS (ESI): m / z, 841.4 [M+H] +

[0569] Step 5: Synthesis of compound LOD010

[0570] Compound 6 (118 mg, 140.33 μmol) was dissolved in 3 mL of N,N-dimethylformamide solution. Compound 7 (63.08 mg, 140.33 μmol) and N,N-diisopropylethylamine (54.96 mg, 421 μmol) were added. At 0°C, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (65.34 mg, 168.40 μmol) was added to the reaction solution, and the reaction mixture was stirred at 25°C for 1 hour. The reaction was confirmed by LCMS. The reaction solution was purified by high-performance liquid chromatography to give compound LOD010 (45 mg, yield: 23.13%).

[0571] The preparative conditions for high-performance liquid chromatography (HPLC) are as follows: The preparative chromatogram manufacturer is Shimadzu, model LC-20AP. The chromatographic column is a YMC-Triart Prep C18 250*50mm*7um. The mobile phase is water (0.225% HCOOH)-acetonitrile, with water elution ratios ranging from 1% to 24%.

[0572] LCMS(ESI): m / z, 1272.4 [M+H] +

[0573] 1H NMR(400MHz,DMSO-d6)δ9.36(s,2H),9.23(s,1H),9.11(s,1H),8.57(s,1H),8.29(s,1H),8.18–8.07(m,2H),8.05(s,1H) ,7.99(s,1H),7.60(s,1H),7.29(d,J=14.3Hz,1H),7.23(d,J=7.7Hz,5H),6.51(s,1H),5.41(s,2H),5.29(s,2H),4.65(d J=6.6Hz, 2H), 4.45(s, 7H), 3.82–3.66(m 8H), 3.55(dd J=11.9,6.2Hz,8H),3.46(d,J=9.3Hz,13H),3.03(d,J=13.7Hz,1H),2.88–2 .70(m,1H),2.37(t,J=6.2Hz,2H),1.93–1.80(m,2H),0.88(t,J=7.2Hz,3H).

[0574] Example 22: Preparation of ADC

[0575] Take 0.1 mL of trastuzumab antibody (trastuzumab for injection). Add 50 mg / mL of TCEP (tris(2-carboxyethyl)phosphine) to the reaction tube and dilute to 10 mg / mL with PBS (pH 7.4). Add 66.67 μL of 10 mM TCEP (tris(2-carboxyethyl)phosphine) to the antibody solution, mix well, and incubate at room temperature for 3 hours. Add 50 μL of 30 mg / mL Linker-Payload DMSO solution to the above solution system, mix well, and incubate at room temperature for 4 hours. After the reaction is complete, ultrafilter the solution to PBS (pH 6.5) using a 30,000 MWCO protein concentrator. The antibody conjugates were obtained and their quality was determined by SEC-HPLC, HIC-HPLC, and other analytical methods. The results are shown in Table 1.

[0576] Table 1. Quality analysis results of ADC samples

[0577] Cell viability test

[0578] Example 1: Cell killing experiment of Payload

[0579] SK-BR-3 (ATCC), CAPAN-1 (ATCC), MDA-MB-231 (ATCC), and HCT116 (ATCC) cells were selected as cell lines for in vitro detection. 2000 cells per well were seeded in 96-well cell culture plates. The test payload was first prepared as a stock solution using DMSO, and then diluted with 10% FBS to prepare 10 concentration gradients of 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, and 0 μg / mL test solutions. Equal volumes were added to the 96-well cell culture plates and incubated at 37℃ in a 5% CO2 incubator for 96 h. After incubation, the cell culture plates were removed from the incubator and allowed to stand at room temperature for 30 min. An equal volume of CTG (Promega) was added and mixed well. After standing for 10 min, the luminescence value was measured using an M5 microplate reader, and the IC50 was calculated. 50 The test results are shown in Table 2.

[0580] Table 2 Results of cell viability test

[0581]

[0582]

[0583] Example 2: ADC endocytosis activity experiment

[0584] ADC endocytic activity was detected using SK-BR-3 and CAPAN-1 cells via FACS. Cells were digested with trypsin and washed once with FACS buffer (PBS containing 1% BSA). After centrifugation, cells were resuspended in FACS buffer, and the cell density was adjusted to 4 × 10⁶ cells / mL, then pre-chilled on ice for 30 minutes. Samples were diluted to 20 μg / mL with FACS buffer and pre-chilled on ice for 30 minutes. An equal volume of cell suspension and diluted sample was added to EP tubes, and the tubes were incubated at 4°C for 2 hours, followed by washing three times with pre-chilled FACS buffer. Cells were resuspended in 250 μL of pre-chilled FACS buffer. 100 μL of cell suspension and 1.1 mL of pre-chilled FACS buffer were added to EP tubes pre-warmed at 37°C, and 100 μL of cell suspension and 1.1 mL of pre-chilled FACS buffer were added to EP tubes pre-chilled at 4°C. The obtained mixture was used to collect 100 μL of cell suspension at 0, 1, 2, 4, and 20 h and placed in pre-chilled 96-well plates. After centrifugation, PE-labeled goat anti-human IgG secondary antibody was added to FACS pre-chilled buffer. After incubation at 4 °C for 1 hour, the cells were washed twice with FACS pre-chilled buffer. Cells were resuspended in PBS and their fluorescence was detected using flow cytometry (Backman CytoFLEX). Endocytosis activity (%) = (1 - MFI 37 °C / MFI 4 °C) × 100. The endocytosis rates in SK-BR-3 and CAPAN-1 cells are shown in Tables 3 and 4.

[0585] Table 3: Endocytosis rate of SK-BR-3 cells

[0586] Sample ID 0h 1h 2h 4h 20h CP0103 0％ 27％ 27％ 43％ 71％ CP0104 0％ 26％ 25％ 38％ 68％ CP0116 0％ 25％ 23％ 38％ 70％ CP0117 0％ 26％ 24％ 36％ 71％

[0587] Table 4: Invasive rate of CAPAN-1 cells

[0588] Sample ID 0h 1h 2h 4h 20h CP0103 0％ 12％ 14％ 20％ 57％ CP0104 0％ 12％ 14％ 22％ 69％ CP0116 0％ 17％ 16％ 24％ 60％ CP0117 0％ 10％ 14％ 21％ 59％

[0589] Example 3: Cell killing by ADC

[0590] SK-BR-3 and CAPAN-1 cells were selected as cell lines for in vitro detection, with 2000 cells per well seeded in 96-well cell culture plates. The ADC to be tested was prepared in 10% FBS cell culture medium to create 10 concentration gradients of 1000, 200, 40, 8, 1.6, 0.32, 0.064, 0.0128, 0.00256, and 0 nM. Equal volumes of these solutions were added to the 96-well cell culture plates and incubated at 37°C in a 5% CO2 incubator for 144 h. After incubation, the cell culture plates were removed from the incubator and allowed to stand at room temperature for 30 min. An equal volume of CTG was added to the culture medium and mixed well. After standing for 10 min, the luminescence value was measured using an M5 microplate reader, and the IC50 was calculated. 50Results. The cell-killing results of SK-BR-3 cells are shown in Table 5, and the cell-killing results of CAPAN-1 cells are shown in Table 6. The results show that the cell-killing activity of the newly developed payload-corresponding ADCs is superior to that of the DXd-corresponding ADCs.

[0591] Table 5: SK-BR-3 cell killing results

[0592] Sample ID <![CDATA[IC 50 (nM)]]> CP0103 0.081 CP0104 0.091 CP0116 0.083 CP0117 0.119

[0593] Table 6: Results of CAPAN-1 cell killing

[0594] Sample ID <![CDATA[IC 50 (nM) <!-- 69 -->]]> CP0012 51.527 CP0103 1.787 CP0104 4.594 CP0116 1.119 CP0117 2.065

[0595] Example 4: Bystander Kill of ADC

[0596] HER2-positive SK-BR-3 cells and HER2-negative MDA-MB-468 cells were mixed at a 2:1 ratio and added to 6-well plates at a concentration of 2 × 10⁵ cells per well. An equal volume of sample was then added to bring the final concentration to 1 nM. Cells were cultured at 37°C in a 5% CO₂ incubator for 4 days. After culture, cells were digested and counted. Cells were then treated with PE-labeled goat anti-human IgG (…). HER2-positive cells (catalog number AB98596) were stained with HER2 antibody. Control cells were first incubated with HER2 antibody for 30 min, washed, and then stained with PE-labeled goat anti-human IgG. After secondary antibody incubation, the cells were washed, and the proportion of PE-positive and PE-negative cells was analyzed by flow cytometry. The absolute number of PE-positive and PE-negative cells in each group was calculated based on the total number of cells. PE-positive cells were HER2-positive cells SK-BR-3, and PE-negative cells were HER2-negative cells MDA-MB-468. The results are shown in Table 7. The results showed that the bystander killing activity of the newly developed Payload-corresponding ADC was superior to that of the DXd-corresponding ADC (CP0012) and T-DM1 (commercially available). Batch number: B2810B01).

[0597] Table 7: Bystander Kill Activity of ADCs

[0598] Sample ID Side kill rate CP0103 42.43％ CP0104 60.53％ CP0116 73.74％ CP0117 71.61％ T-DM1 18.24％

[0599] Example 5: In vivo efficacy of ADC

[0600] Antitumor effect of HER2-ADC in Balb / cnude mouse model of subcutaneous transplantation of human pancreatic cancer cells Capan-1: The human pancreatic cancer cell line Capan-1 (purchased from Nanjing Kebai Biotechnology Co., Ltd.) was subcutaneously injected into the right axilla of Balb / cnude mice (purchased from Biocytogen Jiangsu Gene Biotechnology Co., Ltd., 6-7 weeks old, female), with 1×10⁻⁶ ADCs injected into each mouse. 7 Cells were mixed with Matrigengel Matrix (ABW, CAT#082706) at a 1:1 ratio.

[0601] Based on tumor volume and animal weight, mice were randomly divided into 6 groups of 5 mice each, with an average tumor volume of approximately 150-200 mm. 3 The drug is administered via tail vein injection, as a single dose.

[0602] Tumor volume is presented as mean ± SEM. Tumor volume comparisons between groups were performed using Student's t-test / ANOVA. A p-value < 0.05 was considered statistically significant. Graphpad Prism 8.0 software was used for plotting.

[0603] The formula for calculating tumor volume (TV) is: TV = 0.5 × major diameter × minor diameter 2 .

[0604] Tumor inhibition rate (TGI): TGI = [1 - (average tumor volume at each measurement in a certain treatment group - average tumor volume at the start of administration in that treatment group) / (average tumor volume at each measurement in the negative control group - average tumor volume at the start of administration in the negative control group)] × 100%.

[0605] Tumor volume changes in each group were observed until day 42 during this trial. The tumor inhibition rates (on day 42) of each treatment group compared to the PBS group are shown in Table 8. Compared to the PBS group, all ADC administration groups significantly inhibited tumor growth, including CP0012 (5 mg / kg), CP0103 (5 mg / kg), CP0104 (5 mg / kg), CP0116 (5 mg / kg), and CP0117.

[0606] The tumor inhibition rates of (5 mg / kg) were 96.05%, 93.94%, 95.07%, 103.29%, and 105.36%, respectively. Compared with the PBS group,

[0607] The p-values ​​for each treatment group were all less than 0.05, indicating statistical differences.

[0608] Table 8. Efficacy of ADCs in the treatment of xenografts in Capan-1 tumor-bearing mice (TGI)

[0609]

[0610] During the experiment, the body weight of mice in each group showed a normal growth trend, as shown in Table 9. No obvious abnormalities were observed in general observation of mice in each group, indicating that the animals tolerated the current drug well.

[0611] Table 9: Changes in body weight (g) of mice in each group

[0612]

[0613] In summary, in the Capan-1 pancreatic cancer model, all the ADC antibodies of this invention can significantly inhibit tumor growth and are well tolerated by the animals.

[0614] Example 7: Plasma stability and solution stability

[0615] The ADC compound of the present invention exhibits good plasma stability and solution stability.

Claims

1. A camptothecin compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, the camptothecin compound being a compound of Formula I or a compound of Formula II: R 1 and R 2 are independently H, D, halogen, C 1-6 alkyl or C 1-6 alkoxy; or, R 1 and R 2 are independently connected to form a C 1-10 alkylene or C 1-10 heteroalkylene; R 3 and R 4 are independently H or D; or, R 3 and R 4 are joined to form a C 1-10 alkylene or C 1-10 heteroalkylene; each C 1-10 the heteroatom species of the heteroalkylene group is independently selected from one, two, or three of N, O, and S; the number of heteroatoms is independently 1, 2, or 3; m and n are independently 0, 1 or 2; M is independently C 1-6 alkylene.

2. The camptothecin compound, pharmaceutically acceptable salt thereof, solvate thereof, or solvate of a pharmaceutically acceptable salt thereof according to claim 1, wherein which satisfies one or more of the following conditions: (1) said R 1 and R 2 , said C 1-6 alkyl is independently C 1-4 1-6 alkyl, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl, for example methyl; (2) said R 1 and R 2 wherein said C 1-6 alkyl is independently C 1-4 alkyl, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl, and further for example methyl; and said C 1-4 alkoxy is independently C 1-4 alkoxy, for example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy or t-butoxy, and further for example methoxy; (3) said R 1 and R 2 wherein said halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine; (4) each C 1-10 alkylene is straight-chain alkylene; each C 1-10 alkylene is independently C 1-4 alkylene; for example (5) each C 1-10 heteroalkylene is straight-chain; each C 1-10 heteroalkylene independently can be C 1-4 heteroalkylene, for example C 3-4 heteroalkylene; each C 1-10 the heteroatoms in the heteroalkylene group can be O, the number of heteroatoms independently can be 1 or 2, for example 2; each C 1-10 heteroalkylene independently can be (6) In M, the C 1-6 alkylene is a straight-chain alkylene; the C 1-6 alkylene can be C 1-4 alkylene, for example For example, the C (7) the compound of Formula I is a compound of Formula I-A and / or I-B: (8) m≠n, the compound of Formula II is a compound of Formula II-A and / or II-B:

3. The camptothecin-type compound as described in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, which satisfies one or more of the following conditions: (1) R 1 independently H or halogen, e.g., halogen; (2) R 2 independently H, halogen, C 1-4 alkyl or C 1-4 alkoxy; for example R 2 is halogen, C 1-4 alkyl or C 1-4 alkoxy; also for example R 2 is C 1-4 alkyl; (3) R 1 and R 2 are independently connected to form a C 1-10 heteroalkylene; for example, R 1 and R 2 are independently connected to form a C 1-4 heteroalkylene; the heteroatoms in said C 1-4 heteroalkylene are O, the number of heteroatoms is 1 or 2; (4) R 3 and R 4 to form C 1-10 alkylene; for example, R 3 and R 4 to form C 1-4 alkylene; (5) m and n are independently 0 or 1, for example, m and n are both 0 or both 1; (6) M is independently C 1-4 alkylene; Preferably, in the camptothecin compound, R 1 independently H or halogen; R 2 independently H, halogen, C 1-4 alkyl or C 1-4 alkoxy; Or, R 1 and R 2 Independently connected to form C 1-4 Heteroalkyl; the C 1-4 The heteroatom in the heteroalkylene group is O, and the number of heteroatoms is independently 1 or 2; R 3 and R 4 are H; or R 3 and R 4 are joined to form a C 1-4 alkylene; m and n are independently 0 or 1; M is independently C 1-4 alkylene; More preferably, the camptothecin compound is a compound of Formula I: wherein R is halogen; and 1 halogen; and R 2 halogen, C 1-4 alkyl or C 1-4 alkoxy; Or, R 1 and R 2 Connection forms C 1-4 Heteroalkyl; the C 1-4 The heteroatom in the heteroalkylene group is O, and the number of heteroatoms is 1 or 2; R 3 and R 4 is H; or R 3 and R 4 are joined to form C 1-4 alkylene; M is C 1-4 alkylene.

4. A camptothecin compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, the camptothecin compound being any one of the following compounds: Preferably, the camptothecin compound is any one of the following compounds: a compound eluting after the following chromatographic conditions Z; said chromatographic conditions Z are: the column is an InfinityLab Poroshell 120 EC-C18 4.5*100 mm 2.7 pm; the mobile phase consists of mobile phase A and B, mobile phase A is trifluoroacetic acid in water, mobile phase B is trifluoroacetic acid in acetonitrile, the volume percentage of trifluoroacetic acid in said mobile phase A and mobile phase B independently is 0.05%; the elution conditions are 0.1 min with mobile phase A and mobile phase B in the volume ratio of 95:5, followed by an increase of the volume percentage of mobile phase B from 5% to 95% within 6.9 min; the flow rate is 1.5 mL / min; and / or, 1 a compound having the H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.62 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.92 (t, J = 7.6 Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 7.36 (s, 1H), 6.55 (s, 1H), 5.40 (d, J = 33.8 Hz, 4H), 4.89 (t, J = 5.4 Hz, 1H), 4.38 (t, J = 5.1 Hz, 2H), 3.81 (q, J = 5.2 Hz, 2H), 1.88 (p, J = 7.0 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); preferably said compound eluting after the following chromatographic conditions Z has a retention time of 6.097 min; the compound eluting first under the chromatographic conditions Z; and / or, 1 H NMR (400 MHz, DMSO-d6) for a compound δ 7.87 (d, J = 10.7 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 6.53 (d, J = 4.5 Hz, 1H), 5.43 (s, 2H), 5.31 (d, J = 9.0 Hz, 2H), 4.75 (t, J = 5.4 Hz, 1H), 4.25 (t, J = 5.0 Hz, 2H), 3.71 - 3.64 (m, 2H), 2.90 (t, J = 6.5 Hz, 2H), 2.40 (d, J = 10.9 Hz, 3H), 1.87 (p, J = 6.9 Hz, 2H), 0.88 (t, J = 7.3 Hz, 4H); preferably the retention time for said first eluting compound is 4.868 min; a compound eluting after the chromatographic conditions Z; and / or, 1 H NMR (400 MHz, DMSO-d6) for a compound δ 7.82 (d, J = 10.9 Hz, 1H), 7.33 (s, 1H), 6.53 (s, 1H), 5.43 (d, J = 1.4 Hz, 2H), 5.29 (s, 2H), 4.89 (t, J = 5.5 Hz, 1H), 4.38 (t, J = 5.1 Hz, 2H), 3.82 (q, J = 5.2 Hz, 2H), 3.22 (d, J = 7.0 Hz, 2H), 3.13 (t, J = 6.6 Hz, 2H), 2.41 (d, J = 1.9 Hz, 3H), 1.87 (hept, J = 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); preferably the retention time for said compound eluting after is 4.990 min; the compound eluting first under the chromatographic conditions Z; and / or, 1 H NMR (400 MHz, DMSO-d6) is a compound with δ 8.37 (d, J = 13.1 Hz, 1H), 8.35 - 8.23 (m, 1H), 8.08 (ddd, J = 18.7, 11.6, 8.6 Hz, 1H), 7.34 (d, J = 4.6 Hz, 1H), 7.13 (d, J = 22.6 Hz, 1H), 6.57 (s, 1H), 5.43 (s, 1H), 5.25 (s, 1H), 5.16 (s, 1H), 4.73 (d, J = 5.1 Hz, 1H), 4.24 - 4.16 (m, 2H), 3.61 (d, J = 4.2 Hz, 2H), 1.96 (dtt, J = 75.4, 14.2, 6.9 Hz, 2H), 0.94 - 0.79 (m, 3H); preferably the retention time of the first eluting compound is 6.337 min; a compound eluting after the chromatographic condition Z; and / or, 1 H NMR (400 MHz, DMSO-d6) for a compound δ 9.30 (s, 1H), 8.73 (dd, J = 12.5, 8.6 Hz, 1H), 8.26 (dd, J = 11.2, 8.1 Hz, 1H), 7.33 (s, 1H), 6.55 (s, 1H), 5.43 (d, J = 2.1 Hz, 2H), 5.31 (s, 2H), 4.90 (s, 1H), 4.43 - 4.33 (m, 2H), 3.86 - 3.75 (m, 2H), 1.87 (p, J = 6.9 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H); preferably the retention time of said compound eluting after is 6.652 min; a compound eluting first through the chromatographic conditions Z; and / or, 1 H NMR (400 MHz, DMSO-d6) for a compound δ 8.40 (s, 1H), 8.07 - 7.70 (m, 2H), 7.39 - 7.16 (m, 1H), 6.55 (d, J = 3.6 Hz, 1H), 5.49 - 5.10 (m, 4H), 4.81 (dt, J = 71.0, 5.4 Hz, 1H), 4.29 (dt, J = 73.5, 5.1 Hz, 2H), 3.71 (dq, J = 78.4, 5.2 Hz, 2H), 1.87 (hept, J = 7.0 Hz, 2H), 0.87 (q, J = 5.9, 4.5 Hz, 3H); preferably the retention time of said first eluting compound is 6.568 min; a compound eluting after the chromatographic conditions Z; and / or, 1 H NMR (400 MHz, DMSO-d6) for a compound δ 9.34 (s, 1H), 8.58 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 10.7 Hz, 1H), 7.32 (s, 1H), 6.55 (s, 1H), 5.43 (d, J = 1.9 Hz, 2H), 5.28 (s, 2H), 4.90 (t, J = 5.4 Hz, 1H), 4.38 (dd, J = 5.8, 4.4 Hz, 2H), 3.80 (q, J = 5.2 Hz, 2H), 1.97 - 1.78 (m, J = 7.2 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); preferably the retention time for said compound eluting after is 6.896 min; a compound eluting first through the chromatographic conditions Z; and / or, 1 H NMR (400 MHz, DMSO-d6) for a compound δ 8.44 (s, 1H), 8.04 (t, J = 11.9 Hz, 1H), 7.48 (d, J = 9.1 Hz, 1H), 7.30 (d, J = 3.8 Hz, 1H), 6.53 (d, J = 3.6 Hz, 1H), 5.42 (s, 2H), 5.28 (d, J = 30.6 Hz, 2H), 4.81 (dt, J = 65.8, 5.3 Hz, 1H), 4.30 (dt, J = 65.0, 5.1 Hz, 2H), 4.08 (d, J = 8.6 Hz, 3H), 3.71 (dq, J = 77.2, 5.2 Hz, 2H), 1.86 (p, J = 7.1 Hz, 2H), 0.91 - 0.79 (m, 3H); preferably the retention time for said first eluting compound is 6.211 min; a compound eluting after the chromatographic conditions Z; and / or, 1 H NMR (400 MHz, pyridine-d5) δ 9.32 (s, 1H), 8.21 (d, J = 11.8 Hz, 1H), 8.05 (s, 1H), 7.95 (d, J = 8.9 Hz, 1H), 5.97 (d, J = 16.1 Hz, 1H), 5.63 (d, J = 16.1 Hz, 1H), 5.54 (d, J = 6.2 Hz, 2H), 4.60 (dd, J = 5.8, 4.1 Hz, 2H), 4.25 (t, J = 4.9 Hz, 2H), 3.99 (s, 3H), 2.16 (q, J = 7.3 Hz, 2H), 1.19 (t, J = 7.3 Hz, 3H); preferably, the retention time of said compound eluting after is 6.571 min; the compound eluting first under the chromatographic conditions Z; and / or, 1 H NMR (400 MHz, DMSO-d6) for a compound δ 9.32 + 8.31 (s, 1H), 8.04 + 7.40 (s, 1H), 7.60 - 7.47 (m, 1H), 7.31 - 7.19 (m, 1H), 6.56 - 6.44 (m, 1H), 6.30 (d, J = 15.0 Hz, 2H), 5.42 (s, 2H), 5.32 - 5.16 (m, 2H), 4.80 (dt, J = 70.7, 5.3 Hz, 1H), 4.27 (dt, J = 66.7, 5.1 Hz, 2H), 3.86 - 3.55 (m, 2H), 1.86 (hept, J = 7.0, 6.6 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H); preferably the retention time of the first eluting compound is 5.702 min; a compound eluting after the chromatographic condition Z; and / or, 1 H NMR (400 MHz, DMSO-d6) for a compound δ 9.20 (s, 1H), 7.97 (s, 1H), 7.51 (s, 1H), 7.23 (s, 1H), 6.51 (s, 1H), 6.31 (d, J = 2.0 Hz, 2H), 5.41 (s, 2H), 5.19 (s, 2H), 4.89 (t, J = 5.4 Hz, 1H), 4.35 (t, J = 5.1 Hz, 2H), 3.80 (q, J = 5.2 Hz, 2H), 1.96 - 1.78 (m, J = 7.2 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); preferably the retention time of said compound eluting after is 6.032 min; a compound eluting first through the chromatographic conditions Z; and / or, 1 a compound having H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.01 (s, 1H), 7.68 - 7.52 (m, 1H), 7.27 (d, J = 4.0 Hz, 1H), 6.49 (s, 1H), 5.41 (s, 2H), 5.20 (d, J = 14.5 Hz, 2H), 4.43 (s, 4H), 4.39 - 4.30 (m, 2H), 3.80 (d, J = 5.2 Hz, 2H), 1.96 - 1.77 (m, 2H), 0.89 (td, J = 7.4, 3.2 Hz, 3H); preferably, the first eluting compound has a retention time of 5.778 min; a compound eluting after the chromatographic condition Z; and / or, 1 H NMR (400 MHz, DMSO-d6) for a compound is δ 9.15 (s, 1H), 7.95 (s, 1H), 7.55 (s, 1H), 7.25 (s, 1H), 6.49 (s, 1H), 5.41 (s, 2H), 5.15 (d, J = 1.9 Hz, 2H), 4.45 (s, 4H), 4.35 (dd, J = 5.8, 4.4 Hz, 2H), 3.80 (t, J = 5.1 Hz, 2H), 2.01 - 1.73 (m, J = 7.3 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H); preferably the retention time of said compound eluting after is 6.086 min.

5. A camptothecin compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, the camptothecin compound being a compound of Formula I-1 or Formula II-1: wherein L is a linker precursor; M, m, n, R 1 , R 2 , R 3 and R 4 are as defined in any one of claims 1-4; Preferably, L is wherein LD is a linker, L 1 is a single bond or a linking unit; L 2 is a single amino acid residue or a short peptide consisting of 2-10 amino acid residues, which are natural or unnatural amino acids; L 3 is a spacer; More preferably, it satisfies one or more of the following conditions: (1) LD is Ring A is a 5-6 membered heteroalkene ring or a 5-6 membered heteroaromatic ring, one or more carbon atoms of which are replaced with C(O); the heteroatom species of the 5-6 membered heteroalkene ring and 5-6 membered heteroaromatic ring are independently selected from one, two, or three of N, O, and S; the number of heteroatoms is independently 1, 2, or 3; R 5 is a leaving group, for example -S(O)2-C 1-6 alkyl; p is 0 or 1; (2) L 1 independently or each Z is independently C 1-6 alkylene; each t is independently an integer from 1 to 16; preferably, L 1 the "1" position is connected to ring A; the "2" position is connected to L 2 ​ (3) L 2 independently a single amino acid residue, a dipeptide residue, a tripeptide residue, or a tetrapeptide residue; preferably, the carbonyl of the single amino acid residue, dipeptide residue, tripeptide residue, and tetrapeptide residue is attached to L 3 is a bond; the NH of the single amino acid residue, dipeptide residue, tripeptide residue, and tetrapeptide residue is attached to L 1 is a bond.

6. The camptothecin compound as described in claim 5, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, which satisfies one or more of the following conditions: (1) R 5 in particular -S(O)2-C 1-6 in particular -S(O)2-C 1-6 in particular -S(O)2-C 1-4 in particular -S(O)2-C (2) in cyc A, the number of olefinic bonds in the 5-6 membered heteroalkene ring can be 1 or 2, e.g., 1; the species of heteroatom in the 5-6 membered heteroalkene ring can be N, the number of heteroatoms can be 1 or 2, e.g., 1; also for example (3) in ring A, the heteroatom species of the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms is 1, 2 or 3, for example, 2; for example, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring; for example, a pyrimidine ring; (4) in Z, the C 1-6 alkylene is straight-chain alkylene; for example for example (5) the compound of Formula I-1 is a compound of Formula I-1A and / or I-1B: (5) m≠n, the compound of Formula II-1 is a compound of Formula II-1A and / or II-1B:

7. The camptothecin compound as described in claim 5, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, which satisfies one or more of the following conditions: (1) R 5 -S(O)2-C 1-4 alkyl; p is 1; (2) ring A is independently a 5-6 membered heteroalkene ring or a 5-6 membered heteroaromatic ring, the heteroatom species of the 5-6 membered heteroalkene ring is N, and the number of heteroatoms is 1 or 2; one or more carbon atoms in the 5-6 membered heteroalkene ring is replaced by C(O); the heteroatom species of the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms is 1, 2 or 3; preferably, ring A is independently a 5-6 membered heteroaromatic ring, the heteroatom species of the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms is 1, 2 or 3; (3) t is independently 1, 2, 3, 4, 5, 6, 7 or 8, for example, 4; (4) L 1 independently are wherein the "1 " position is attached to ring A; the "2" position is attached to L 2 ring A; and the "3" position is attached to (5) L 2 independently is a tetrapeptide residue; the tetrapeptide residue can be a tetrapeptide residue consisting of glycine and phenylalanine; preferably, the carbonyl in the tetrapeptide residue is attached to L 3 ; the NH in the tetrapeptide residue is attached to L 1 ; (6) L 3 independently are wherein NH is attached to L 2 ; Preferably, in the compound, LD is Ring A is a 5-6 membered heteroalkene ring or a 5-6 membered heteroaromatic ring, one or more carbon atoms of which are replaced with C(O); the heteroatom species of the 5-6 membered heteroalkene ring and 5-6 membered heteroaromatic ring are independently selected from one, two, or three of N, O, and S; the number of heteroatoms is independently 1, 2, or 3; R 5 -S(O)2-C 1-6 alkyl; p is 0 or 1; L 1 independently each Z is independently C 1-6 alkylene; L 1 the "1 " position is connected to ring A; the "2" position is connected to L 2 alkylene; L t is independently 1, 2, 3, 4, 5, 6, 7 or 8; L 2 independently is a tetrapeptide residue; the carbonyl in the tetrapeptide residue is attached to L 3 ; the NH in the tetrapeptide residue is attached to L 1 ; L 3 independently wherein NH is attached to L 2 ; R 1 independently H or halogen; R 2 independently H, halogen, C 1-4 alkyl or C 1-4 alkoxy; Or, R 1 and R 2 Connection forms C 1-4 Heteroalkyl; the C 1-4 The heteroatom in the heteroalkylene group is O, and the number of heteroatoms is 1 or 2; R 3 and R 4 is H; or R 3 and R 4 are joined to form C 1-4 alkylene; m and n are independently 0 or 1; M is independently C 1-4 alkylene; More preferably, the camptothecin compound satisfies one or more of the following conditions: (1) To (2) L 1 For Preferably, the "1" position is attached to ring A and the "2" position is attached to L 2 ; (3) L 2 For NH -(Gly)2-Phe-Gly- C＝O , for example, where the carbonyl end is attached to L 3 ; the NH end is attached to L 1 .

8. The camptothecin compound as described in claim 5, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, the compound is any one of the following compounds:

9. A drug conjugate, the drug conjugate being a drug conjugate of Formula I-2 or Formula II-2: T is an antibody; G is a linker; d is a natural number and / or a decimal number from 1 to 8; M, m, n, R 1 , R 2 , R 3 and R 4 are as defined in any one of claims 1-4; Preferably, G is wherein, Ring B is a linker to which an antibody is attached; L 1 , L 2 and L 3 are as defined in any one of claims 5-8; More preferably, ring B is independently a 5-6 membered heteroalkyl ring or a 5-6 membered heteroaromatic ring, one or more carbon atoms in the 5-6 membered heteroalkyl ring is replaced with C(O); the heteroatom species in the 5-6 membered heteroalkyl ring and the 5-6 membered heteroaromatic ring is independently selected from one, two or three of N, O and S; and the number of heteroatoms is independently 1, 2 or 3.

10. The drug conjugate of claim 9, wherein, which satisfies one or more of the following conditions: (1) in ring B, the heteroatom species in the 5-6 membered heteroalkane ring can be N, the number of heteroatoms independently can be 1 or 2, e.g., 1; the 2 carbon atoms in the 5-6 membered heteroalkene ring are replaced with C(O); each 5-6 membered heteroalkane ring can be (2) in ring B, the 5-6 membered heteroaromatic ring has one heteroatom species of N, and the number of heteroatoms can be 1, 2 or 3, for example, 2; for example, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring, and for example, a pyrimidine ring; (3) T is an anti-HER2 antibody, for example, trastuzumab; (4) t is a natural number and / or a decimal number of 7-8; for example, 7.43, 7.68, 7.93, 7.95 or 8; (5) Ring B is a 5-6 membered heteroalkene ring or a 5-6 membered heteroaromatic ring; one or more carbon atoms in the 5-6 membered heteroalkene ring is replaced with C(O); the heteroatom species in the 5-6 membered heteroalkane ring is N, the number of heteroatoms is 1 or 2; the heteroatom species in the 5-6 membered heteroaromatic ring is N, the number of heteroatoms is 1, 2 or 3; for example is Preferably, the "1" position is connected to T and the "2" position is connected to L 1 ; (6) the drug conjugate of formula I-2 is a drug conjugate of formula I-2A or I-2B: (7) m≠n, the drug conjugate of formula II-2 is a drug conjugate of formula II-2A or II-2B: Preferably, in the drug conjugate: T is an anti-HER2 antibody t is a natural number and / or a decimal number of 1-8; ring B is a 5-6 membered heteroalkyl ring or a 5-6 membered heteroaromatic ring; one or more carbon atoms in the 5-6 membered heteroalkyl ring is replaced with C(O); the heteroatom in the 5-6 membered heteroalkyl ring is N, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms is 1, 2 or 3; L 1 independently are each Z is independently C 1-6 alkylene; L 1 the "1 " position is attached to ring A; the "2" position is attached to L 2 ring A; the "2" position is attached to L L 2 independently is a tetrapeptide residue consisting of glycine and phenylalanine; the carbonyl in the tetrapeptide residue is bonded to L 3 is a bond; the NH in the tetrapeptide residue is bonded to L 1 is a bond; L 3 independently are wherein NH is attached to L 2 ; R 1 R is halogen; R 2 is C 1-4 alkyl; Or R 1 and R 2 Connection forms C 1-4 Heteroalkyl; the C 1-4 The heteroatom in the heteroalkylene group is of type O, and the number of heteroatoms is 1 or 2; R 3 and R 4 is H.

11. The drug conjugate of claim 9, wherein, the drug conjugate is any one of the following compounds: wherein T is trastuzumab, and t is as defined in any one of claims 9-10; Preferably, the drug conjugate of formula I-2 or formula II-3 is any one of the following compounds: is trastuzumab.

12. A pharmaceutical composition comprising: (1) a compound of formula I or II as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof, a compound of formula I-1 or II-1 as described in any one of claims 5-8, or a pharmaceutically acceptable salt thereof, or a drug conjugate of formula I-2 or II-2 as described in any one of claims 9-11; and (2) a pharmaceutical excipient.

13. Use of a compound of formula I or II as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof, a compound of formula I-1 or II-1 as described in any one of claims 5-8, or a pharmaceutically acceptable salt thereof, or a drug conjugate of formula I-2 or II-2 as described in any one of claims 9-11, or a pharmaceutical composition as described in claim 12, in the preparation of a medicament for the prevention and / or treatment of cancer; the cancer is pancreatic cancer, breast adenocarcinoma, gastric cancer, colon cancer or breast cancer.

14. Use of the drug conjugate as shown in Formula I-2 or II-2 according to any one of claims 9-11 in the preparation of a medicament for preventing and / or treating a cancer associated with the target of trastuzumab; the cancer associated with the target of trastuzumab is pancreatic cancer, breast adenocarcinoma, gastric cancer, colon cancer or breast cancer.

15. A method for preparing the drug conjugate as shown in Formula I-2 or II-2 according to any one of claims 9-11, comprising the steps of: coupling an antibody with the compound as shown in Formula I-1 or a pharmaceutically acceptable salt thereof in a solvent in the presence of a reducing agent to obtain a compound as shown in Formula I-2 or a pharmaceutically acceptable salt thereof, or coupling an antibody with the compound as shown in Formula II-1 or a pharmaceutically acceptable salt thereof in a solvent in the presence of a reducing agent to obtain a compound as shown in Formula II-2 or a pharmaceutically acceptable salt thereof. Preferably, the solvent is PBS buffer; the reducing agent can be a thiol reducing agent, such as TCEP. ​ ​

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