Camptothecin derivatives and their complexes, as well as methods for preparing them and their medical applications.

Abstract

This invention relates to camptothecin derivatives and their complexes, as well as methods for preparing them and their medical applications. The invention also relates to novel camptothecin derivative derivatives and ligand-drug complexes containing them in the treatment of cancer, pharmaceutical compositions containing the complexes, and applications of the complexes.

Description

[Technical Field]

[0001] The present invention relates to novel camptothecin derivatives and their complexes, as well as methods for preparing the same, pharmaceutical compositions containing the same, and their use in the preparation of antitumor drugs. [Background technology]

[0002] Antibody-drug conjugates (ADCs) are a relatively novel type of anticancer drug that combines the selectivity of monoclonal antibodies with the cytotoxic properties of cytotoxic agents. ADCs have attracted significant attention as a new therapeutic approach and continue to evolve. ADCs are designed to conjugate a monoclonal antibody or antibody fragment to a biologically active cytotoxic agent via a linker, maximizing the antibody binding specificity to tumor cell surface antigens and the high efficiency of the cytotoxic agent, while avoiding drawbacks such as low efficacy of the antibody itself and high side effects of the cytotoxic agent. In other words, compared to conventional chemotherapy drugs, antibody-drug conjugates can kill tumor cells with greater precision and reduce side effects on normal cells. Therefore, the linker in ADC drugs is not only the molecular component that forms a covalent bond between the antibody and the small molecule drug, but also a crucial component with design characteristics in targeted drug therapy. This involves considerations in many aspects: linker incorporation must not induce aggregation, ensure acceptable PK properties, improve blood circulation stability, and efficiently release the active molecule at the target site.

[0003] Camptothecin (CPT) is a pentacyclic quinoline alkaloid originally isolated from the wood and bark of the Chinese bellflower tree, a tree native to China. Camptothecin exhibits remarkable antitumor activity by inhibiting topoisomerase I. Topoisomerase I is an enzyme that is overexpressed in many tumor cell lines and is crucial for DNA synthesis. Camptothecin can bind to the Topo I-DNA complex and stabilize this complex, thereby inhibiting the rejoining of cleaved DNA strands and inhibiting DNA replication and RNA synthesis. Due to its broad antitumor activity and unique mechanism of action, the development of clinical analogues of camptothecin has been ongoing. Currently, there are only three camptothecin analogs on the market: irinotecan (approved by Pfizer in the US with FDA approval in 1994), topotecan (approved by Novartis in 2007 with FDA approval), and belototecan (approved for manufacture and sale in South Korea by Cheonggeundang Pharmaceutical in 2003).

[0004] However, most camptothecin and its derivatives have poor solubility and low activity under physiological conditions, limiting the clinical development of camptothecin analogs. Therefore, these limitations can be overcome by formulating camptothecin into an ADC. Irinotecan is a prodrug, and its active metabolite, SN-38, has poor water solubility and a short half-life. Immunomedics uses certolizumab, which recognizes cancer cells expressing Trop-2, as a toxic substance conjugated with SN-38 for the treatment of adult patients with metastatic triple-negative breast cancer (TNBC). Humanized certolizumab lyophilized powder injection (sacituzumab govitecan-Hziy) was approved by the FDA as a therapeutic agent in April 2022 (US7999083 B2).

[0005] The amino group of exatecan (DX-8951f) contributes to its water solubility, and the rigidity conferred by the cyclohexane ring is thought to favor the balance between the active lactone form and the inactive hydrolyzable hydroxy acid, thereby improving its activity. However, clinical trials did not reach the expected endpoint. Daiichi Sankyo produced DXd using aminohydroxyacetylation, but its activity was 2 to 4 times lower than that of exatecan (US 20210169852 A). Using an enzymatically cleavable Gly-Gly-Phe-Gly tetrapeptide linker to ligate DXd, an ADC (Enhertu) was produced by conjugating it with an anti-HER2 antibody, demonstrating great potential against HER2-expressing cancers in clinical practice. As a result, on December 20, 2019, Enhertu received early approval from the FDA for administration to adult patients with HER2-positive unresectable or metastatic breast cancer who had a history of treatment with two or more anti-HER2 drugs for metastatic disease. The cyclohexylamine ring in DXd is thought to stabilize the biologically active lactone form, but its chiral center complicates the synthesis process and SAR studies. To overcome this challenge, researchers at Immunogen designed a novel camptothecin analog with an antibody-binding site at position 7 by opening the cyclohexylamine ring and removing the extra chiral center. The ADC produced by conjugating it with an antibody against the human epidermal growth factor receptor (HuEGFR) was effective in an EGFR-positive HSC-2 tumor xenograft model (US20210077482A1). Researchers at MediBoston developed an ADC with better preclinical results by inducing an antibody-binding functional group at position 9 and introducing a hydrophilic peptide linker using a similar approach (WO 2021173773).

[0006] Camptothecin analogs have excellent tumor activity. Especially when combined with humanized antibodies, they have excellent target activity, anti-tumor activity, and a low starting dose, resulting in reduced toxicity and an expanded therapeutic range. However, different types of camptothecin derivatives not only have significantly different half-lives, membrane permeability, and in vitro activities, but also greatly different toxicities against different cancer cells. Therefore, in order to achieve a certain clinical effect, we expect to enhance the activity and membrane permeability of camptothecin derivatives to cancer cells (that is, enhance the bystander effect of camptothecin derivatives) by designing new structures, and improve the killing power against tumor cells with low or no antigen expression.

Summary of the Invention

[0007] In one aspect of the present invention, there is provided a compound represented by general formula (A) or a pharmaceutically acceptable salt thereof, TIFF2026510566000001.tif14151 where, Dr is selected from the following structures: TIFF2026510566000002.tif75139R d is hydrogen, halogen, hydroxy group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, -NR d R e 、-(CH2) m -OH、-(CH2) m -NR d R e 、-OC(=O)NR f -(CH2) m -OH、-OC(=O)NR f -(CH2) m -NR[[ID=3,6]] d R e 、-(CH2) m -C(=O)OH、-(CH2) m -C(=O)-NR d R e 、-(CH2) m -C(=O)NR f -(CH2) n -OH、-(CH2) m-C(=O)NR f -(CH2) n -NR d R e , -NR f -(CH2) m -OH, -NR f -(CH2) m -NR d R e -O-(CH2) m -OH, -O-(CH2) m -NR d R e , -NR f C(=O)O-(CH2) m -OH, -NR b C(=O)O-(CH2) m -NR d R e ,-(CH2) m -NR f C(=O)O-(CH2) n -OH-, -(CH2) m -NR f C(=O)O-(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -OH, -(CH2) m -NR f C(=O)-(CH2) n -NR d R e ,-(CH2) m -NR f C(=O)-(CH2) n -OH, -(CH2) m -NR f C(=O)-G-(CH2) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, alkynyl group, and cycloalkyl group are optionally further substituted with one or more groups selected from halogen, deuterium, amino group, alkyl group, and hydroxyl group. R 2 is selected from hydrogen, halogen, hydroxy group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, and the alkyl group, alkoxy group, alkenyl group, alkynyl group are optionally further substituted by one or more groups selected from halogen, R 3 is hydrogen, halogen, hydroxy group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, CH2=, -NR d R e , -(CH2) m -OH, -(CH2) m -NR d R e , -OC(=O)NR f -(CH2) m t -OH, -OC(=O)NR f -(CH2) m -NR d R e , -(CH2) m -C(=O)OH, -(CH2) m -C(=O)-NR d R e , -(CH2) m -C(=O)NR f -(CH2) n -OH, -(CH2) m -C(=O)NR f -(CH2) n -NR d R e , -NR f -(CH2) m -OH, -NR f -(CH2) m -NR d R e , -NR f [[ID=,69]]-C(=O)R d , -NR f -C(=O)-(CH2) m -R d , -NR f C(=O)O-(CH2) m -R d , -O-(CH2) m -OH, -O-(CH2) m -NRd R e 、-NR f C(=O)O-(CH2) m -OH、-NR f C(=O)NR d -(CH2) m -OH、-NR f C(=O)NR d -(CH2) m -O-(CH2) n -OH、-NR f C(=O)O-(CH2) m -O-(CH2) n -OH、-NR f C(=O)NR d -(CH2) m -O-(CH2) n -NR d R e 、-NR f C(=O)O-(CH2) m -O-(CH2) n -NR d R e 、-NR f C(=O)NR d -(CH2) m -NR d R e 、-NR f C(=O)O-(CH2) m -NR d R e 、-(CH2) m -NR f C(=O)O-(CH2) n -OH、-(CH2) m -NR f C(=O)O-(CH2) n -NR d R e 、-(CH2) m -OC(=O)NR f -(CH2) n -NR d R e 、-(CH2) m -OC(=O)NR f -(CH2) n -OH、-(CH2) m -NR f C(=O)-(CH2) n-NR d R e ,-(CH2) m -NR f C(=O)-(CH2) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, or alkynyl group is optionally further substituted with one or more groups selected from halogen, deuterium, amino group, alkyl group, or hydroxyl group. R 4 Hydrogen, halogen, hydroxyl group, carboxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, -NR d R e ,-(CH2) m -OH, -(CH2) m -NR d R e -OC(=O)NR f -(CH2) m -OH, -OC(=O)NR f -(CH2) m -NR d R e ,-(CH2) m -C(=O)OH, -(CH2) m -C(=O)-NR d R e ,-(CH2) m -C(=O)NR f -(CH2) n -OH, -(CH2) m -C(=O)NR f -(CH2) n -NR d R e , -NR f -(CH2) m -OH, -NR f -(CH2) m -NR d R e -O-(CH2) m -OH, -O-(CH2) m -NR d R e , -NR f C(=O)O-(CH2) m -OH, -NR b C(=O)O-(CH2)m -NR d R e ,-(CH2) m -NR f C(=O)O-(CH2) n -OH-, -(CH2) m -NR f C(=O)O-(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -OH, -(CH2) m -NR f C(=O)-(CH2) n -NR d R e ,-(CH2) m -NR f C(=O)-(CH2) n -OH, -(CH2) m -NR f C(=O)-G-(CH2) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, alkynyl group, and cycloalkyl group are optionally further substituted with one or more groups selected from halogen, deuterium, amino group, alkyl group, and hydroxyl group, and the -(CH2) m - is optionally substituted with one or more deuterium or halogens, and G is selected from a cycloalkylene group, a heterocyclylene group, a heteroarylene group, or an arylene group. R 5 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally further substituted with one or more groups selected from halogens. R 6This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally further substituted with one or more groups selected from halogens. R 7 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally further substituted with one or more groups selected from halogens. R d and R e Each is independently selected from hydrogen and alkyl groups. R f is hydrogen, alkyl group, -C(O)R c ,-S(O)R c -S(O)2R c Selected from, the alkyl group is optionally further substituted with a cycloalkyl group, where R c It is selected from hydrogen, hydroxyl group, and alkyl group. L1 is a bond, -(CH2) m -*, -O-*, -NR a -*,-(CH2) m -O-*, -(CH2) m -NR a -*, -OC(=O)NR b -(CH2) m -O-*, -OC(=O)NR b -(CH2) m -NR a -*,-(CH2) m -C(=O)O-*, -(CH2) m -C(=O)NR a -*,-(CH2) m -C(=O)NR b -(CH2) n -O-*, -(CH2) m -C(=O)NR b -(CH2) n -NR a -*, -NR b -(CH2)m -O-*, -NR b -(CH2) m -NR a -*, -O-(CH2) m -O-*, -O-(CH2) m -NR a -*, -NR b C(=O)O-(CH2) m -O-*, -NR b C(=O)O-(CH2) m -NR a -*,-(CH2) m -NR b C(=O)O-(CH2) n -O-*, -(CH2) m -NR b C(=O)O-(CH2) n -NR a -*,-(CH2) m -OC(=O)NR b -(CH2) n -NR a -*,-(CH2) m -OC(=O)NR b -(CH2) n -O-*, -(CH2) m -NR b C(=O)-(CH2) n -NR a -*,-(CH2) m -NR b C(=O)-(CH2) n -O-* is selected, where * is the connection site to L2. R a and R b These are, independently, hydrogen, alkyl group, and -C(O)R c ,-S(O)R c -S(O)2R c Selected from, the alkyl group is optionally further substituted with a cycloalkyl group, where R c It is selected from hydrogen, hydroxyl group, and alkyl group. L2 is a combination, Selected from TIFF2026510566000003.tif23139, where * is the connection point to L1, L is The filename is TIFF2026510566000004.tif1766, L3 is an amino acid residue formed from two or more amino acids, and L3 is optionally selected from one or more of the following structures, and L6 is selected from one or more of the following structures. TIFF2026510566000005.tif161157 Here, R, R aa , R bb Each is independently selected from hydrogen and alkyl groups. L4 is The filename is TIFF2026510566000006.tif2374, Z1 is a bond, -(CH2) p -,-(C2H4O) q -,-(CH2) p -C(O)NH-, -(CH2) p -O-(CH2) p -C(O)NH-, -(CH2) p -C(O)-L6-NH-, -(CH2) p -O-(CH2) p -C(O)-L6-NH-, -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, -NH-, -O-sum-OC(O)NH-, m is an integer between 1 and 6. n is an integer between 1 and 6. s is an integer between 1 and 6. t is an integer between 0 and 10. s1, s2, s3, and s4 are each independent integers between 0 and 10, preferably integers between 0 and 8, and integers between 0 and 6, and also preferably integers between 0 and 4, and particularly preferably integers between 0 and 2, and integers between 1 and 2. s5 and s6 are each independent integers between 1 and 6. t1 is an integer between 1 and 6. t2 is an integer between 0 and 6. t3 is an integer between 1 and 6. t4 is an integer between 0 and 10. t5 is an integer between 0 and 10. p is an integer between 1 and 10. q is an integer between 1 and 10. Q is the linker unit.

[0008] Here, Z1 is connected to Q.

[0009] In certain specific embodiments, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Dr is selected from the following structure: TIFF2026510566000007.tif4151L1 is -O-*, -NR a -*,-(CH2) m -O-*, -(CH2) m -NR a -*, -OC(=O)NR b -(CH2) m -O-*, -OC(=O)NR b -(CH2) m -NR a -*,-(CH2) m -C(=O)O-*, -(CH2) m -C(=O)NR a -*, -NR b -(CH2) m -O-*, -NR b -(CH2) m -NR a -*, -O-(CH2) m -O-*, -O-(CH2) m -NR a -*, -NR b C(=O)O-(CH2) m -O-*, -NR b C(=O)O-(CH2) m -NR a -*,-(CH2) m -NR b C(=O)-(CH2) n -NR a -*,-(CH2) m -NR b C(=O)-(CH2) n -O-* is selected, where * is the connection site to L2. R a These are selected from hydrogen and C1-C6 alkyl groups. R b is hydrogen, alkyl group, -C(O)R c ,-S(O)R c -S(O)2R c Selected from, here, R c These are selected from hydrogen, a hydroxyl group, and a C1-C6 alkyl group. m is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably between 1 and 2. n is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably between 1 and 2. R 1 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally further substituted with one or more groups selected from halogens, preferably C1-C6 alkyl group and C1-C6 alkoxy group. R 2 The group is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally further substituted with one or more groups selected from halogens, preferably halogens.

[0010] In another specific embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Dr is selected from the following structure: TIFF2026510566000008.tif4251L1 is -O-*, -NR a -*,-(CH2) m -O-*, -(CH2) m -NR a-*, -OC(=O)NR b -(CH2) m -O-*, -OC(=O)NR b -(CH2) m -NR a -*,-(CH2) m -C(=O)O-*, -(CH2) m -C(=O)NR a -*, -NR b -(CH2) m -O-*, -NR b -(CH2) m -NR a -*, -O-(CH2) m -O-*, -O-(CH2) m -NR a -*, -NR b C(=O)O-(CH2) m -O-*, -NR b C(=O)O-(CH2) m -NR a -*,-(CH2) m -NR b C(=O)-(CH2) n -NR a -*,-(CH2) m -NR b C(=O)-(CH2) n -O-* is selected, where * is the connection site to L2. R a These are selected from hydrogen and C1-C6 alkyl groups. R b is hydrogen, alkyl group, -C(O)R c ,-S(O)R c -S(O)2R c Selected from, the alkyl group is optionally further substituted with a cycloalkyl group, where R c These are selected from hydrogen, a hydroxyl group, and a C1-C6 alkyl group. m is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably between 1 and 2. n is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably between 1 and 2. R 1This includes hydrogen, halogens, hydroxyl groups, amino groups, cyano groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C6 cycloalkyl groups, and -NR. d R e ,-(CH2) m -OH, -(CH2) m -NR d R e -OC(=O)NR f -(CH2) m -OH, -OC(=O)NR f -(CH2) m -NR d R e ,-(CH2) m -C(=O)OH, -(CH2) m -C(=O)-NR d R e ,-(CH2) m -C(=O)NR f -(CH2) n -OH, -(CH2) m -C(=O)NR f -(CH2) n -NR d R e , -NR f -(CH2) m -OH, -NR f -(CH2) m -NR d R e -O-(CH2) m -OH, -O-(CH2) m -NR d R e , -NR f C(=O)O-(CH2) m -OH, -NR b C(=O)O-(CH2) m -NR d R e ,-(CH2) m -NR f C(=O)O-(CH2) n -OH-, -(CH2) m -NR f C(=O)O-(CH2) n -NR d R e,-(CH2) m -OC(=O)NR f -(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -OH, -(CH2) m -NR f C(=O)-(CH2) n -NR d R e ,-(CH2) m -NR f C(=O)-(CH2) n -OH, -(CH2) m -NR f C(=O)-G-(CH2) n -OH is selected, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, and C3-C6 cycloalkyl group are optionally further substituted with one or more groups selected from halogen, deuterium, amino group, C1-C6 alkyl group, and hydroxyl group, preferably C1-C6 alkyl group and C1-C6 alkoxy group, and the -(CH2) m - is optionally substituted with one or more deuterium or halogens, and G is selected from a cycloalkylene group, a heterocyclylene group, a heteroarylene group, or an arylene group. R 2 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally further substituted with one or more groups selected from halogens, preferably halogens. R d , R e , R f m and n are defined as shown in general formula (A).

[0011] In another specific embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Dr is selected from the following structure: TIFF2026510566000009.tif4049L1 is a bond, -(CH2) m -*, -O-*, -(CH2) m -O-*, -NR a -*,-(CH2) m -NR a -*, -NR b -(CH2) m -O-*, -NR b -(CH2) m -NR a -*, -O-(CH2) m -O-*, -O-(CH2) m -NR a -*,-(CH2) m -OC(=O)NR b -(CH2) n -NR a -*,-(CH2) m -OC(=O)NR b -(CH2) n -O-*, -(CH2) m -NR b C(=O)-(CH2) n -NR a -*,-(CH2) m -NR b C(=O)-(CH2) n -O-* is selected, where * is the connection site to L2. R a These are selected from hydrogen and C1-C6 alkyl groups. R b is hydrogen, alkyl group, -C(O)R c ,-S(O)R c -S(O)2R c Selected from, the alkyl group is optionally further substituted with a cycloalkyl group, where R c These are selected from hydrogen, a hydroxyl group, and a C1-C6 alkyl group. m is an integer between 1 and 6, preferably between 1 and 4. n is an integer between 1 and 6, preferably between 1 and 4. R 2 The group is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally further substituted with one or more groups selected from halogens, preferably halogens.

[0012] In another specific embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Dr is selected from the following structure: TIFF2026510566000010.tif3948L1 is selected from -O-*, where * is the linking site to L2. R 2 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally further substituted with one or more groups selected from halogens, preferably halogens. R 3 This includes hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, CH2=, -NR d R e ,-(CH2) m -OH, -(CH2) m -NR d R e -OC(=O)NR f -(CH2) m -OH, -OC(=O)NR f -(CH2) m -NR d R e ,-(CH2) m -C(=O)OH, -(CH2)m -C(=O)-NR d R e 、-(CH2) m -C(=O)NR f -(CH2) n -OH、-(CH2) m -C(=O)NR f -(CH2) n -NR d R e 、-NR f -(CH2) m -OH、-NR f -(CH2) m -NR d R e 、-NR f -C(=O)R d 、-NR f -C(=O)-(CH2) m -R d 、-NR f C(=O)O-(CH2) m -R d 、-O-(CH2) m -OH、-O-(CH2) m -NR d R e 、-NR f C(=O)O-(CH2) m -OH、-NR f C(=O)NR d -(CH2) m -OH、-NR f C(=O)NR d -(CH2) m -O-(CH2) n -OH、-NR f C(=O)O-(CH2) m -O-(CH2) n -OH、-NR f C(=O)NR d -(CH2) m -O-(CH2) n -NR d R e 、-NR f C(=O)O-(CH2) m -O-(CH2) n -NR d R e 、-NR fC(=O)NR d -(CH2) m -NR d R e , -NR f C(=O)O-(CH2) m -NR d R e ,-(CH2) m -NR f C(=O)O-(CH2) n -OH, -(CH2) m -NR f C(=O)O-(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -OH, -(CH2) m -NR f C(=O)-(CH2) n -NR d R e ,-(CH2) m -NR f C(=O)-(CH2) n -OH is selected, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally further substituted with one or more groups selected from halogens, deuterium, amino groups, C1-C6 alkyl groups, and hydroxyl groups, preferably hydrogen or a hydroxyl group. R 4 This includes hydrogen, halogens, hydroxyl groups, carboxyl groups, amino groups, cyano groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C6 cycloalkyl groups, and -NR. d R e ,-(CH2) m -OH, -(CH2) m -NR d R e -OC(=O)NR f -(CH2)m -OH、-OC(=O)NR f -(CH2) m -NR d R e 、-(CH2) m -C(=O)OH、-(CH2) m -C(=O)-NR d R e 、-(CH2) m -C(=O)NR f -(CH2) n -OH、-(CH2) m -C(=O)NR f -(CH2) n -NR d R e 、-NR f -(CH2) m -OH、-NR f -(CH2) m -NR d R e 、-O-(CH2) m -OH、-O-(CH2) m -NR d R e 、-NR f C(=O)O-(CH2) m -OH、-NR b C(=O)O-(CH2) m -NR d R e 、-(CH2) m -NR f C(=O)O-(CH2) n -OH-、-(CH2) m -NR f C(=O)O-(CH2) n -NR d R e 、-(CH2) m -OC(=O)NR f -(CH2) n -NR d R e 、-(CH2) m -OC(=O)NR f -(CH2) n -OH、-(CH2) m -NR f C(=O)-(CH2) n -NRd R e ,-(CH2) m -NR f C(=O)-(CH2) n -OH, -(CH2) m -NR f C(=O)-G-(CH2) n -OH is selected, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, and C3-C6 cycloalkyl group are optionally further substituted with one or more groups selected from halogen, deuterium, amino group, C1-C6 alkyl group, and hydroxyl group, preferably a hydroxyl group, a C1-C6 alkyl group, and a C1-C6 alkoxy group, and the -(CH2) m - is optionally substituted with one or more deuterium or halogens, and G is selected from a cycloalkylene group, a heterocyclylene group, a heteroarylene group, or an arylene group. R d , R e , R f m and n are defined as shown in general formula (A).

[0013] In another specific embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Dr is selected from the following structure: TIFF2026510566000011.tif3948L1 is selected from -O-*, where * is the linking site to L2. R 2 The group is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally further substituted with one or more groups selected from halogens, preferably halogens. R 3This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, and CH2=, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally substituted with one or more groups further selected from halogens, preferably hydrogen or a hydroxyl group. R 4 The group is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally substituted with one or more groups further selected from halogens, preferably a hydroxyl group, a C1-C6 alkyl group, and a C1-C6 alkoxy group.

[0014] In another specific embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Dr is selected from the following structure: TIFF2026510566000012.tif3550L1 is -(CH2) m -O-*, -(CH2) m -NR a - Selected from *, where * is the connection point to L2, m is an integer between 1 and 6, preferably between 1 and 4. R a These are selected from hydrogen and C1-C6 alkyl groups. R 5 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally further substituted with one or more groups selected from halogens, preferably halogens. R 7The group is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally substituted with one or more groups further selected from halogens, preferably a hydroxyl group and an amino group.

[0015] In another specific embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Dr is selected from the following structure: TIFF2026510566000013.tif3550L1 is selected from -O-*, where * is the linking site to L2. R 5 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally further substituted with one or more groups selected from halogens, preferably halogens. R 6 This group is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally substituted with one or more groups further selected from halogens, preferably a hydroxyl group and an amino group. R 7The group is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, and C2-C6 alkynyl group are optionally substituted with one or more groups further selected from halogens, preferably a hydroxyl group and an amino group.

[0016] In certain preferred embodiments, the compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Dr is Selected from TIFF2026510566000014.tif78150.

[0017] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L1 is -NR a -*,-(CH2) m -NR a -*, -OC(=O)NR b -(CH2) m -NR a -*,-(CH2) m -C(=O)NR a -*,-(CH2) m -C(=O)NR b -(CH2) n -NR a -*, -NR b -(CH2) m -NR a -*, -O-(CH2) m -NR a -*, -NR b C(=O)O-(CH2) m -NR a -*,-(CH2) m -NR b C(=O)O-(CH2) n -NR a -*,-(CH2) m -OC(=O)NR b -(CH2) n -NR a-* or -(CH2) m -NR b C(=O)-(CH2) n -NR a -Selected from *, where * is a connection point to L2, L2 is a combination or Selected from TIFF2026510566000015.tif2235, where * is the connection point to L1, R a , R b m and n are as defined in general formula (A).

[0018] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L1 is a bond, -O-*, -(CH2) m -O-*, -NR a -*, -OC(=O)NR b -(CH2) m -O-*, -(CH2) m -C(=O)O-*, -(CH2) m -C(=O)NR b -(CH2) n -O-*, -NR b -(CH2) m -O-*, -O-(CH2) m -O-*, -NR b C(=O)O-(CH2) m -O-*, -(CH2) m -NR b C(=O)O-(CH2) n -O-*, -(CH2) m -OC(=O)NR b -(CH2) n -O-* or -(CH2) m -NR b C(=O)-(CH2) n -O-* is selected, where * is a connection site to L2, L2 is a combination, Selected from TIFF2026510566000016.tif23139, where * is the connection point to L1, R a , R b m and n are as defined in general formula (A).

[0019] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L3 is an amino acid residue formed from two or more amino acids selected from phenylalanine, alanine, glycine, valine, leucine, isoleucine, tryptophan, tyrosine, histidine, lysine, citrulline, serine, threonine, cysteine, glutamic acid, glutamine, aspartic acid, asparagine, methionine, and arginine, and L3 optionally includes one or more structures selected from the following: TIFF2026510566000017.tif161157 Preferably, TIFF2026510566000018.tif46145 The filename is TIFF2026510566000019.tif75120. Here, R, R aa , R bb Each is independently selected from hydrogen and a C1-C6 alkyl group. s is an integer between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. s5 and s6 are each independent integers between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. t is an integer between 0 and 10, preferably between 2 and 8, and particularly preferably between 3 and 7. t1 is an integer between 1 and 6, preferably between 1 and 4, also preferably between 2 and 4, and also preferably 1 or 2. t2 is an integer between 0 and 6, preferably between 1 and 4, and also preferably 1 or 2. t3 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably 1 or 2. t4 is an integer between 0 and 10. t5 is an integer between 0 and 10.

[0020] In another embodiment, L3 is an amino acid residue formed from two or more amino acids selected from phenylalanine, alanine, glycine, valine, leucine, isoleucine, tryptophan, tyrosine, histidine, lysine, citrulline, serine, threonine, cysteine, glutamic acid, glutamine, aspartic acid, asparagine, methionine, and arginine, and L3 comprises one or more structures optionally selected from: TIFF2026510566000020.tif126157R,R aa , R bb s, t, t1-t5, and s5-s6 are as described above.

[0021] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L3 is The filename is TIFF2026510566000021.tif18120, where * represents a linking site to L2, and · represents a linking site to a carbonyl group or methylene group. Here, L 1b and L' 1b Each of these is an amino acid residue formed independently from one or more amino acids selected from phenylalanine, alanine, glycine, valine, leucine, isoleucine, tryptophan, tyrosine, histidine, lysine, citrulline, serine, threonine, cysteine, glutamic acid, glutamine, aspartic acid, asparagine, methionine, and arginine. L 1a This is a combination or one or more of the following structures: TIFF2026510566000022.tif161157 Preferably, TIFF2026510566000023.tif45150 The filename is TIFF2026510566000024.tif77138. Here, R is selected from hydrogen and C1-C6 alkyl groups, preferably hydrogen. R aa , R bb Each of these is independently selected from C1-C6 alkyl groups. s is an integer between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. s5 and s6 are each independent integers between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. t is an integer between 0 and 10, preferably between 2 and 8, and particularly preferably between 3 and 7. t1 is an integer between 1 and 6, preferably between 1 and 4, also preferably between 2 and 4, and also preferably 1 or 2. t2 is an integer between 0 and 6, preferably between 1 and 4, and also preferably 1 or 2. t3 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably 1 or 2. t4 is an integer between 0 and 10. t5 is an integer between 0 and 10.

[0022] In another embodiment, L3 is The filename is TIFF2026510566000025.tif14120, where * represents a linking site to L2, and · represents a linking site to a carbonyl group or methylene group. Here, L 1b and L' 1b Each of these is an amino acid residue formed independently from one or more amino acids selected from phenylalanine, alanine, glycine, valine, leucine, isoleucine, tryptophan, tyrosine, histidine, lysine, citrulline, serine, threonine, cysteine, glutamic acid, glutamine, aspartic acid, asparagine, methionine, and arginine. L 1a This is a combination or one or more of the following structures: TIFF2026510566000026.tif115157R,R aa , R bb s, t, t1-t5, and s5-s6 are as described above.

[0023] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L3 is TIFF2026510566000027.tif81157 Selected from TIFF2026510566000028.tif169157, Here, L 1b and L' 1b These are amino acid residues formed from one or more amino acids selected from phenylalanine, alanine, glycine, valine, leucine, isoleucine, tryptophan, tyrosine, histidine, lysine, citrulline, serine, threonine, cysteine, glutamic acid, glutamine, aspartic acid, asparagine, methionine, and arginine, respectively. R is selected from hydrogen and C1-C6 alkyl groups, preferably hydrogen. R aa , R bb Each of these is independently selected from C1-C6 alkyl groups. s is an integer between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. s5 and s6 are each independent integers between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. t is an integer between 0 and 10, preferably between 2 and 8, and particularly preferably between 3 and 7. t1 is an integer between 1 and 6, preferably between 1 and 4, also preferably between 2 and 4, and also preferably 1 or 2. t2 is an integer between 0 and 6, preferably between 1 and 4, and also preferably 1 or 2. t3 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably 1 or 2. t4 is an integer between 0 and 10. t5 is an integer between 0 and 10. * indicates the connection point to L2. TIFF2026510566000029.tif78 is a linking site to a carbonyl group or a methylene group.

[0024] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L3 is TIFF2026510566000030.tif117157 Selected from TIFF2026510566000031.tif122150, Here, L 1b and L' 1b These are amino acid residues formed from one or more amino acids selected from phenylalanine, alanine, glycine, valine, leucine, isoleucine, tryptophan, tyrosine, histidine, lysine, citrulline, serine, threonine, cysteine, glutamic acid, glutamine, aspartic acid, asparagine, methionine, and arginine, respectively. R is selected from hydrogen and C1-C6 alkyl groups, preferably hydrogen. R aa , R bb Each of these is independently selected from C1-C6 alkyl groups. s5 and s6 are each independent integers between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. t is an integer between 0 and 10, preferably between 2 and 8, and particularly preferably between 3 and 7. t1 is an integer between 1 and 6, preferably between 1 and 4, also preferably between 2 and 4, and also preferably 1 or 2. t2 is an integer between 0 and 6, preferably between 1 and 4, and also preferably 1 or 2. t3 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably 1 or 2. t4 is an integer between 0 and 10. t5 is an integer between 0 and 10. * indicates the connection point to L2. TIFF2026510566000032.tif78 is a linking site to a carbonyl group or a methylene group.

[0025] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L 1b and L' 1b Each of these is an amino acid residue formed from one or more amino acids selected from glycine, phenylalanine, citrulline, leucine, isoleucine, alanine, valine, asparagine, glutamine, arginine, glutamic acid, and lysine, and is preferably an amino acid residue formed from two or more amino acids selected from glycine, phenylalanine, citrulline, valine, lysine, glutamine, glutamic acid, leucine, and alanine.

[0026] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L 1b and L' 1bare each independently, -Gly-*, -Val-*, -Gly-Phe-Gly-*, -Phe-Gly-*, -Gly-Val-Cit-*, -Val-Cit-*, -Gly-Val-Arg-*, -Val-Arg-*, -Gly-Val-Ala-*, -Val-Ala-*, -Gly-Phe-*, -Phe-Gly-*, -Gly-Gly-Gly-*, Gly-Gly-*, -Gly-Val-Gly-*, -Gly-Ala-Gly-*, -Gly-Phe-Cit-*, -Gly-Phe-Val-*, -Gly-Phe-Ala-*, -Gly-Phe-Lys-*, -Phe-Lys-*, -Gly-Val-*, -Gly-Cit-*, -Gly-Ala-*, -Gly-Gly-Lys-*, Gly-Lys’-*, -Ala-Ala-Ala-*, -Gln-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, -Asp-Val-Cit-*, -Lys-Gly-Val-Ala-*, -Lys-Gly-Val-Cit-*, -Lys-Gly-Gly-Val-Ala-*, -Lys-Gly-Gly-Val-Cit-*, Gly-Gly-Phe-Gly-*, -Lys-Gln-Val-Cit-*, -Lys-Gln-Val-Ala-*, -Lys-Glu-Val-Cit-*, -Lys-Glu-Val-ALa-*, -Lys-Asp-Val-Cit-*, -Lys-Asp-Val-Ala-*, Glu-Val-Cit-*, Glu-Val-Ala-*, -Lys-Val-Ala-*, -Lys-Val-Cit-*, -Val-Lys-Gly-*, -Val-Lys*,Preferably -Gly-Phe-Gly-*, -Gly-Val-Cit-*, -Val-Cit-*, -Gly-Val-Ala-*, -Val-Ala-*, -Gly-Phe-Gly-*, -Phe-Gly-*, -Gly-Phe-Lys-, -Phe-Lys-*, -Gl n-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, -Lys-Gly-Val-Ala-*, -Lys-Gly-Val-Cit-*, -Lys-Gly-Gly-Val-Ala-*, -Lys-Gly-Gly-Val-Cit-*, G Selected from ly-Gly-Phe-Gly-*, -Lys-Gln-Val-Cit-*, -Lys-Gln-Val-Ala-*, -Lys-Glu-Val-Cit-*, -Lys-Glu-Val-ALa-*, -Lys-Asp-Val-Cit-*, -Lys-Asp-Val-Ala-*, Glu-Val-Cit-*, Glu-Val-Ala-*, -Lys-Val-Ala-*, -Lys-Val-Cit-*, -Val-Lys-Gly-*, -Val-Lys-*, -Asp-Val-Cit-*, where * is the linkage site to L2.

[0027] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L3 is TIFF2026510566000033.tif213157 TIFF2026510566000034.tif245132 TIFF2026510566000035.tif240150 TIFF2026510566000036.tif240140 Selected from TIFF2026510566000037.tif110124, * indicates the connection point to L2. TIFF2026510566000038.tif78 is a linking site to a carbonyl group or a methylene group.

[0028] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Q is Selected from TIFF2026510566000039.tif64150, preferably, TIFF2026510566000040.tif27143 The filename is TIFF2026510566000041.tif20113.

[0029] In another preferred embodiment, a compound represented by the general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Z1 is a bond, -(CH2) p -,-(CH2) p -C(O)NH-, -(CH2) p -O-(CH2) p -C(O)NH-, -(CH2) p -C(O)-L6-NH-, -(CH2) p -O-(CH2) p The elements are selected from -C(O)-L6-NH-, -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)- and -OC(O)NH-, where p is an integer from 1 to 10, preferably from 1 to 6, particularly preferably from 2 to 4, and most preferably from 2 to 3. s1, s2, s3, and s4 are each independent integers between 0 and 10, preferably between 0 and 8, preferably between 0 and 6, also preferably between 0 and 4, and particularly preferably between 0 and 2, and between 1 and 2. L6 is Selected from TIFF2026510566000042.tif6480, s is an integer between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. t is an integer between 0 and 10, preferably between 2 and 8, and particularly preferably between 3 and 7. Preferably, L6 is The filename is TIFF2026510566000043.tif43116.

[0030] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Z1 is a bond, -(CH2) p -,-(CH2) p -C(O)NH-, -(CH2) p -O-(CH2) p Selected from -C(O)NH-, -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, and -OC(O)NH-, s1 is an integer between 0 and 6, preferably an integer between 0 and 2. s2 is an integer between 0 and 6, preferably an integer between 0 and 2. s3 is 0, s4 is 0, p is an integer between 1 and 10, preferably between 1 and 6, particularly preferably between 2 and 4, and most preferably between 2 and 3.

[0031] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Z1 is -(CH2) p -C(O)NH-, -(CH2) p -O-(CH2) p -C(O)NH-, -C(O)NH- selected, s1 is an integer between 1 and 6, preferably between 2 and 6. s2 is an integer between 1 and 10, preferably between 2 and 10. s3 is 0, s4 is 0, p is an integer between 1 and 10, preferably between 1 and 6, particularly preferably between 2 and 4, and most preferably between 2 and 3.

[0032] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Q-L4- is TIFF2026510566000044.tif44157 Selected from TIFF2026510566000045.tif19150, Here, Z1 is selected from -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)- and -OC(O)NH-, and is preferably -C(O)NH-. p is an integer between 1 and 10, preferably between 1 and 6, particularly preferably between 2 and 4, and most preferably between 2 and 3. s1 is an integer between 0 and 6, preferably an integer between 0 and 2. s2 is an integer between 1 and 10, preferably an integer between 1 and 8. s3 is an integer between 0 and 6, preferably an integer between 0 and 2. s4 is an integer between 1 and 6, preferably an integer between 1 and 2. s7 is an integer between 0 and 6, preferably an integer between 1 and 2. s8 is an integer between 1 and 4, preferably an integer between 1 and 2. s9 is an integer between 1 and 10, preferably an integer between 1 and 8. s 10 is an integer between 1 and 4, preferably an integer between 1 and 2.

[0033] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L is TIFF2026510566000046.tif109157 TIFF2026510566000047.tif245146 Selected from TIFF2026510566000048.tif153150, Here, L 1bis an amino acid residue formed from two or more amino acids selected from glycine, phenylalanine, citrulline, leucine, isoleucine, alanine, valine, asparagine, glutamine, arginine, glutamic acid, and lysine, preferably an amino acid residue formed from two or more amino acids selected from glycine, phenylalanine, citrulline, leucine, alanine, valine, glutamine, glutamic acid, and lysine, particularly preferably -Gly-*, -Val-*, -Gly-Phe-Gly-*, -Phe-Gly-*, -Gly-Val-Cit-*, -Val-Cit-*, -Gly-Val-Arg-*, -Val-Arg-*, -Gly-Val-Ala-*, -Val-Ala-*, -Gly-Phe-*, -Phe-Gly-*, -Gly-Gly-Gly-*, Gly-Gly-*, -Gly-Val-Gly-*, -Gly-Ala-Gly-*, -Gly-Phe-Cit-*, -Gly-Phe-Val-*, -Gly-Phe-Ala-*, -Gly-Phe-Lys-*, -Phe-Lys-*, -Gly-Val-*, -Gly-Cit-*, -G ly-Ala-*, -Gly-Gly-Lys-*, Gly-Lys'-*, -Ala-Ala-Ala-*, -Gln-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, -Asp-Val-Cit-*, -Lys-Gly-Val-Al a-*, -Lys-Gly-Val-Cit-*, -Lys-Gly-Gly-Val-Ala-*, -Lys-Gly-Gly-Val-Cit-*, Gly-Gly-Phe-Gly-*, -Lys-Gln-Val-Cit-*, -Lys-Gln-Val-Ala-*, -Lys-Glu-Val-Cit-*, -Lys-Glu-Val-ALa-*, -Lys-Asp-Val-Cit-*, -Lys-Asp-Val-Ala-*, Glu-Val-Cit-*, Glu-Val-Ala-*, -Lys-Val-Ala-*, -Lys-V al-Cit-*, -Val-Lys-Gly-*, -Val-Lys-*, preferably -Gly-Phe-Gly-*, -Gly-Val-Cit-*, -Val-Cit-*, -Gly-Val-Ala-*, -Val-Ala-*, -Gly-Phe-Gly-*,-Phe-Gly-*, -Gly-Phe-Lys-, -Phe-Lys-*, -Gln-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, -Lys-Gly-Val-Ala-* , -Lys-Gly-Val-Cit-*, -Lys-Gly-Gly-Val-Ala-*, -Lys-Gly-Gly-Val-Cit-*, Gly-Gly-Phe-Gly-*, -Lys-Gln-Val-Cit -*, -Lys-Gln-Val-Ala-*, -Lys-Glu-Val-Cit-*, -Lys-Glu-Val-ALa-*, -Lys-Asp-Val-Cit-*, -Lys-Asp-Val-Ala-*, Gl u-Val-Cit-*, Glu-Val-Ala-*, -Lys-Val-Ala-*, -Lys-Val-Cit-*, -Val-Lys-Gly-*, -Val-Lys-*, -Asp-Val-Cit-*, * indicates the connection point to L2. Z1 is selected from -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)- and -OC(O)NH-, and is preferably -C(O)NH-. p is an integer between 1 and 10, preferably an integer between 1 and 6. s1 is an integer between 0 and 6, preferably an integer between 0 and 2. s2 is an integer between 1 and 6, preferably an integer between 1 and 2. s3 is an integer between 0 and 6, preferably an integer between 0 and 2. s4 is an integer between 1 and 6, preferably an integer between 1 and 2. t is an integer between 0 and 10. t1 is an integer between 1 and 6, preferably between 1 and 4, also preferably between 2 and 4, and also preferably 1 or 2. t2 is an integer between 0 and 6, preferably between 1 and 4, and also preferably 1 or 2. t3 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably 1 or 2.

[0034] In certain preferred embodiments, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L 1bis an amino acid residue formed from one or more amino acids selected from glycine, phenylalanine, citrulline, leucine, isoleucine, alanine, valine, asparagine, glutamine, arginine, glutamic acid, and lysine, preferably an amino acid residue formed from two or more amino acids selected from glycine, phenylalanine, citrulline, leucine, alanine, valine, glutamine, glutamic acid, and lysine, particularly preferably -Gly-*, -Val-*, -Gly-Phe-Gly-*, -Phe-Gly-*, - Gly-Val-Cit-*, -Val-Cit-*, -Gly-Val-Arg-*, -Val-Arg-*, -Gly-Val-Ala-*, -Val-Ala-*, -Gly-Phe-*, -Phe-Gly-*, -Gly-Gly-Gly-*, Gly-Gly-*, - Gly-Val-Gly-*, -Gly-Ala-Gly-*, -Gly-Phe-Cit-*, -Gly-Phe-Val-*, -Gly-Phe-Ala-*, -Gly-Phe-Lys-*, -Phe-Lys-*, -Gly-Val-*, -Gly-Cit-*, -Gl y-Ala-*, -Gly-Gly-Lys-*, Gly-Lys'-*, -Ala-Ala-Ala-*, -Gln-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, -Asp-Val-Cit-*, -Lys-Gly-Val-Ala -*, -Lys-Gly-Val-Cit-*, -Lys-Gly-Gly-Val-Ala-*, -Lys-Gly-Gly-Val-Cit-*, Gly-Gly-Phe-Gly-*, -Lys-Gln-Val-Cit-*, -Lys-Gln-Val-Ala-*, - Lys-Glu-Val-Cit-*, -Lys-Glu-Val-ALa-*, -Lys-Asp-Val-Cit-*, -Lys-Asp-Val-Ala-*, Glu-Val-Cit-*, Glu-Val-Ala-*, -Lys-Val-Ala-*, -Lys-Va l-Cit-*, -Val-Lys-Gly-*, -Val-Lys-*, preferably -Gly-Phe-Gly-*, -Gly-Val-Cit-*, -Val-Cit-*, -Gly-Val-Ala-*, -Val-Ala-*, -Gly-Phe-Gly-*,-Phe-Gly-*, -Gly-Phe-Lys-, -Phe-Lys-*, -Gln-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, -Lys-Gly-Val-Ala-* , -Lys-Gly-Val-Cit-*, -Lys-Gly-Gly-Val-Ala-*, -Lys-Gly-Gly-Val-Cit-*, Gly-Gly-Phe-Gly-*, -Lys-Gln-Val-Cit -*, -Lys-Gln-Val-Ala-*, -Lys-Glu-Val-Cit-*, -Lys-Glu-Val-ALa-*, -Lys-Asp-Val-Cit-*, -Lys-Asp-Val-Ala-*, Gl u-Val-Cit-*, Glu-Val-Ala-*, -Lys-Val-Ala-*, -Lys-Val-Cit-*, -Val-Lys-Gly-*, -Val-Lys-*, -Asp-Val-Cit-*. ,

[0035] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L' 1bThis is an amino acid residue formed from one or more amino acids selected from glycine, phenylalanine, citrulline, leucine, isoleucine, alanine, valine, asparagine, glutamine, arginine, glutamic acid, and lysine, preferably an amino acid residue formed from two or more amino acids selected from glycine, phenylalanine, citrulline, leucine, aspartic acid, alanine, valine, glutamine, glutamic acid, and lysine, and particularly preferably -Gly-*, -Val-*, -Gly-Phe-Gly-*, and -Ph e-Gly-*, -Gly-Val-Cit-*, -Val-Cit-*, -Gly-Val-Arg-*, -Val-Arg-*, -Gly-Val-Ala-*, -Val-Ala-*, -Gly-Phe-*, -Phe-Gly-*, -Gly-Gly-Gly-*, G ly-Gly-*, -Gly-Val-Gly-*, -Gly-Ala-Gly-*, -Gly-Phe-Cit-*, -Gly-Phe-Val-*, -Gly-Phe-Ala-*, -Gly-Phe-Lys-*, -Phe-Lys-*, -Gly-Val-*, -Gl y-Cit-*, -Gly-Ala-*, -Gly-Gly-Lys-*, Gly-Lys'-*, -Ala-Ala-Ala-*, -Gln-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, -Asp-Val-Cit-*, -Lys -Gly-Val-Ala-*, -Lys-Gly-Val-Cit-*, -Lys-Gly-Gly-Val-Ala-*, -Lys-Gly-Gly-Val-Cit-*, Gly-Gly-Phe-Gly-*, -Lys-Gln-Val-Cit-*, -Lys-Gl n-Val-Ala-*, -Lys-Glu-Val-Cit-*, -Lys-Glu-Val-ALa-*, -Lys-Asp-Val-Cit-*, -Lys-Asp-Val-Ala-*, Glu-Val-Cit-*, Glu-Val-Ala-*, -Lys-Val -Ala-*, -Lys-Val-Cit-*, -Val-Lys-Gly-*, -Val-Lys-*, preferably -Gly-Phe-Gly-*, -Gly-Val-Cit-*, -Val-Cit-*, -Gly-Val-Ala-*, -Val-Ala-*,-Gly-Phe-Gly-*, -Phe-Gly-*, -Gly-Phe-Lys-, -Phe-Lys-*, -Gln-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, -Lys-Gl y-Val-Ala-*, -Lys-Gly-Val-Cit-*, -Lys-Gly-Gly-Val-Ala-*, -Lys-Gly-Gly-Val-Cit-*, Gly-Gly-Phe-Gly-*, -Lys-Gln- Val-Cit-*, -Lys-Gln-Val-Ala-*, -Lys-Glu-Val-Cit-*, -Lys-Glu-Val-ALa-*, -Lys-Asp-Val-Cit-*, -Lys-Asp-Val-Ala- *, Glu-Val-Cit-*, Glu-Val-Ala-*, -Lys-Val-Ala-*, -Lys-Val-Cit-*, -Val-Lys-Gly-*, -Val-Lys-*, -Asp-Val-Cit-*. ,

[0036] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L 1b and L' 1b These are -Gly-* or -Val-*.

[0037] In another preferred embodiment, a compound represented by general formula (A) described in the present invention or a pharmaceutically acceptable salt thereof, wherein the compound is TIFF2026510566000049.tif194111 TIFF2026510566000050.tif231130 TIFF2026510566000051.tif231124 TIFF2026510566000052.tif240142 TIFF2026510566000053.tif227150 TIFF2026510566000054.tif236157 TIFF2026510566000055.tif221150 TIFF2026510566000056.tif222128 TIFF2026510566000057.tif240134 TIFF2026510566000058.tif230139 TIFF2026510566000059.tif231116 TIFF2026510566000060.tif239157 TIFF2026510566000061.tif245123 TIFF2026510566000062.tif231117 TIFF2026510566000063.tif187125 TIFF2026510566000064.tif240123 TIFF2026510566000065.tif245143 TIFF2026510566000066.tif235157 Selected from TIFF2026510566000067.tif46134.

[0038] In another aspect of the present invention, a compound represented by general formula (I) or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof are provided. TIFF2026510566000068.tif4550 Here, R 8 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally further substituted with one or more groups selected from halogens. R 9 Hydrogen, halogen, hydroxyl group, carboxyl group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, -NR d R e ,-(CH2) m -OH, -(CH2)m -NR d R e 、-OC(=O)NR f -(CH2) m -OH、-OC(=O)NR f -(CH2) m -NR d R e 、-(CH2) m -C(=O)OH、-(CH2) m -C(=O)-NR d R e 、-(CH2) m -C(=O)NR f -(CH2) n -OH、-(CH2) m -C(=O)NR f -(CH2) n -NR d R e 、-NR f -(CH2) m -OH、-NR f -(CH2) m -NR d R e 、-O-(CH2) m -OH、-O-(CH2) m -NR d R e 、-NR f C(=O)O-(CH2) m -OH、-NR b C(=O)O-(CH2) m -NR d R e 、-(CH2) m -NR f C(=O)O-(CH2) n -OH、-(CH2) m -NR f C(=O)O-(CH2) n -NR d R e 、-(CH2) m -OC(=O)NR f -(CH2) n -NR d R e 、-(CH2) m -OC(=O)NR f -(CH2) n-OH, -(CH2) m -NR f C(=O)-(CH2) n -NR d R e ,-(CH2) m -NR f C(=O)-(CH2) n -OH, -(CH2) m -NR f C(=O)-G-(CH2) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, alkynyl group, and cycloalkyl group are optionally further substituted with one or more groups selected from deuterium, halogen, amino group, alkyl group, and hydroxyl group, and the -(CH2) m - is optionally substituted with one or more deuterium or halogens, G is selected from cycloalkylene groups, heterocyclylene groups, heteroarylene groups, and arylene groups. R 10 These are hydrogen, halogen, hydroxyl group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, CH2=, -NR d R e ,-(CH2) m -OH, -(CH2) m -NR d R e -OC(=O)NR f -(CH2) m -OH, -OC(=O)NR f -(CH2) m -NR d R e ,-(CH2) m -C(=O)OH, -(CH2) m -C(=O)-NR d R e ,-(CH2) m -C(=O)NR f -(CH2) n -OH, -(CH2) m -C(=O)NR f -(CH2) n -NR d R e , -NR f -(CH2)m -OH、-NR f -(CH2) m -NR d R e 、-NR f -C(=O)R d 、-NR f -C(=O)-(CH2) m -R d 、-NR f C(=O)O-(CH2) m -R d 、-O-(CH2) m -OH、-O-(CH2) m -NR d R e 、-NR f C(=O)O-(CH2) m -OH、-NR f C(=O)NR d -(CH2) m -OH、-NR f C(=O)NR d -(CH2) m -O-(CH2) n -OH、-NR f C(=O)O-(CH2) m -O-(CH2) n -OH、-NR f C(=O)NR d -(CH2) m -O-(CH2) n -NR d R e 、-NR f C(=O)O-(CH2) m -O-(CH2) n -NR d R e 、-NR f C(=O)NR d -(CH2) m -NR d R e 、-NR f C(=O)O-(CH2) m -NR d R e 、-(CH2) m -NR f C(=O)O-(CH2) n -OH、-(CH2) m-NR f C(=O)O-(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -OH, -(CH2) m -NR f C(=O)-(CH2) n -NR d R e ,-(CH2) m -NR f C(=O)-(CH2) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, or alkynyl group is optionally substituted with one or more groups further selected from halogens. R d and R e Each of these is independently selected from hydrogen and C1-C6 alkyl groups. R f is hydrogen, C1-C6 alkyl group, -C(O)R c ,-S(O)R c -S(O)2R c Selected from, the C1-C6 alkyl group is optionally further substituted with a C3-C6 cycloalkyl group, where R c These are selected from hydrogen, a hydroxyl group, and a C1-C6 alkyl group. m is an integer between 1 and 6. n is an integer between 1 and 6.

[0039] In certain preferred embodiments, the compound represented by general formula (I) described in the present invention or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, wherein R 8 This is a halogen, preferably fluorine or chlorine.

[0040] In another preferred embodiment, a compound represented by the general formula (I) described in the present invention, or a stereoisomer, tautomer, endo form, racemate, enantiomer, diastereomer or a mixed form thereof, or a pharmaceutically usable salt thereof, wherein R 9 is a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, -NR d R e , -(CH2) m -OH, -(CH2) m -NR d R e , -(CH2) m -NR b C(=O)O-(CH2) n -OH, -(CH2) m -OC(=O)NR f -(CH2) n -OH, -(CH2) m -NR f C(=O)-(CH2) n -OH, -O-(CH2) m -NR d R e , -O-(CH2) m -OH, -(CH2) m -NR f C(=O)-G-(CH2) n -OH, wherein the -(CH2) m - is optionally substituted by one or more deuteriums or halogens, G is selected from a cycloalkylene group, a heterocyclylene group, a heteroarylene group, an arylene group, R d and R e are each independently selected from hydrogen and a C1-C6 alkyl group, preferably hydrogen, R f is selected from hydrogen and a C1-C6 alkyl group, preferably hydrogen, m is an integer from 1 to 6, preferably an integer from 1 to 4, n is an integer from 1 to 6, preferably 1 or 2.

[0041] In another preferred embodiment, the compound represented by general formula (I) described in the present invention or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, wherein R 10 is hydrogen, hydroxyl group, amino group, -(CH2) m -OH, -OC(=O)NR f -(CH2) m -OH, -(CH2) m -C(=O)OH, -(CH2) m -C(=O)NR f -(CH2) n -OH, -NR f -(CH2) m -OH, -NR f C(=O)O-(CH2) m -OH, -NR f C(=O)NR d -(CH2) m -OH, -NR f C(=O)NR d -(CH2) m -O-(CH2) n -OH, -NR f C(=O)O-(CH2) m -O-(CH2) n -OH, -NR f C(=O)NR d -(CH2) m -O-(CH2) n -NR d R e , -NR f C(=O)O-(CH2) m -O-(CH2) n -NR d R e , -NR f C(=O)NR d -(CH2) m -NR d R e , -NR f C(=O)O-(CH2) m -NR d R e Selected from, R d and Re Each of these is independently selected from hydrogen and C1-C6 alkyl groups, preferably hydrogen. R f is hydrogen, C1-C6 alkyl group, -C(O)R c ,-S(O)R c -S(O)2R c Selected from, here, R c These are selected from hydrogen, a hydroxyl group, and a C1-C6 alkyl group. m is an integer between 1 and 6, preferably between 1 and 4, and also preferably 1 or 2. n is an integer between 1 and 6, preferably 1 or 2.

[0042] In another preferred embodiment, the compound represented by general formula (I) described in the present invention or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, wherein R 9 is hydrogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, hydroxyl group, carboxyl group, -NR d R e ,-(CH2) m -OH, -(CH2) m -NR d R e ,-(CH2) m -NR f C(=O)O-(CH2) n -OH, -(CH2) m -OC(=O)NR f -(CH2) n -OH, -(CH2) m -NR f C(=O)-(CH2) n -OH, -O-(CH2) m -NR d R e -O-(CH2) m - Selected from OH, R d and R e Each of these is independently selected from hydrogen and C1-C6 alkyl groups. R f These are selected from hydrogen and C1-C6 alkyl groups. m is an integer between 1 and 6. n is an integer between 1 and 4, preferably 1 or 2.

[0043] In another preferred embodiment, the compound represented by general formula (I) described in the present invention or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, wherein R 10 These are hydrogen, hydroxyl group, amino group, CH2=, and -(CH2) m -OH, -OC(=O)NR f -(CH2) m -OH, -(CH2) m -C(=O)OH, -(CH2) m -C(=O)NR f -(CH2) n -OH, -NR f -(CH2) m -OH, -NR f -C(=O)R d , -NR f -C(=O)-(CH2) m -R d , -NR f C(=O)O-(CH2) m -R d , -NR f -C(=O)-(CH2) m -OH, -NR f C(=O)O-(CH2) m - Selected from OH, R d and R e Each of these is independently selected from hydrogen and C1-C6 alkyl groups. R f is hydrogen, C1-C6 alkyl group, -C(O)R c ,-S(O)R c -S(O)2R c Selected from, the C1-C6 alkyl group is optionally further substituted with a C3-C6 cycloalkyl group, where R cThese are selected from hydrogen, a hydroxyl group, and a C1-C6 alkyl group. m is an integer between 1 and 6, preferably between 1 and 4 or between 4 and 6. n is an integer between 1 and 4, preferably 1 or 2.

[0044] In another preferred embodiment, the compound represented by general formula (I) described in the present invention or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, TIFF2026510566000069.tif124150 TIFF2026510566000070.tif243150 TIFF2026510566000071.tif245150 TIFF2026510566000072.tif245156 TIFF2026510566000073.tif245159 Selected from TIFF2026510566000074.tif2653.

[0045] In another aspect of the present invention, a compound represented by general formula (II) or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof are provided. TIFF2026510566000075.tif4153 Here, R 11 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally further substituted with one or more groups selected from halogens. R 12 This includes hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, -NR d R e ,-(CH2) m-OH、-(CH2) m -NR d R e 、-OC(=O)NR f -(CH2) m -OH、-OC(=O)NR f -(CH2) m -NR d R e 、-(CH2) m -C(=O)OH、-(CH2) m -C(=O)-NR d R e 、-(CH2) m -C(=O)NR f -(CH2) n -OH、-(CH2) m -C(=O)NR f -(CH2) n -NR d R e 、-NR f -(CH2) m -OH、-NR f -(CH2) m -NR d R e 、-O-(CH2) m -OH、-O-(CH2) m -NR d R e 、-NR f C(=O)O-(CH2) m -OH、-NR b C(=O)O-(CH2) m -NR a -*、-(CH2) m -NR b C(=O)O-(CH2) n -O-*、-(CH2) m -NR f C(=O)O-(CH2) n -NR d R e 、-(CH2) m -OC(=O)NR f -(CH2) n -NR d R e 、-(CH2) m -OC(=O)NR f -(CH2) n-OH, -(CH2) m -NR f C(=O)-(CH2) n -NR d R e ,-(CH2) m -NR f C(=O)-(CH2) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, or alkynyl group is optionally substituted with one or more groups further selected from halogens. R 13 This includes hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, -NR d R e ,-(CH2) m -OH, -(CH2) m -NR d R e -OC(=O)NR f -(CH2) m -OH, -OC(=O)NR f -(CH2) m -NR d R e ,-(CH2) m -C(=O)OH, -(CH2) m -C(=O)-NR d R e ,-(CH2) m -C(=O)NR f -(CH2) n -OH, -(CH2) m -C(=O)NR f -(CH2) n -NR d R e , -NR f -(CH2) m -OH, -NR f -(CH2) m -NR d R e -O-(CH2) m -OH, -O-(CH2) m -NR d R e , -NR f C(=O)O-(CH2) m -OH, -NRb C(=O)O-(CH2) m -NR a -*,-(CH2) m -NR b C(=O)O-(CH2) n -O-*, -(CH2) m -NR f C(=O)O-(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -OH, -(CH2) m -NR f C(=O)-(CH2) n -NR d R e ,-(CH2) m -NR f C(=O)-(CH2) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, or alkynyl group is optionally substituted with one or more groups further selected from halogens. R d and R e Each of these is independently selected from hydrogen and C1-C6 alkyl groups. R f is hydrogen, C1-C6 alkyl group, -C(O)R c ,-S(O)R c -S(O)2R c Selected from, here, R c These are selected from hydrogen, a hydroxyl group, and a C1-C6 alkyl group. m is an integer between 1 and 6. n is an integer between 1 and 6.

[0046] In certain preferred embodiments, the compound represented by general formula (II) or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, wherein R 11 The halogen is selected from halogens, preferably fluorine or a cyano group.

[0047] In another preferred embodiment, the compound represented by general formula (II) described in the present invention or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, wherein R 12 These are hydroxyl groups, amino groups, C1-C6 alkyl groups, and -(CH2) m -OH, -(CH2) m -NR d R e Selected from, R d and R e Each of these is independently selected from hydrogen and C1-C6 alkyl groups. m is an integer between 1 and 6, preferably between 1 and 4.

[0048] In another preferred embodiment, the compound represented by general formula (II) described in the present invention or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, wherein R 13 The group is selected from either a hydroxyl group or an amino group.

[0049] In another preferred embodiment, the compound represented by general formula (II) described in the present invention or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, wherein R 13 is a hydroxyl group, C 1-6 Selected from alkoxy groups.

[0050] In another preferred embodiment, the compound represented by general formula (II) described in the present invention, or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, Selected from TIFF2026510566000076.tif140157.

[0051] Another aspect of the present invention provides a ligand-drug conjugate represented by general formula (B) or a pharmaceutically acceptable salt thereof, TIFF2026510566000077.tif19157 Here, Dr is selected from the following structure: TIFF2026510566000078.tif43139 TIFF2026510566000079.tif3698R 1 Hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, -NR d R e ,-(CH2) m -OH, -(CH2) m -NR d R e -OC(=O)NR f -(CH2) m -OH, -OC(=O)NR f -(CH2) m -NR d R e ,-(CH2) m -C(=O)OH, -(CH2) m -C(=O)-NR d R e ,-(CH2) m -C(=O)NR f -(CH2) n -OH, -(CH2) m -C(=O)NR f -(CH2) n -NR d R e , -NR f -(CH2) m -OH, -NR f-(CH2) m -NR d R e -O-(CH2) m -OH, -O-(CH2) m -NR d R e , -NR f C(=O)O-(CH2) m -OH, -NR b C(=O)O-(CH2) m -NR d R e ,-(CH2) m -NR f C(=O)O-(CH2) n -OH-, -(CH2) m -NR f C(=O)O-(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -OH, -(CH2) m -NR f C(=O)-(CH2) n -NR d R e ,-(CH2) m -NR f C(=O)-(CH2) n -OH, -(CH2) m -NR f C(=O)-G-(CH2) n -Selected from OH, the alkyl group, alkoxy group, alkenyl group, alkynyl group, and cycloalkyl group are optionally further substituted with one or more groups selected from halogen, deuterium, amino group, alkyl group, and hydroxyl group, and the -(CH2) m - is optionally substituted with one or more deuterium or halogens, and G is selected from a cycloalkylene group, a heterocyclylene group, a heteroarylene group, or an arylene group. R 2This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally further substituted with one or more groups selected from halogens. R 3 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, CH2=, -NR d R e ,-(CH2) m -OH, -(CH2) m -NR d R e -OC(=O)NR f -(CH2) m -OH, -OC(=O)NR f -(CH2) m -NR d R e ,-(CH2) m -C(=O)OH, -(CH2) m -C(=O)-NR d R e ,-(CH2) m -C(=O)NR f -(CH2) n -OH, -(CH2) m -C(=O)NR f -(CH2) n -NR d R e , -NR f -(CH2) m -OH, -NR f -(CH2) m -NR d R e , -NR f -C(=O)R d , -NR f -C(=O)-(CH2) m -R d , -NR f C(=O)O-(CH2) m -R d -O-(CH2) m -OH, -O-(CH2) m -NR d R e、-NR f C(=O)O-(CH2) m -OH、-NR f C(=O)NR d -(CH2) m -OH、-NR f C(=O)NR d -(CH2) m -O-(CH2) n -OH、-NR f C(=O)O-(CH2) m -O-(CH2) n -OH、-NR f C(=O)NR d -(CH2) m -O-(CH2) n -NR d R e 、-NR f C(=O)O-(CH2) m -O-(CH2) n -NR d R e 、-NR f C(=O)NR d -(CH2) m -NR d R e 、-NR f C(=O)O-(CH2) m -NR d R e 、-(CH2) m -NR f C(=O)O-(CH2) n -OH、-(CH2) m -NR f C(=O)O-(CH2) n -NR d R e 、-(CH2) m -OC(=O)NR f -(CH2) n -NR d R e 、-(CH2) m -OC(=O)NR f -(CH2) n -OH、-(CH2) m -NR f C(=O)-(CH2) n -NR d Re ,-(CH2) m -NR f C(=O)-(CH2) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, or alkynyl group is optionally further substituted with one or more groups selected from halogen, deuterium, amino group, alkyl group, or hydroxyl group. R 4 Hydrogen, halogen, hydroxyl group, carboxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, -NR d R e ,-(CH2) m -OH, -(CH2) m -NR d R e -OC(=O)NR f -(CH2) m -OH, -OC(=O)NR f -(CH2) m -NR d R e ,-(CH2) m -C(=O)OH, -(CH2) m -C(=O)-NR d R e ,-(CH2) m -C(=O)NR f -(CH2) n -OH, -(CH2) m -C(=O)NR f -(CH2) n -NR d R e , -NR f -(CH2) m -OH, -NR f -(CH2) m -NR d R e -O-(CH2) m -OH, -O-(CH2) m -NR d R e , -NR f C(=O)O-(CH2) m -OH, -NR b C(=O)O-(CH2) m -NRd R e ,-(CH2) m -NR f C(=O)O-(CH2) n -OH-, -(CH2) m -NR f C(=O)O-(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -NR d R e ,-(CH2) m -OC(=O)NR f -(CH2) n -OH, -(CH2) m -NR f C(=O)-(CH2) n -NR d R e ,-(CH2) m -NR f C(=O)-(CH2) n -OH, -(CH2) m -NR f C(=O)-G-(CH2) n -Selected from OH, the alkyl group, alkoxy group, alkenyl group, alkynyl group, and cycloalkyl group are optionally further substituted with one or more groups selected from halogen, deuterium, amino group, alkyl group, and hydroxyl group, and the -(CH2) m - is optionally substituted with one or more deuterium or halogens, and G is selected from a cycloalkylene group, a heterocyclylene group, a heteroarylene group, or an arylene group. R 5 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally further substituted with one or more groups selected from halogens. R 6This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally further substituted with one or more groups selected from halogens. R 7 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally further substituted with one or more groups selected from halogens. R d and R e Each is independently selected from hydrogen and alkyl groups. R f is hydrogen, alkyl group, -C(O)R c ,-S(O)R c -S(O)2R c Selected from, the C1-C6 alkyl group is optionally further substituted with a C3-C6 cycloalkyl group, where R c It is selected from hydrogen, hydroxyl group, and alkyl group. L1 is a bond, -(CH2) m -*, -O-*, -NR a -*,-(CH2) m -O-*, -(CH2) m -NR a -*, -OC(=O)NR b -(CH2) m -O-*, -OC(=O)NR b -(CH2) m -NR a -*,-(CH2) m -C(=O)O-*, -(CH2) m -C(=O)NR a -*,-(CH2) m -C(=O)NR b -(CH2) n -O-*, -(CH2) m -C(=O)NR b -(CH2) n -NR a -*, -NR b-(CH2) m -O-*, -NR b -(CH2) m -NR a -*, -O-(CH2) m -O-*, -O-(CH2) m -NR a -*, -NR b C(=O)O-(CH2) m -O-*, -NR b C(=O)O-(CH2) m -NR a -*,-(CH2) m -NR b C(=O)O-(CH2) n -O-*, -(CH2) m -NR b C(=O)O-(CH2) n -NR a -*,-(CH2) m -OC(=O)NR b -(CH2) n -NR a -*,-(CH2) m -OC(=O)NR b -(CH2) n -O-*, -(CH2) m -NR b C(=O)-(CH2) n -NR a -*,-(CH2) m -NR b C(=O)-(CH2) n -O-* is selected, where * is the connection site to L2. R a and R b These are, independently, hydrogen, alkyl group, and -C(O)R c ,-S(O)R c -S(O)2R c Selected from, the alkyl group is optionally further substituted with a cycloalkyl group, where R c It is selected from hydrogen, hydroxyl group, and alkyl group. L2 is a combination, Selected from TIFF2026510566000080.tif23138, where * is the connection point to L1, L' is The filename is TIFF2026510566000081.tif1668. Q' is, Selected from TIFF2026510566000082.tif70150, Here, * represents the connection point to L4, TIFF2026510566000083.tif78 is the connection point to PC, L3 is an amino acid residue formed from two or more amino acids, and L3 is optionally selected from one or more of the following structures, and L6 is selected from one or more of the following structures. TIFF2026510566000084.tif165157 Here, R, R aa , R bb Each is independently selected from hydrogen and alkyl groups. L4 is The filename is TIFF2026510566000085.tif2066. Z1 is a bond, -(CH2) p -,-(C2H4O) q -,-(CH2) p -C(O)NH-, -(CH2) p -O-(CH2) p -C(O)NH-, -(CH2) p -C(O)-L6-NH-, -(CH2) p -O-(CH2) p -C(O)-L6-NH-, -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, -NH-, -O-sum-OC(O)NH-, m is an integer between 1 and 6. n is an integer between 1 and 6. s is an integer between 1 and 6. t is an integer between 0 and 10. s1, s2, s3, and s4 are each independent integers between 0 and 10, preferably integers between 0 and 8, and integers between 0 and 6, and also preferably integers between 0 and 4, and particularly preferably integers between 0 and 2, and integers between 1 and 2. s5 and s6 are each independent integers between 1 and 6. t1 is an integer between 1 and 6. t2 is an integer between 0 and 6. t3 is an integer between 1 and 6. t4 is an integer between 0 and 10. t5 is an integer between 0 and 10. p is an integer between 1 and 10. q is an integer between 1 and 10. v is between 1 and 10, and v can be a decimal or an integer. Pc is an antibody or its antigen-binding fragment, or a modified antibody. The aforementioned modified antibody is Pc'-((L5) w -F) x It has a structure, and here, Pc' is an antibody, L5 is a linker, w is either 0 or 1. F is a click probe or sulfhydryl group or its precursor that can bind to Q' after a reaction such as a metal-free click reaction, and preferably F is an azide group. x is an integer between 1 and 8.

[0052] Here, Z1 is connected to Q'.

[0053] In certain preferred embodiments, a ligand-drug complex represented by general formula (B) or a pharmaceutically acceptable salt thereof, wherein L3 is TIFF2026510566000086.tif51157 Selected from TIFF2026510566000087.tif196157, R is selected from hydrogen and C1-C6 alkyl groups, preferably hydrogen. R aa , R bb Each of these is independently selected from C1-C6 alkyl groups. s is an integer between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. s5 and s6 are each independent integers between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. t is an integer between 0 and 10, preferably between 2 and 8, and particularly preferably between 3 and 7. t1 is an integer between 1 and 6, preferably between 1 and 4, also preferably between 2 and 4, and also preferably 1 or 2. t2 is an integer between 0 and 6, preferably between 1 and 4, and also preferably 1 or 2. t3 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably 1 or 2. t4 is an integer between 0 and 10. t5 is an integer between 0 and 10. * indicates the connection point to L2. TIFF2026510566000088.tif78 is a linking site to a carbonyl group or a methylene group. L 1b and L' 1b Each of these is an amino acid residue formed from one or more amino acids selected from glycine, phenylalanine, citrulline, leucine, isoleucine, alanine, valine, asparagine, glutamine, arginine, glutamic acid, and lysine, and preferably an amino acid residue formed from two or more amino acids selected from glycine, phenylalanine, citrulline, valine, lysine, glutamine, glutamic acid, leucine, and alanine. Preferably, L 1b and L' 1bThese are, independently of each other: -Gly-*, -Val-*, -Gly-Phe-Gly-*, -Phe-Gly-*, -Gly-Val-Cit-*, -Val-Cit-*, -Gly-Val-Arg-*, -Val-Arg-*, -Gly-Val-Ala-*, -Val-Ala-*, -Gly-Phe-*, -Phe-Gly-*, -Gl y-Gly-Gly-*, Gly-Gly-*, -Gly-Val-Gly-*, -Gly-Ala-Gly-*, -Gly-Phe-Cit-*, -Gly-Phe-Va l-*, -Gly-Phe-Ala-*, -Gly-Phe-Lys-*, -Phe-Lys-*, -Gly-Val-*, -Gly-Cit-*, -Gly-Ala-*, -Gly-Gly-Lys-*, Gly-Lys'-*, -Ala-Ala-Ala-*, -Gln-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, -Asp-Val-Cit-*, preferably -Gly-Phe-Gly-*, -Gly-Val-Cit-*, -Val-Cit-*, -G These are ly-Val-Ala-*, -Val-Ala-*, -Gly-Phe-Gly-*, -Phe-Gly-*, -Gly-Phe-Lys-, -Phe-Lys-*, -Gln-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, and -Asp-Val-Cit-, where * is the linking site to L2.

[0054] In certain preferred embodiments, a ligand-drug complex represented by general formula (B) or a pharmaceutically acceptable salt thereof, wherein L' is The filename is TIFF2026510566000089.tif1668. Q' is, Selected from TIFF2026510566000090.tif68144, Here, * represents the connection point to L4, TIFF2026510566000091.tif78 is the connection point to PC, L3 is an amino acid residue formed from two or more amino acids selected from glycine, phenylalanine, citrulline, leucine, isoleucine, alanine, valine, asparagine, glutamine, arginine, glutamic acid, and lysine, preferably an amino acid residue formed from two or more amino acids selected from glycine, phenylalanine, citrulline, valine, lysine, glutamine, glutamic acid, leucine, and alanine. L4 is The filename is TIFF2026510566000092.tif2174. Z1 is a bond, -(CH2) p -,-(CH2) p -C(O)NH-, -(CH2) p -O-(CH2) p -C(O)NH-, -(CH2) p -C(O)-L6-NH-, -(CH2) p -O-(CH2) p -C(O)-L6-NH-, -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, -NH-, -O-sum-OC(O)NH-, s1 is an integer between 1 and 6, preferably between 2 and 6. s2 is an integer between 1 and 10, preferably between 2 and 10. s3 is 0, s4 is 0, p is an integer between 1 and 10, preferably between 1 and 6, particularly preferably between 2 and 4, and most preferably between 2 and 3. L6 is Selected from TIFF2026510566000093.tif6579, s is an integer between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. t is an integer between 0 and 10, preferably between 2 and 8, and particularly preferably between 3 and 7. Preferably, L6 is The filename is TIFF2026510566000094.tif45125.

[0055] In certain specific embodiments, a ligand-drug complex represented by the general formula (B) described in the present invention or a pharmaceutically acceptable salt thereof, wherein L5 is The filename is TIFF2026510566000095.tif1990. Z2 and Z3 are each independently selected from -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, -NH-, -O- and -OC(O)NH-, preferably -C(O)NH-. r1 is an integer between 1 and 8, preferably between 1 and 6, and particularly preferably between 1 and 3. r2 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably between 1 and 2. r3 is an integer between 0 and 6, preferably between 0 and 4, and particularly preferably between 0 and 2. r4 is an integer between 0 and 6, preferably between 0 and 4, and particularly preferably between 0 and 2. r5 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably between 1 and 2.

[0056] In another specific embodiment, the ligand-drug complex represented by the general formula (B) described in the present invention or a pharmaceutically acceptable salt thereof, wherein when w is 0, F is a sulfhydryl group, and when w is 1, F is a click probe that can bind to Q' after a reaction such as a metal-free click reaction, preferably F is an azide group.

[0057] In another specific embodiment, a ligand-drug complex represented by the general formula (B) described in the present invention or a pharmaceutically acceptable salt thereof, wherein Pc is a modified antibody, and the modified antibody has the following structure: TIFF2026510566000096.tif1893 Here, Pc' is an antibody, Z2 and Z3 are each independently selected from -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, -NH-, -O- and -OC(O)NH-, preferably -C(O)NH-. r1 is an integer between 1 and 8, preferably between 1 and 6, and particularly preferably between 1 and 3. r2 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably between 1 and 2. r3 is an integer between 0 and 6, preferably between 0 and 4, and particularly preferably between 0 and 2. r4 is an integer between 0 and 6, preferably between 0 and 4, and particularly preferably between 0 and 2. r5 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably between 1 and 2.

[0058] In certain preferred embodiments, a ligand-drug conjugate represented by general formula (B) or a pharmaceutically acceptable salt thereof, where Pc is a modified antibody and Pc-Q' is TIFF2026510566000097.tif3298 Selected from TIFF2026510566000098.tif189129, Pc' is an antibody, Z2 and Z3 are each independently selected from -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, -NH-, -O- and -OC(O)NH-, preferably -C(O)NH-. r1 is an integer between 1 and 8, preferably between 1 and 6, and particularly preferably between 1 and 3. r2 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably between 1 and 2. r3 is an integer between 0 and 6, preferably between 0 and 4, and particularly preferably between 0 and 2. r4 is an integer between 0 and 6, preferably between 0 and 4, and particularly preferably between 0 and 2. r5 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably between 1 and 2.

[0059] In certain preferred embodiments, the ligand-drug complex represented by general formula (B) or a pharmaceutically acceptable salt thereof is: TIFF2026510566000099.tif181139 TIFF2026510566000100.tif222131 TIFF2026510566000101.tif240127 TIFF2026510566000102.tif222119 TIFF2026510566000103.tif222125 TIFF2026510566000104.tif238144 TIFF2026510566000105.tif220139 TIFF2026510566000106.tif245108 TIFF2026510566000107.tif231102 TIFF2026510566000108.tif231106 TIFF2026510566000109.tif231108 TIFF2026510566000110.tif215121 TIFF2026510566000111.tif222102 Selected from TIFF2026510566000112.tif71103, Here, v is between 1 and 10, and v can be a decimal or an integer. Pc is an antibody or its antigen-binding fragment, Pc' is an antibody.

[0060] In some embodiments, a ligand-drug conjugate represented by the general formula (B) described in the present invention or a pharmaceutically acceptable salt thereof, wherein the antibody is selected from mouse antibodies, chimeric antibodies, humanized antibodies and fully human antibodies.

[0061] In some other embodiments, a ligand-drug conjugate represented by the general formula (B) described in the present invention or a pharmaceutically acceptable salt thereof, wherein the antibody or antigen-binding fragment is an anti-HER2 (ErbB2) antibody, an anti-EGFR antibody, an anti-B7-H3 antibody, an anti-c-Met antibody, an anti-HER3 (ErbB3) antibody, an anti-HER4 (ErbB4) antibody, an anti-ROR1 antibody, an anti-CLDN6 antibody, an anti-CLDN9 antibody, an anti-CLDN18.2 antibody, Anti-NaPi-2b antibody, anti-TNF-α antibody, anti-ENPP3 antibody, anti-DLL3 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD28 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD37 antibody, anti-CD38 antibody, anti-CD44 Antibodies, anti-CD45 antibodies, anti-CD47 antibodies, anti-CD48 antibodies, anti-CD56 antibodies, anti-CD70 antibodies, anti-CD73 antibodies, anti-CD98 antibodies, anti-CD105 antibodies, anti-CEA antibodies, anti-EphA2 antibodies, anti-MUCI antibodies, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-CD79 antibody, anti-TROP-2 antibody, anti-CD79B antibody, anti-Mesothelin antibody, anti-Nectin-4 antibody, anti-TPBG antibody, or an antigen-binding fragment thereof.

[0062] In some other embodiments, the ligand-drug conjugate represented by the general formula (B) described in the present invention or a pharmaceutically acceptable salt thereof, wherein the antibody or antigen-binding fragment is selected from trastuzumab, cetuximab, pertuzumab, nimotuzumab, enoblituzumab, emibetuzumab, inotuzumab, pinatuzumab, brentuximab, gemtuzumab, bivatuzumab, lorvotuzumab, or an antigen-binding fragment thereof.

[0063] In some other embodiments, the ligand-drug complex represented by the general formula (B) described in the present invention or a pharmaceutically acceptable salt thereof is: TIFF2026510566000113.tif196150 TIFF2026510566000114.tif215100 TIFF2026510566000115.tif240130 TIFF2026510566000116.tif207122 TIFF2026510566000117.tif245150 TIFF2026510566000118.tif228158 TIFF2026510566000119.tif214157 TIFF2026510566000120.tif240111 TIFF2026510566000121.tif231112 TIFF2026510566000122.tif245111 TIFF2026510566000123.tif231127 TIFF2026510566000124.tif245107 Selected from TIFF2026510566000125.tif166113, Here, v is an integer or decimal number between 1 and 10, preferably an integer between 2 and 8.

[0064] The present invention further relates to a pharmaceutical composition comprising a ligand-drug complex represented by the general formula (B) described in the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0065] The present invention further relates to the use of a compound represented by general formula (A) or a pharmaceutically acceptable salt thereof in the preparation of ligand-drug conjugates.

[0066] The present invention further relates to the use of a compound represented by general formula (I) described in the present invention or its stereoisomers, tautomers, endoforms, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, in the preparation of ligand-drug conjugates, or a compound represented by general formula (II) described in the present invention or its stereoisomers, tautomers, endoforms, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof.

[0067] The present invention further relates to the use of ligand-drug conjugates or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, in the preparation of agents for treating tumors or cancer, preferably, said cancers including breast cancer, ovarian cancer, soft tissue sarcoma, liposarcoma, lung cancer, non-small cell lung cancer, gastric cancer, melanoma, head and neck cancer, cervical cancer, and prostate cancer.

[0068] The present invention further relates to the use of ligand-drug conjugates or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, in agents for treating tumors or cancer, preferably the cancers including breast cancer, ovarian cancer, soft tissue sarcoma, liposarcoma, lung cancer, non-small cell lung cancer, gastric cancer, melanoma, head and neck cancer, cervical cancer, and prostate cancer.

[0069] The present invention further relates to a method for treating a tumor or cancer, comprising administering to a subject requiring such treatment an effective amount of a ligand-drug conjugate described in the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, preferably the cancer being breast cancer, ovarian cancer, soft tissue sarcoma, liposarcoma, lung cancer, non-small cell lung cancer, gastric cancer, melanoma, head and neck cancer, cervical cancer, and prostate cancer.

[0070] The present invention further relates to the use of a compound represented by general formula (I) described in the present invention or its stereoisomers, tautomers, endoforms, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, or a compound represented by general formula (II) or its stereoisomers, tautomers, endoforms, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, or a pharmaceutical composition containing thereof, preferably, said cancer includes breast cancer, ovarian cancer, soft tissue sarcoma, liposarcoma, lung cancer, non-small cell lung cancer, gastric cancer, melanoma, head and neck cancer, cervical cancer, and prostate cancer.

[0071] The present invention further relates to the use of a compound represented by general formula (I) described in the present invention or its stereoisomers, tautomers, endoforms, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, or a compound represented by general formula (II) or its stereoisomers, tautomers, endoforms, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, or a pharmaceutical composition containing thereof, preferably, said cancer includes breast cancer, ovarian cancer, soft tissue sarcoma, liposarcoma, lung cancer, non-small cell lung cancer, gastric cancer, melanoma, head and neck cancer, cervical cancer, and prostate cancer.

[0072] The present invention further relates to a method for treating a tumor or cancer, comprising administering to a subject as needed an effective amount of a compound represented by general formula (I) or its stereoisomers, tautomers, endoforms, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, or a compound represented by general formula (II) or its stereoisomers, tautomers, endoforms, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, or a pharmaceutical composition containing thereof, preferably, said cancer includes breast cancer, ovarian cancer, soft tissue sarcoma, liposarcoma, lung cancer, non-small cell lung cancer, gastric cancer, melanoma, head and neck cancer, cervical cancer, and prostate cancer.

[0073] Detailed description of the invention Unless otherwise specified, all technical and scientific terms used herein are consistent with the common understanding of those skilled in the art in which the present invention pertains. The present invention may also be carried out or tested using any methods and materials similar or equivalent to those described herein, but preferred methods and materials are described herein.

[0074] Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0075] The term "linker unit (or linking fragment)" refers to a fragment or linkage of a chemical structure in which one end is bound to a ligand and the other end is bound to a drug, or is bound to another linker before being bound to a drug.

[0076] The term "ligand-drug conjugate" refers to a ligand binding to a biologically active drug via a stable linker unit. Preferably, in the present invention, the "ligand-drug conjugate" refers to an antibody-drug conjugate (ADC) in which a monoclonal antibody or antibody fragment binds to a camptothecin derivative, which is a biologically active toxic drug, via a stable linker unit.

[0077] Examples of three-letter and one-letter amino acid codes and their structures used in the present invention are shown in the table below: TIFF2026510566000126.tif227130 TIFF2026510566000127.tif174132

[0078] The term "antibody" refers to immunoglobulins, which have a tetrapeptide chain structure consisting of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. Because the amino acid composition and sequence of the constant region of the immunoglobulin heavy chain differ, their antigenicity also differs. This allows immunoglobulins to be classified into five classes, also called isotypes: IgM, IgD, IgG, IgA, and IgE, with corresponding heavy chains being μ, δ, γ, α, and ε, respectively. Ig of the same class can be further classified into different subclasses based on differences in the amino acid composition of its hinge region and the number and position of disulfide bonds in the heavy chain; for example, IgG can be classified into IgG1, IgG2, IgG3, and IgG4. The light chains are divided into κ or λ chains based on differences in the constant region. Each of the five classes of Ig can have either a κ or λ chain.

[0079] The amino acid sequences of approximately 110 amino acids near the N-terminus of the antibody's heavy and light chains are significantly different and are therefore designated as the variable region (Fv region), while the amino acid sequence near the C-terminus is relatively stable and is therefore designated as the constant region. The variable region includes three hypervariable regions (HVRs) and four relatively less variable framework regions (FRs). The three hypervariable regions determine the specificity of the antibody and are also known as complementarity-determining regions (CDRs). Each light chain variable region (LCVR) and heavy chain variable region (HCVR) consists of three CDR regions and four FR regions, arranged from the terminal to the carboxyl terminus as FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3, while the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3. The number and position of CDR amino acid residues in the LCVR and HCVR regions of the antibody or antigen-binding fragment described in the present invention conform to known Kabat numbering rules (LCDR1-3, HCDR2-3) or Kabat and Chothia numbering rules (HCDR1).

[0080] An "antigen-binding fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be achieved using fragments of a full-length antibody. Examples of binding fragments included in an "antigen-binding fragment" include (i) a monovalent fragment, the Fab fragment, consisting of VL, VH, CL, and CH1 structural domains; (ii) a bivalent fragment, the F(ab')2 fragment, containing two Fab fragments linked by a disulfide bond in the hinge region; (iii) an Fd fragment consisting of VH and CH1 structural domains; (iv) an Fv fragment consisting of the VH and VL structural domains of a single arm of the antibody; (v) a single structural domain or dAb fragment consisting of the VH structural domain; and (vi) an isolated complementarity-determining region (CDR), or (vii) a combination of two or more isolated CDRs that can be linked by an optionally synthesized linker. Furthermore, although the two structural domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be linked using a synthetic linker via recombination, thereby pairing the VL and VH regions to produce a single protein chain (called single-chain Fv (scFv)) that forms a monovalent molecule. Such single-chain antibodies are also intended to be included in the term "antigen-binding fragment" of antibodies. Such antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as complete antibodies. The antigen-binding portion can be produced by recombinant DNA technology or by enzymatic or chemical cleavage of intact immunoglobulins. Antibodies can be different isotypes, such as IgG (e.g., IgG1, IgG2, IgG3, or IgG4 subtypes), IgA1, IgA2, IgD, IgE, or IgM antibodies.

[0081] The term "alkyl group" refers to an aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, particularly preferably an alkyl group containing 1 to 10 carbon atoms, and most preferably an alkyl group containing 1 to 6 carbon atoms (including 1, 2, 3, 4, 5, or 6 carbon atoms). Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl Examples include the n-octyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and their various branched isomers.Particularly preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, and 2,3-dimethylbutyl group. The alkyl group may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available bond site, preferably the substituent is independently selected from one or more of the following groups: alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, alkylamino group, halogen, sulfhydryl group, hydroxyl group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocyclylalkoxy group, cycloalkylthio group, heterocyclylalkylthio group, and oxo group.

[0082] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where the definitions of alkyl group and cycloalkyl group are as described above. Non-limiting examples of alkoxy groups include methoxy group, ethoxy group, propoxy group, butoxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, and cyclohexyloxy group. Alkoxy groups may be optionally substituted or unsubstituted, and if substituted, preferably the substituent is independently selected from one or more alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclylalkoxy groups, cycloalkylthio groups, and heterocyclylalkylthio groups.

[0083] The term "cycloalkyl group" refers to substituents of saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbons, where a cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, particularly preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms (including 3, 4, 5, 6, 7, or 8 carbon atoms). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, while polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings, and crosslinked rings.

[0084] The term "heterocyclyl group" refers to a substituent of a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, comprising 3 to 20 ring atoms, where one or more ring atoms are nitrogen, oxygen, or S(O). mThe heteroatoms are selected from (where m is an integer 0, 1, or 2) but do not include the -OO-, -OS-, or -SS- ring portion, and the remaining ring atoms are carbon. Preferably, the ring contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms (1, 2, 3, or 4 heteroatoms), and particularly preferably, the cycloalkyl ring contains 3 to 10 ring atoms (including 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidyl, piperidyl, piperadyl, morpholyl, thiomorpholyl, and homopiperazyl groups. Polycyclic heterocyclic groups include spiro rings, fused rings, and bridging rings.

[0085] The term "spiros heterocyclyl group" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5-20 membered monocyclic rings, and one or more of these ring atoms are nitrogen, oxygen, or S(O). m A heteroatom selected from (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more (preferably 1, 2, or 3) double bonds, but there are no rings with a fully conjugated π-electron system. Preferably, it is 6 to 14 members, and particularly preferably 7 to 10 members. Depending on the number of spiro atoms shared between the rings, the spiros heterocyclyl group is divided into a monospiros heterocyclyl group, a disspiros heterocyclyl group, or a polyspiros heterocyclyl group, preferably a monospiros heterocyclyl group and a disspiros heterocyclyl group. Particularly preferred are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiros heterocyclyl groups. As a non-limiting example of a spiros heterocyclyl group, TIFF2026510566000128.tif29111 is one example.

[0086] The term "condensed cycloalkyl group" refers to a 5-20 membered polycyclic heterocyclyl group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system, and one or more of the ring atoms are nitrogen, oxygen, or S(O). m A heteroatom selected from (where m is an integer 0, 1, or 2), with the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, and particularly preferably 7 to 10 members (7-membered, 8-membered, 9-membered, or 10-membered rings). Depending on the number of constituent rings, it can be divided into dicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl groups, preferably dicyclic or tricyclic, and particularly preferably 5-membered / 5-membered or 5-membered / 6-membered dicyclic fused heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups include: TIFF2026510566000129.tif54144 is one example.

[0087] The term "bridged heterocyclyl group" refers to a 5-14 member polycyclic heterocyclyl group in which any two rings share two atoms that are not directly linked, and one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system, and one or more of the ring atoms are nitrogen, oxygen, or S(O). m A heteroatom selected from (where m is an integer 0, 1, or 2), with the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, and particularly preferably 7 to 10 members (7-membered, 8-membered, 9-membered, or 10-membered rings). Depending on the number of constituent rings, it can be divided into dicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocyclyl groups, preferably dicyclic, tricyclic, or tetracyclic, and particularly preferably dicyclic or tricyclic. Non-limiting examples of bridging heterocyclyl groups include: TIFF2026510566000130.tif37102 is one example.

[0088] The heterocyclyl ring may be condensed with an aryl group, a heteroaryl group, or a cycloalkyl group, but here the ring linked to the parent structure is a heterocyclyl group, and as a non-limiting example, Examples include TIFF2026510566000131.tif2198.

[0089] The heterocyclyl group may optionally be substituted or unsubstituted, and if substituted, preferably the substituent is independently selected from one or more alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclylalkoxy groups, cycloalkylthio groups, heterocyclylalkylthio groups, and oxo groups.

[0090] The term "aryl group" refers to a 6-14 member all-carbon monocyclic or fused polycyclic ring (i.e., a ring sharing adjacent carbon atom pairs) having a conjugated π-electron system, preferably 6-10 member (6, 7, 8, 9, or 10 member), such as a phenyl group and a naphthalenyl group, preferably a phenyl group. The aryl group ring may be fused to a heteroaryl group, a heterocyclyl group, or a cycloalkyl group, where the ring linked to the parent structure is an aryl group ring, and a non-limiting example thereof is: TIFF2026510566000132.tif38150 is one example.

[0091] The aryl group may be substituted or unsubstituted, and if substituted, preferably the substituent is independently selected from one or more alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclylalkoxy groups, cycloalkylthio groups, and heterocyclylalkylthio groups.

[0092] The term "heteroaryl group" refers to a heteroaryl group system containing 1 to 4 heteroatoms (1, 2, 3, or 4 heteroatoms) and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Preferably, the heteroaryl group is 5 to 10-membered (5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered heteroaryl group). Particularly preferred are 5-membered or 6-membered groups, such as furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, and tetrazolyl groups. The ring of the heteroaryl group may be condensed with an aryl group, a heterocyclyl group, or a cycloalkyl group, where the ring linked to the parent structure is the ring of the heteroaryl group, and a non-limiting example is: TIFF2026510566000133.tif41150 is one example.

[0093] The heteroaryl group may optionally be substituted or unsubstituted, and if substituted, preferably the substituent is independently selected from one or more alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclylalkoxy groups, cycloalkylthio groups, and heterocyclylalkylthio groups.

[0094] The term "amino protecting group" is used to protect an amino group with a group that can be easily removed in order to keep the amino group intact while the rest of the molecule reacts. Non-limiting examples include the 9-fluorenyl methoxycarbonyl group, the tert-butoxycarbonyl group, the acetyl group, the benzyl group, the allyl group, and the p-methoxybenzyl group. These groups are optionally substituted with one to three substituents (one, two, or three substituents) selected from halogens, alkoxy groups, or nitro groups. Preferably, the amino protecting group is the 9-fluorenyl methoxycarbonyl group.

[0095] The term "halogen-substituted alkyl group" refers to an alkyl group that is substituted with one or more halogens, where the definition of an alkyl group is as described above.

[0096] The term "deuterated alkyl group" refers to a group in which an alkyl group is substituted with one or more deuterium atoms, where the definition of an alkyl group is as described above.

[0097] The term "hydroxyalkyl group" refers to a group in which an alkyl group is substituted with one or more hydroxyl groups, where the definition of an alkyl group is as described above.

[0098] The term "hydroxyl group" refers to the -OH group.

[0099] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0100] The term "amino group" refers to -NH2.

[0101] The term "nitro group" refers to -NO2.

[0102] The term "cyano group" refers to -CN.

[0103] The term "acylamino group" refers to -C(O)N(alkyl group) or (cycloalkyl group), where the definitions of alkyl group and cycloalkyl group are as described above.

[0104] The term "carboxylic acid ester group" refers to -C(O)O(alkyl group) or (cycloalkyl group), where the definitions of alkyl group and cycloalkyl group are as described above.

[0105] The present invention also includes compounds represented by formula (I) in various deuterated forms. Each available hydrogen atom bonded to a carbon atom can be independently substituted with a deuterium atom. Those skilled in the art can synthesize compounds represented by formula (I) in deuterated forms by referring to relevant literature. When preparing compounds represented by formula (I) in deuterated forms, commercially available deuterated starting materials may be used, or they may be synthesized using conventional techniques employing deuterating reagents, which include, but are not limited to, deuterated borane, trideuteroboranetetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0106] The terms "optional" or "optionally" mean that they are possible but not necessarily to occur due to the circumstances or conditions described below, and the description includes cases where such circumstances or conditions occur or do not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that an alkyl group may be present but is not necessarily to occur, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0107] "Substitution" refers to the substitution of one or complex hydrogen atoms in a group with a corresponding number of substituents that are independent of each other, preferably up to five hydrogen atoms, and particularly preferably one, two, or three. Of course, substituents are only placed where they are chemically possible, and those skilled in the art can determine whether substitution is possible or not (experimentally or theoretically) without special effort. For example, an amino group or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond (such as an olefinic bond).

[0108] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / medicinal salts or prodrugs with other chemical components, and other components, such as physiologically / medicinal carriers and excipients. The purpose of a pharmaceutical composition is to exert biological activity by facilitating administration to a living organism and contributing to the absorption of the active ingredient.

[0109] The terms “pharmaceutically acceptable salt” or “pharmaceutically usable salt” refer to salts of the ligand-drug conjugates of the present invention, or salts of the compounds described in the present invention, which are safe and effective when administered to mammals and possess the desired biological activity. Since the ligand-drug conjugates of the present invention contain at least one amino group, they can form salts with acids. Non-limiting examples of pharmaceutically usable salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, sorbate, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, methanesulfonate, ethyl sulfonate, benzenesulfonate, and p-toluenesulfonate.

[0110] The term "carrier" as used in the present invention refers to a system that alters the mode of drug entry and distribution into the body, controls the drug release rate, and delivers the drug to a target organ. Drug carrier release and targeting systems can reduce drug degradation and loss, reduce side effects, and increase bioavailability. For example, polymeric surfactants that can be used as carriers can self-assemble due to their unique amphiphilic structure to form various forms of aggregates, preferably micelles, microemulsions, gels, liquid crystals, vesicles, etc. These aggregates have the ability to encapsulate drug molecules while also having good permeability to membranes, making them excellent drug carriers.

[0111] The term "excipient" refers to any additives in a pharmaceutical preparation other than the active ingredient, and is also called a food additive. For example, binders, fillers, disintegrants, and lubricants in tablets; the matrix components of semi-solid ointments and creams; and preservatives, antioxidants, flavoring agents, fragrances, solubilizers, emulsifiers, solubilizers, osmotic pressure regulators, and colorants in liquid preparations can all be considered excipients.

[0112] Pharmaceutical compositions containing the active ingredient may be in forms suitable for oral administration, such as tablets, sugar-coated tablets, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Oral compositions may be prepared according to any method known in the art for preparing medicinal compositions, and such compositions may contain one or more components selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a pleasant and palatable medicinal formulation. Tablets contain the active ingredient and non-toxic, pharmaceutically usable excipients suitable for mixing for the preparation of tablets. These excipients may be inactive excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents such as crystalline cellulose, croscarmellose sodium, corn starch, starch, and alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone, and acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques that mask the taste of the drug or slow its disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period. For example, water-soluble taste-masking substances such as hydroxypropyl methylcellulose or hydroxypropylcellulose, or time-extending substances such as ethylcellulose or cellulose acetate butyrate can be used.

[0113] Oral formulations can also be provided as rigid gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol, or with an oil-soluble medium such as peanut oil, liquid paraffin, or olive oil.

[0114] The aqueous suspension comprises the active substance and an excipient suitable for the preparation of the aqueous suspension for mixing. Such excipients may be suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic, or naturally occurring phospholipids such as lecithin, or condensation products of enoyloxyenzyme and fatty acids such as polyoxyethylene monostearate, or condensation products of ethylene oxide and long-chain aliphatic alcohols such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide and a partial ester derived from fatty acids and hexitol such as poly(ethylene oxide)sorbitan monooleate, or condensation products of ethylene oxide and a partial ester derived from fatty acids and hexitol anhydride such as poly(ethylene oxide)dehydrated sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethylparaben and n-propylparaben, one or more colorants, one or more flavorings, and one or more sweeteners such as sucrose, saccharin, and aspartame.

[0115] Oily suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin. Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetanol. For formulations with a pleasant mouthfeel, the aforementioned sweeteners and flavoring agents may be added. These compositions can be preserved by adding antioxidants such as butylhydroxyanisole or α-tocopherol.

[0116] By adding water, dispersible powders and granules suitable for preparing aqueous suspensions can be provided together with the active ingredient and a dispersant or wetting agent, suspending agent, or one or more preservatives for mixing. Suitable dispersants or wetting agents and suspending agents are as described above. Excipients such as sweeteners, flavoring agents, and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.

[0117] The pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally derived phospholipids such as soy lecithin, and esters or partial esters derived from fatty acids such as sorbitan monooleate and hexitol anhydride, and condensation products of the said partial esters and ethylene oxide such as poly(ethylene oxide)sorbitan monooleate. The emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Usable sweeteners include syrups and elixirs prepared with glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may contain mitigating agents, preservatives, colorants, and antioxidants.

[0118] The pharmaceutical composition of the present invention may be in the form of a sterile, injectable aqueous solution. Suitable and acceptable solvents include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile oil-in-water microemulsion for injection in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. This oil solution is then added to a mixture of water and glycerol and processed to form a microemulsion. The injection solution or microemulsion may be injected into the patient's bloodstream by local, large-volume injection. Alternatively, the solution and microemulsion may be administered in a manner that maintains a constant circulating concentration of the compound of the present invention. A continuous intravenous drug delivery device may be used to maintain this constant concentration.

[0119] The pharmaceutical compositions of the present invention may be in the form of sterile aqueous or oily suspensions for intramuscular and subcutaneous administration. They can be formulated with suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared with non-toxic, parenterally acceptable diluents or solvents, such as solutions prepared in 1,3-butanediol. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. For this purpose, any mixed fixative oils containing synthetic monoglycerides or diacylglycerols can be used. Additionally, fatty acids such as oleic acid can also be used in the preparation of injectable formulations.

[0120] Those skilled in the art are well aware that the dosage of a drug administered depends on a variety of factors, including but not limited to the activity of the specific compound used, the patient's age, weight, health status, behavioral background, diet, administration time, mode of administration, excretion rate, and drug combinations. Furthermore, optimal treatment methods, such as the treatment method, the daily dose of the general formula compound, and the types of pharmaceutically usable target salts, can be verified based on conventional treatment plans. [Brief explanation of the drawing]

[0121] [Figure 1] Figure 1 shows the tumor growth curve of the NCI-N87 gastric cancer-bearing mouse model in Test Example 3. [Figure 2] Figure 2 shows the tumor growth curve of the human breast cancer JIMT-1 tumor mouse model in Test Example 4. [Figure 3A] Figure 3A shows the proliferation inhibition curve of Her2-negative 468-luc cells in Test Example 6. [Figure 3B] Figure 3B shows the proliferation inhibition curve of Her2-positive N87 cells in Test Example 6. [Figure 3C] Figure 3C shows the growth inhibition curves of N87 cells and 468-luc cells in co-culture in Test Example 6. [Figure 4] Figure 4 shows the body weight change curve after a single dose of 200 mg / kg was administered to rats in Test Example 7. [Figure 5] Figure 5 shows the body weight change curve after a single dose of 200 mg / kg was administered to rats in Test Example 7. [Figure 6A] Figure 6A shows the tumor growth curve of the NCI-N87 gastric cancer-bearing mouse model in Test Example 5. [Figure 6B] Figure 6B shows the tumor growth curve of the NCI-N87 gastric cancer-bearing mouse model in Test Example 5. [Modes for carrying out the invention]

[0122] The compounds of the present invention and their preparations are further understood by examples illustrating numerous methods of preparing or using the compounds. However, it should be understood that these examples do not limit the scope of the invention. Modifications of the invention that are currently known or to be further developed are considered to fall within the scope of the invention described herein and for which protection is claimed.

[0123] The compounds of the present invention are prepared using simple starting materials and general preparation procedures. The present invention presents typical or tendency reaction conditions such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, other reaction conditions may be used unless otherwise specified. Optimization conditions may vary depending on the specific reactants or solvent used, but generally, reaction optimization procedures and conditions can be determined.

[0124] Furthermore, in this invention, several protecting groups can be used to protect specific groups from unwanted reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, the protection or deprotection of numerous protecting groups is described in detail in "Protecting Groups in Organic Preparations" by TW Greene and GMWuts (3rd edition, Wiley, New York, 1999 and its references).

[0125] The separation and purification of compounds and intermediates employ appropriate methods and procedures depending on the specific requirements, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination thereof. Specific uses of these methods can be found in the examples described in this invention. Of course, other similar separation and purification methods may also be employed. These compounds can be characterized using conventional methods, including physical constants and spectral data.

[0126] The structure of the compound was confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift was 10 -6 The values ​​are expressed in units of ppm. NMR measurements were performed using a Brukerdps 400 nuclear magnetic resonance spectrometer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and deuterated water (D2O). Tetramethylsilane (TMS) was used as the internal standard solution.

[0127] Low molecular weight mass spectrometry measurements were performed using an LC (Waters 2695) / MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector).

[0128] MS measurements at the ADC were performed using UPLC-MS, Thermo Fisher Scientific, Dionex UltiMate 3000 UPLC-Q Exactive MS; and a high-resolution mass spectrometer, Thermo Q EXACTIVE HF-X.

[0129] ADC analysis of HIC was performed using Agilent 1200 high-performance liquid chromatography. The column used was Thermo MAbPac HIC-Bulty (5 μm, 4.6 × 100 mm). Mobile phase A was a mixture of 1.5 M ammonium sulfate and 25 mM phosphate (pH 7.0) - isopropanol (95:5), and mobile phase B was a mixture of 25 mM phosphate (pH 7.0) - isopropanol (80:20). Gradient elution was performed at a flow rate of 1.0 ml / min.

[0130] For the ADC analysis of SEC, Agilent 1200 high-performance liquid chromatography was used, with a Waters BioResolve SEC mAb column (2.5 μm, 7.8 × 300 mm) and PBS as the mobile phase, performing isocratic elution at a flow rate of 0.5 ml / min.

[0131] For ADC analysis of RP for HIC testing, Agilent 1200 high-performance liquid chromatography was used, with a Thermo MAbPac RP column (4 μm, 3 × 100 mm). A 0.1% trifluoroacetic acid solution was used as mobile phase A, and acetonitrile-isopropanol-trifluoroacetic acid (80:20:0.1) was used as mobile phase B. Gradient elution was performed at a flow rate of 1.0 ml / min.

[0132] For preparative high-performance liquid chromatography, an lc6000 high-performance liquid chromatography system (manufacturer: Innovation Tongheng) was used. The column was Daisogel C18 10μm 100A (30mm × 250mm), and the mobile phase was acetonitrile / water, using an Oriendo BRIX-2860 column. Another column was Phenomenex Luna C18 250 × 50mm × 10μm. The mobile phase was water (0.225% trifluoroacetic acid)-acetonitrile.

[0133] For thin-layer chromatography, Qingdao Marine Chemical GF254 silica gel plates were used. The silica gel plates used for thin-layer chromatography (TLC) were 0.20 mm to 0.25 mm in thickness, while the plates used for separation and purification of preparative thin-layer chromatography were 0.5 mm in thickness.

[0134] In column chromatography, silica gel of 100-200 mesh, 200-300 mesh, and 300-400 mesh from Qingdao Marine Chemical was generally used as the carrier.

[0135] The known starting materials of the present invention can be synthesized by methods known in the art, or purchased from companies such as Wanghua Mall, Beijing Ouhe, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinukai, Annaij Chemical, Shanghai Bide, Haoyuan Pharmaceutical, Yilai Biotechnology, and Duchuang Pharmaceutical.

[0136] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0137] An argon atmosphere or nitrogen atmosphere refers to a reaction flask connected to an argon balloon or nitrogen balloon with a volume of approximately 1 L.

[0138] The reaction solvent, organic solvent, or inert solvent is described as a solvent that does not participate in the reaction under the described reaction conditions, and examples include benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ethyl ether, methanol, N-methylpyrrolidone (NMP), pyridine, etc. Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0139] The chemical reactions described in this invention are generally carried out at atmospheric pressure. The reaction temperature was -78°C to 200°C. The reaction time and conditions were, for example, between -78°C and 200°C at 1 atmosphere, and completed in about 1 to 24 hours. If the reaction was carried out overnight, the reaction time was usually 16 hours. Unless otherwise specified in the examples, the reaction temperature was room temperature between 20°C and 30°C.

[0140] The reaction process in the embodiment was monitored by thin-layer chromatography (TLC). The developing solvent systems used in the reaction included A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, and C: acetone system. The volume ratio of the solvents was adjusted according to the polarity of the compound.

[0141] Examples of eluent systems for column chromatography and developing solvent systems for thin-layer chromatography used in the purification of compounds include A: dichloromethane and methanol systems, and B: petroleum ether and ethyl acetate systems. Depending on the polarity of the compound, the volume ratio of the solvents can be adjusted, or the solvent can be prepared by adding small amounts of alkaline or acidic reagents such as triethylamine or trifluoroacetic acid.

[0142] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those known to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described may be applied to the methods of the present invention.

[0143] The compounds of the present invention are prepared according to the exemplary procedures described herein and their variations known to those skilled in the art.

[0144] Preparation example Preparation Example 1: Preparation of (9R)-9-ethyl-5-fluoro-1,9-dihydroxy-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-1) TIFF2026510566000134.tif60106 NaNO2 (270 mg, 3.91 mmol) was placed in a 25 mL three-necked flask, dissolved in water (6 mL), then glacial acetic acid (1 mL) was added, followed by the addition of glacial acetic acid aqueous solution of exatecan mesylate (Haoyuan Pharmaceutical, 100 mg, 0.188 mmol) (glacial acetic acid (3 mL), water (3 mL)) which was slowly added to the NaNO2 solution and reacted at room temperature for 1.5 hours. The reaction mixture was filtered, the solid was collected, and the solid was dried to obtain a reddish-brown solid. This solid was separated and purified by high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase: water (0.5% formic acid) - acetonitrile, eluting from 40% to 80%), and lyophilized to obtain 12 mg of a pale red powder. Yield: 14%. LCMS (ESI): m / z, 437.1[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 11.0 Hz, 1H), 7.31 (s, 1H), 6.50 (s, 1H), 6.04- 5.83 (m, 1H), 5.48-5.29 (m, 4H), 5.16 (d, J = 5.6 Hz, 1H), 3.23 (dd, J = 13.4, 8.6 Hz, 2H), 3.09-2.98 (m, 1H), 2.37 (s, 3H), 2.02 (dd, J = 16.4, 6.8 Hz, 1H), 1.86 (dq, J = 14.0, 7.2 Hz, 2H), 0.88 (t, J = 7.3 Hz (3H).

[0145] Preparation Example 2: Preparation of (9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl(2-hydroxyethyl)carbamate (PY-1AB) TIFF2026510566000135.tif96157

[0146] Procedure 1: Preparation of (9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl(4-nitrophenyl)carbonate (PY-1D) Compound PY-1 (40.0 mg, 0.09 mmol, 1.0 eq) and triethylamine (27.3 mg, 0.27 mmol, 3.0 eq) were dissolved in dichloromethane (5 mL), and p-nitrophenyl chloroformate (36.2 mg, 0.18 mmol, 2.0 eq) was added at 0°C. The mixture was heated to 35°C and stirred for 3 hours. The reaction mixture was cooled to room temperature and concentrated to obtain the crude product, a yellow solid (60 mg of crude product, 49.3% purity, 0.05 mmol, yield 55.6%). LCMS:RT = 0.909 min, MS (ESI) m / z = 602.1 [M+H] + .

[0147] Procedure 2: Preparation of (9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl(2-hydroxyethyl)carbamate (PY-1AB) Compound PY-1D (0.05 mmol, 1.0 eq) and triethylamine (10.1 mg, 0.1 mmol, 2.0 eq) were dissolved in dichloromethane (5 mL), and ethanolamine (31.4 mg, 0.04 mmol, 1.1 eq) was added at 0°C. The mixture was stirred at 25°C for 3 hours. The reaction mixture was cold-concentrated to obtain the crude product. The crude product was purified by reverse-phase chromatography (column: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; gradient: 6%-46% B over 25 min) to obtain the title compound PY-1AB (2.23 mg, 0.004 mmol, yield 8.00%) as a white solid. LCMS:RT = 1.197 min, MS (ESI) m / z = 524.2 [M+H]+ . 1 HNMR (400MHz, DMSO-d 6 ) δ ppm 7.81 (d, J = 10.8 Hz, 1 H), 7.45 (t, J = 5.6 Hz, 1 H), 7.33 (s, 1 H), 6.52 (s, 1 H), 6.27 (s, 1 H), 5.44 - 5.24 (m, 4 H), 4.70 (t, J = 5.6 Hz, 1 H), 3.48-3.44 (m, 2 H), 3.22-3.12 (m, 4 H), 2.40 (s , 3 H), 2.20-2.17 (m, 1 H), 1.91-1.86 (m, 2 H), 1.27-1.22 (m, 1 H), 0.88 (t, J = 7.2 Hz, 3H).

[0148] Preparation Example 3: Preparation of (9S)-9-ethyl-5-fluoro-9-hydroxy-1-(hydroxymethyl)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-2) and (S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1-methylene-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-2b) TIFF2026510566000136.tif93157

[0149] Procedure 1: Preparation of (E)-N-(3-fluoro-7-(hydroxymethylene)-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-22) In a 100 ml three-necked flask, N-(3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-21) (1.0 g, 4.25 mmol, 1.0 eq) was dissolved in THF (20 mL), cooled to 0°C in ice water, and t-BuOK (12.75 mmol, 1 M, 12.75 mL, 3 eq) was slowly added. The system temperature was maintained at 0°C and stirred for 30 minutes. Then, ethyl formate (787 mg, 10.63 mmol, 2.5 eq) was added to the reaction system and stirred for 2 hours. The mixture was quenched with ammonium chloride (20 ml), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the yellow solid compound (E)-N-(3-fluoro-7-(hydroxymethylene)-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (1.22 g, yield 95%). LCMS (ESI): m / z, 264.1[M+1] + .

[0150] Step 2: Preparation of N-(3-fluoro-7-(hydroxymethyl)-4-methyl-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-23) Under a nitrogen atmosphere, a solution of compound (E)-N-(3-fluoro-7-(hydroxymethylene)-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide PY-22 (400 mg, 1.52 mmol, 1.0 eq) in methanol (50 ml) was mixed with PtO2 (69.00 mg, 303.90 μmol, 0.2 eq), the mixture was purged three times with hydrogen gas, and the mixture was reacted under a hydrogen gas atmosphere for 24 hours (40°C). The residue of the starting material was detected, and further PtO2 (6 9.00 mg, 303.90 μmol, 0.2 eq) was added, and the mixture was reacted for a further 24 hours under a hydrogen gas atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane 1:20~1:5) to obtain the yellow solid compound N-(3-fluoro-7-(hydroxymethyl)-4-methyl-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (324 mg, yield 63%). LCMS (ESI): m / z, 266.1[M+1] + .

[0151] Step 3: Preparation of 8-amino-6-fluoro-2-(hydroxymethyl)-5-methyl-3,4-dihydronaphthalene-1(2H)-one (PY-24) Under ice bath conditions, a solution of compound N-(3-fluoro-7-(hydroxymethyl)-4-methyl-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide PY-23 (180 mg, 0.68 μmol, 1.0 eq) in anhydrous MeOH (15 mL) was mixed with SOCl2 (2.71 mmol, 1 M / L, 2.71 mL, 4.0 eq), then the mixture was purged three times with nitrogen gas and stirred at 50°C for 60 minutes. The solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 40% to 80%) to obtain the pale yellow solid compound 8-amino-6-fluoro-2-(hydroxymethyl)-5-methyl-3,4-dihydronaphthalene-1(2H)-one (28.5 mg, 25% yield). LCMS(ESI): m / z, 264.1[M+1] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.43 (brs, 2H), 6.35 (d, J = 12.0 Hz, 1H), 3.74 (dd, J = 10.8, 4.4 Hz, 1H), 3.60 (dd, J = 10.8, 7.2 Hz, 1H), 2.90 (dt, J = 17.2, 4.8 Hz, 1H), 2.75-2.54 (m, 2H), 2.18-2.08 (m, 1H), 1.98 (s, 3H), 1.84-1.79 (m, 1H).

[0152] Procedure 4: Preparation of (9S)-9-ethyl-5-fluoro-9-hydroxy-1-(hydroxymethyl)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-2) and (S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1-methylene-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-2b) To a solution of compound 8-amino-6-fluoro-2-(hydroxymethyl)-5-methyl-3,4-dihydronaphthalene-1(2H)-one (22 mg, 98.5 μmol, 1.0 eq) in xylene (5 mL), (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione (26 mg, 98.50 μmol, 1.0 eq) and PPTS (5 mg, 19.70 μmol, 0.2 eq) were added. The mixture was then purged three times with nitrogen gas and stirred at 140°C for 3 hours. The solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, from 48% to 80%) to obtain a yellow solid PY-2 (3.42 mg, yield 7%) and a dark brown, slightly viscous solid PY-2b (5.31 mg, yield 10%). PY-2: LCMS(ESI):m / z,451.2[M+1] + . 1 1H NMR (400 MHz, DMSO-d 6) δ 11.80 (s, 1H), 8.14 (s, 1H), 7.17 (d, J = 12.4 Hz, 1H), 6.73 (s, 1H), 6.46 (s, 1H), 6.11 (d, J = 2.0 Hz, 1H), 5.61 (d, J = 2.0 Hz, 1H), 5.36 (s, 1H), 4.73 (d, J = 2.4 Hz, 1H), 2.95 (t, J = 6.8 Hz, 2H), 2.79 (t, J = 6.8 Hz, 2H), 2.25 - 2.03 (m, 5H), 2.00 (d, J = 2.0 Hz, 1H), 1.86-1.76 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H). PY-2b: LCMS(ESI): m / z, 433.2[M+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 10.8 Hz, 1H), 7.62 (s, 1H), 5.77-5.70 (m, 3H), 5.38-5.30 (m, 3H), 3.77 (s, 1H), 3.22-3.19 (m, 2H), 2.85-2.82 (m, 2H), 2.41 (s, 3H), 1.96 - 1.82 (m, 2H), 1.04 (t, J = 8.0 Hz, 3H).

[0153] Preparation Example 4: Preparation of (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-((2-hydroxymethyl)amino)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-4) TIFF2026510566000137.tif3248 Exatecan mesylate (Haoyuan Pharmaceutical) (50 mg, 114.82 μmol) was dissolved in DMF (2 mL), and ethylene oxide (1 M, 1.15 mL) and glacial acetic acid (3.45 mg, 57.41 μmol) were added to the solution. The reaction system was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature, 20 mL of water was added to the system, and it was extracted with ethyl acetate (20 mL x 3). After combining the organic phases, the mixture was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 40% to 80%), and one drop of hydrochloric acid was added to the resulting solution. The mixture was then freeze-dried to obtain the yellow solid compound PY-4 (5.82 mg, yield 21%). LCMS: [M+H] + = 480.9. 1 1H NMR (DMSO-d 6 , 400 MHz): δ (ppm) 0.72 - 0.83 (t, J=14.7 Hz, 3H), 1.72 - 1.85 (m, 2H), 2.13-2.22 (s, 3H), 2.43-2.56 (m, 1H), 2.80- 3.06 (m, 2H), 3.18 - 3.31 (s, 2H), 3.31-3.40 (m, 1H), 3.74-3.82 (m, 2H), 5.08-5.13 (s, 1H), 5.18 - 5.41 (m, 4H), 7.10 -7.14 (s, 1H), 7.15-7.21 (s, 1H).

[0154] Preparation Example 5: Preparation of 2-hydroxyethyl((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-1-yl)carbamate (PY-4Car) TIFF2026510566000139.tif72157

[0155] Procedure 1: Preparation of (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-isocyanate-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-10,13-dione (4Car2) At 0°C, triethylamine (14 mg, 0.14 mmol, 3 eq) and triphosgene (14 mg, 0.046 mmol, 1 eq) were added to a solution of exatecan mesylate (20 mg, 0.046 mmol, 2 mL) in dichloromethane, and the mixture was stirred at 0°C for 3 hours. The mixture was concentrated under reduced pressure to obtain 20 mg of crude product, which was then directly used in the following reaction.

[0156] Procedure 2: Preparation of 2-hydroxyethyl((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-1-yl)carbamate (PY-4Car) The compound (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-isocyanate-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4]:6,7]indolidino[1,2-b]quinoline-10,13-dione (4Car2) (20 mg, 0.043 mmol) was dissolved in dichloromethane, and ethylene glycol (27 mg, 0.43 mmol, 10 eq) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The compound was concentrated under reduced pressure, and the residue was purified by preparative chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 40% to 80%) to obtain 6.5 mg of the yellow solid compound PY-4Car. LCMS: m / z = 524.2 [M+1] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.43 (s, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 10.8 Hz, 1 H), 7.31 (s, 1 H), 6.55 (s, 1 H), 5.43 (s, 2 H), 5.24 (d, J = 7.20 Hz, 2 H), 4.81 (t, J = 5.2 Hz, 1 H), 3.97-4.17 (m, 2 H), 3.61 (d, J=3.6 Hz, 2 H), 3.02-3.18 (m, 2 H), 2.30-2.41 (m, 3 H), 2.05 - 2.28 (m, 2 H), 1.75-1.94 (m, 2 H), 0.87 (t, J = 7. 2 Hz, 3 H).

[0157] Preparation Example 6: Preparation of 4-hydroxybutyl((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl)carbamate (PY-4Car2) TIFF2026510566000140.tif5161 TIFF2026510566000141.tif69134

[0158] Procedure 1: Preparation of 4-((tert-butyldimethylsilyl)oxy)butyl(4-nitrophenyl) carbonate (PY-4car2-b) To a solution of 4-((tert-butyldimethylsilyl)oxy)butan-1-ol (1 g, 4.89 mmol, 1 eq) and bis(p-nitrophenyl) carbonate (2.98 g, 9.79 mmol, 2 eq) in N,N-dimethylformamide (15 mL), N,N-diisopropylethylamine (2.43 mL, 14.68 mmol, 3 eq) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, diluted with dichloromethane (10 mL), and the organic phase was converted to water. The organic phase was washed three times with (10 mL) and once with saturated saline solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1; 10, dichloromethane / petroleum ether = 40%) to obtain the product 4-((tert-butyldimethylsilyl)oxy)butyl(4-nitrophenyl) carbonate (PY-4car2-b) (1.63 g, yield = 90.2%). LCMS (ESI): m / z, 370[M+H] + .

[0159] Procedure 2: Preparation of 4-((tert-butyldimethylsilyl)oxy)butyl((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl)carbamate (PY-4car2-d) To a solution of exatecan (20 mg, 37.62 μmol, 1 eq, mesylate, Haoyuan Pharmaceutical) and N,N-diisopropylethylamine (6.22 μL, 37.62 μmol, 1 eq) in dichloromethane (6 mL), triethylamine (20.92 μL, 150.48 μmol, 4 eq), compound PY-4car2-b (18.1 mg, 48.92 μmol, 1.3 eq), and 1-hydroxybenzotriazole (2.4 mg, 18.81 μmol, 0.5 eq) were added. The mixture was stirred at room temperature for 48 hours, concentrated, and the residue was subjected to high-performance liquid chromatography (preparative chromatograph, Oriendo, model BRIX-2860; column: Welch Xtimate C18). The sample was prepared in 250 × 30 mm × 10 μm. The mobile phase was water (0.225% HCOOH)-acetonitrile (acetonitrile elution ratio: 50% to 60% eluted), and the compound PY-4car2-d (15 mg, yield = 59.8%) was obtained. LCMS(ESI): m / z, 666[M+H] + .

[0160] Procedure 3: Preparation of 4-hydroxybutyl((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl)carbamate (PY-4Car2) Under ice bath conditions, a solution of compound PY-4car2-d (15 mg, 22.53 μmol, 1 eq) in tetrahydrofuran (3 mL) was mixed with triethylamine trifluoride (14.69 μL, 90.12 μmol, 4 eq), stirred for 5 minutes, and then stirred overnight at 25°C. The residue was purified by reverse-phase preparative chromatography (preparative chromatography manufacturer: SHIMADZU, model number LC-20AP. Column: YMC-Triart Prep C18 250 × 30 mm × 10 μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, acetonitrile elution ratio: eluted from 20% to 55%) to obtain the title compound PY-4Car2 (3.77 mg, yield = 30.34%). LCMS(ESI): m / z, 552[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 10.8 Hz, 1H), 7.31 (s, 1H), 6.51 (s, 1H), 5.42 (s, 2H), 5.24 (d, J = 4.2 Hz, 2H), 4.41 (t, J = 5.2 Hz, 1H), 4.15-4.03 (m, 2H), 3.43 (q, J = 6.2 Hz, 2H), 3.29 - 3.06 (m, 3H), 2.38 (d, J = 1.8 Hz, 3H), 2.25-2.08 (m, 2H), 1.93-1.81 (m, 2H), 1.65 (p, J = 6.8 Hz, 2H), 1.50 (p, J = 6.6 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -111.37.

[0161] Preparation Example 7: Preparation of 3-hydroxypropyl((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[d]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl)carbamate (PY-4Car3C) TIFF2026510566000142.tif6154 TIFF2026510566000143.tif94157

[0162] Procedure 1: Preparation of compound 3-((tert-butyldimethylsilyl)oxy)propyl(4-nitrophenyl) carbonate At 0°C, a solution of compound 3-(tert-butyldimethylsilyloxy)propanol (400 mg, 2.10 mmol, 1 eq) in DMF (5 mL) was mixed with bis(p-nitrophenyl) carbonate (1.28 g, 852.31 μL, 4.20 mmol, 2 eq) and DIPEA (543.14 mg, 694.55 μL, 4.20 mmol, 2 eq), stirred at room temperature (25°C) for 16 hours, poured the reaction mixture into 60 mL of water, and extracted three times with ethyl acetate. Each time, 20 mL was added, the organic phase was combined, the organic phase was washed with saline solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to dry the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether 1:30 to 1:20) to obtain the pale yellow oily compound 3-((tert-butyldimethylsilyl)oxy)propyl(4-nitrophenyl) carbonate (740 mg, yield: 99.07%). 1 H NMR (400 MHz, Chloroform-d) δ 8.30-8.26 (m, 2H), 7.40-7.35 (m, 2H), 4.41 (t, J = 6.4 Hz, 2H), 3.76 (t, J = 5.9 Hz, 2H), 1.99-1.93 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H).

[0163] Step 2: Preparation of compound PY-4Car 3C-a To a solution of compound 3-((tert-butyldimethylsilyl)oxy)propyl(4-nitrophenyl) carbonate (32.10 mg, 90.29 μmol, 1.2 eq) and exitecan mesylate (40 mg, 75.24 μmol, 1 eq) in DMF (2 mL), HOBt (10.17 mg, 99.96%, 6.78 μL, 75.24 μmol, 1 eq) and DIPEA (29.17 mg, 99%, 37.31 μL, 225.73 μmol, 3 eq) were added. The mixture was stirred at room temperature (25°C) for 1 hour, and the reaction was confirmed to be complete by LC-MS. The reaction solution was then subjected to preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Oriendo, model number BRIX-2860. Column: Welch Xtimate C18). The sample was prepared to be 150 × 21.2 mm × 5 μm. It was purified using water (0.225% HCOOH)-acetonitrile as the mobile phase (elution ratio of water: elution from 50% to 80%), and then freeze-dried to obtain the pale yellow solid compound PY-4Car 3C-a (45 mg, yield: 91.75%). LCMS: m / z = 652.3 [M+1] + Rt = 3.098 min.

[0164] Step 3: Preparation of compound PY-4Car 3C At room temperature, triethylamine trifluoride (499.70 mg, 98%, 505.26 μL, 3.04 mmol, 50 eq) was added to a solution of compound PY-4Car3C-a (45 mg, 60.75 μmol, 1 eq) in THF (2 mL), and the reaction mixture was stirred at 40°C for 10 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: Shimadzu, model number LC-20AP. Column: Welch Xtimate C18 250 × 30 mm × 10 μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: elution from 30% to 60%), lyophilized, and obtained the yellow solid compound PY-4Car3C (27.40 mg, Yield: 83.90%, Purity: 98.19%). LCMS: m / z = 538.2 [M+1] + Rt = 1.508 min. 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 10.9 Hz, 1H), 7.30 (s, 1H), 6.52 (s, 1H), 5.42 (s, 2H), 5.23 (d, J = 6.4 Hz, 3H), 4.51 (s, 1H), 4.20-4.15 (m, 1H), 4.13-4.05 (m, 1H), 3.50 (t, J = 6.4 Hz, 2H), 3.23 (s, 1H), 3.14-3.07 (m, 1H), 2.37 (d, J = 1.8 Hz, 3H), 2.24-2.09 (m, 2H), 1.92-1.82 (m, 2H), 1.76 (p, J = 6.5 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0165] Preparation Example 8: Preparation of (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-(2-hydroxyethyl)(methyl)amino)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-5) Compound (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-((2-hydroxymethyl)amino)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-4) (25 mg, 52.14 μmol) was dissolved in methanol (2 mL), and paraformaldehyde (7.83 mg, 260.69 μmol) and glacial acetic acid (626.19 μg, 10.43 μmol) were added to the solution, and the reaction system was stirred at 60°C for 2 hours. Sodium cyanoborate hydride (16.38 mg, 260.69 μmol) was added, and the reaction system was stirred at 30°C for 16 hours. The reaction mixture was cooled to room temperature, 20 mL of saturated ammonium chloride solution was added to the reaction system, and it was extracted with ethyl acetate (20 mL x 3). After combining the organic phases, the mixture was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 40% to 80%) to obtain a clean product solution. One drop of hydrochloric acid was added to this solution, and it was freeze-dried to obtain a yellow solid PY-5 (7.63 mg, yield 29.65%). LCMS: [M+H] + = 494.8. 1 H NMR (deuterated dimethyl sulfoxide, 400 MHz): δ (ppm) 0.65-0.81 (t, J=7.4 Hz, 3H), 1.73-1.84 (m, 2H), 2.05-2.22 (s, 3H), 2.48-2.57 (m, 1H), 2.57-2.69 (s, 3H), 2.93-3.15 (m, 2H), 3.19-3.31 (m, 1H), 3.34-3.42 (m, 1H), 3.78-3.92 (m, 2H), 5.08-5.44 (m, 4H), 7.12-7.14 (s, 1H), 7.14-7.18 (d, J=10.4 Hz, 1H).

[0166] Preparation Example 9: Preparation of N-(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-1-yl)-N-(2-hydroxyethyl)formamide (PY-6A1) TIFF2026510566000145.tif6098 Acetic acid (31.31 mg, 521.38 μmol) was added dropwise to a solution of anhydrous tetrahydrofuran (1 mL) and acetic acid (63.87 mg, 625.65 μmol) was allowed to react at 50°C for 1 hour. The reaction system was added to a solution of compound (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-((2-hydroxymethyl)amino)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-4) (100 mg, 208.55 μmol) in anhydrous tetrahydrofuran (5 mL) and allowed to react at 20°C for 4 hours. 20 mL of water was added to the reaction system and extracted with ethyl acetate (20 mL x 3). After combining the organic phases, the mixture was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 40% to 80%), lyophilized, and a white solid compound PY-6A1 (4.02 mg, 7.92 μmol, yield 3.80%) was obtained. LCMS: [M+H] + = 508.2. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 0.77-0.95 (t, J=0.9 Hz, 3H), 1.75-1.91 (m, 2H), 2.15-2.33 (m, 1H), 2.322.39 (s, 3H), 2.94-3.14 (m, 2H), 3.40-3.66 (m, 2H), 4.67-5.30 (m, 3H), 5.31-5.57 (m, 3H), 6.46-6.51 (s, 1H), 7.26-7.30 (s, 1H), 7.71-7.82 (m, 1H), 8.11-8.29 (d, J=44.6 Hz, 1H).

[0167] Preparation Example 10: Preparation of N-(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-1-yl)-N-(2-hydroxyethyl)acetamide (PY-6A2) At 900°C, triethylamine (12 mg, 0.12 mmol, 3 eq) and acetyl chloride (3.27 mg, 41.70 μmol, 1 eq) were added to a solution of the compound (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-((2-hydroxymethyl)amino)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-4) (20 mg, 0.04 mmol) in dichloromethane (1 mL), and the mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 40% to 80%) to obtain the (3.25 mg, 15%) white solid compound PY-6A2. LCMS (ESI): m / z, 522.2 [M+1] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1 H) 7.75 (br d, J = 9.6 Hz, 1 H) 7.25-7.38 (m, 1 H) 6.52 (s, 1 H) 5.30-5.53 (m, 4 H) 4.04 - 4.33 (m, 2 H) 2.85-3.19 (m, 5 H) 2.29-2.41 (m, 4 H) 2.03-2.23 (m, 5 H) 1.83-1.95 (m, 2 H) 0.87 (t, J = 7.2 Hz, 3 H).

[0168] Preparation Example 11: Preparation of N-(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-1-yl)-N-(2-hydroxyethyl)methanesulfonamide (PY-6B1) At 50°C, a solution of the compound (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-((2-hydroxymethyl)amino)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-4) (20 mg, 0.04 mmol) in dichloromethane (1 ml) was mixed with triethylamine (12 mg, 0.12 mmol, 3 eq) and methanesulfonyl chloride (5 mg, 0.04 mmol, 1 eq) and stirred at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 48% to 80%) to obtain the white solid compound PY-6B1 (1.3 mg, yield: 6%). LCMS (ESI): m / z, 558.2 [M+1] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (d, J = 13.6 Hz, 1 H), 7.70-7.81 (m, 1H), 7.28-7.35 (m, 1 H), 6.55 (d, J = 1.6 Hz, 1 H), 5.43 (s, 3 H), 4.15-4.37 (m, 1 H), 2.80-3.11 (m, 4 H), 2.63-2.70 (m, 1 H), 2.27-2.40 (m, 6 H), 2.01-2.24 (m, 2 H), 1.53-1.95 (m, 4 H), 0.80-0.94 (m, 3 H).

[0169] Preparation Example 12: Preparation of (S)-9-ethyl-5-fluoro-9-hydroxy-4-(3-hydroxypropyl)-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-8) TIFF2026510566000148.tif2653 TIFF2026510566000149.tif114144

[0170] Procedure 1: Preparation of 1-bromo-3-fluoro-2-methoxy-5-nitrophenyl (PY-82) 2-Fluoro-1-methoxy-4-nitrophenyl (PY-81) (50 g, 292 mmol) and NBS (57.2 g, 321 mmol) were dissolved in acetic acid (500 mL), to which concentrated sulfuric acid (30 mL) was added and the mixture was stirred overnight at 120 °C. The reaction mixture was concentrated and allowed to stand to precipitate a milky white solid. After filtration, the filtered cake was washed with water and ethanol and dried to obtain compound PY-82 (58 g, yield 79%). LCMS (ESI): m / z, 249.9 [M+H] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.34-8.23 (m, 2H), 4.07 (d, J = 3.2 Hz, 3H).

[0171] Procedure 2: Preparation of 3-bromo-5-fluoro-4-methoxyaniline (PY-83) Compound 1-bromo-3-fluoro-2-methoxy-5-nitrophenyl (PY-82) (50 g, 200 mmol) and iron powder (55.85 g, 1 mol) were sequentially mixed in ethanol (500 mL) with concentrated hydrochloric acid (3.34 mL, 0.55 equiv.) and water (83 mL), and the mixture was stirred overnight at 80°C. The reaction mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE:EA=3:1) to obtain compound PY-83 (40 g, 90% yield). LCMS (ESI): m / z, 219.9 [M+H] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 6.59 (t, J = 2.0 Hz, 1H), 6.41 (dd, J = 13.2, 2.6 Hz, 1H), 5.40 (s, 2H), 3.67 (s, 3H).

[0172] Step 3: Preparation of N-(3-bromo-5-fluoro-4-methoxyphenyl)acetamide (PY-84) Compound 3-bromo-5-fluoro-4-methoxyaniline (PY-83) (10.0 g, 45.4 mmol) and triethylamine (13.9 mL, 2.2 equiv.) were dissolved in dichloromethane (500 mL), to which acetyl chloride (4 mL, 1.2 equiv.) was added and the mixture was stirred overnight at 25°C. The reaction was quenched with 150 mL of saturated ammonium chloride, and 3 × 80 mL of dichloromethane was added for extraction. The organic phase was washed with 80 mL of saturated sodium chloride solution, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE:EA = 3:1) to obtain compound PY-84 (10 g, yield 84%). LCMS (ESI): m / z, 264.0 [M+H] + .

[0173] Step 4: Preparation of (Z)-4-(5-acetamido-3-fluoro-2-methoxyphenyl)butane-3-enoate (PY-85) Compound N-(3-bromo-5-fluoro-4-methoxyphenyl)acetamide (PY-84) (15 g, 57.23 mmol) and Pd(t-Bu3P)2 (1.46 g, 0.05 equiv) were sequentially dissolved in toluene (200.0 mL) and DIPEA (60 mL, 6.0 equiv.) and ethyl crotonate (1.5 equiv., 10.89 mL) were added, and the mixture was stirred overnight at 13°C. The reaction mixture was concentrated directly under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE:EA = 1:2) to obtain compound PY-85 (7.9 g, yield 46%). LCMS (ESI): m / z, 296.1 [M+H] + .

[0174] Step 5: Preparation of ethyl 4-(5-acetamido-3-fluoro-2-methoxyphenyl)butanoate (PY-86) Compound (Z)-4-(5-acetamido-3-fluoro-2-methoxyphenyl)butane-3-enoate (PY-85) (8.0 g, 27.08 mmol) was dissolved in methanol (100.0 mL) and palladium-carbon (0.1 equiv., 2.88 g) was added, and the mixture was reacted overnight at 50°C. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and dried to obtain the crude product, compound PY-86, which was used directly in the following procedure. LCMS (ESI): m / z, 298.1 [M+H] + .

[0175] Procedure 6: Preparation of 4-(5-acetamido-3-fluoro-2-methoxyphenyl)butanoic acid (PY-87) Ethyl 4-(5-acetamido-3-fluoro-2-methoxyphenyl)butanoate (PY-86) (8 g, 26.91 mmol) was mixed with methanol / tetrahydrofuran / water (120 ml) in a 1:1:1 ratio, to which lithium hydroxide (3 equiv., 1.93 g) was added and the mixture was reacted overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and impurities were extracted with ethyl acetate (2 × 80 ml) to remove the organic phase. Concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 1, and further extraction was performed with ethyl acetate (3 × 80 ml). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound PY-87 (3.8 g, yield: 70%). LCMS (ESI): m / z, 270.1 [M+H] + ; 292.1 [M+Na] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.07 (s, 1H), 9.99 (s, 1H), 7.50 (dd, J = 13.6, 2.4 Hz, 1H), 7.09-7.03 (m, 1H), 3.77 (d, J = 1.2 Hz, 3H), 2.63-2.53 (m, 2H), 2.25 (t, J = 7.2 Hz, 2H), 2.02 (s, 3H), 1.75 (dq, J = 9.2, 7.2 Hz, 2H).

[0176] Step 7: Preparation of N-(3-fluoro-4-methoxy-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-88) At 95°C, compound 4-(5-acetamido-3-fluoro-2-methoxyphenyl)butanoic acid (PY-87) (1 g, 3.71 mmol) was stirred in PPA (polyphosphate) solution for 3 hours. The reaction mixture was poured into ice water, washed with water, extracted with ethyl acetate (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 45% to 85%), lyophilized, and compound PY-88 (110 mg, yield 11%) was obtained. LCMS (ESI): m / z, 252.1 [M+H] + ; 274.0 [M+Na] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.05 (s, 1H), 8.37 (d, J = 14.8 Hz, 1H), 3.81 (d, J = 1.2 Hz, 3H), 2.95 (t, J = 6.0 Hz, 2H), 2.66 (dd, J = 7.2, 5.6 Hz, 2H), 2.16 (s, 3H), 1.99 (q, J = 6.4 Hz, 2H).

[0177] Step 8: Preparation of N-(3-fluoro-4-hydroxy-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-89) Compound N-(3-fluoro-4-methoxy-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-88) (1.3 g) was dissolved in DCE (20 ml), AlCl3 (5 eq) was added, and the mixture was stirred at 60°C for 5 hours. The mixture was diluted with water (100 ml), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the yellow solid compound PY-89 (910 mg). LCMS (ESI): m / z, 238.0 [M+1] + .

[0178] Procedure 9: Preparation of 4-acetamido-2-fluoro-5-oxy-5,6,7,8-tetrahydronaphthyl-1-yl-trifluoromethanesulfonate (PY-810) Compound N-(3-fluoro-4-hydroxy-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-89) (0.9 g) was dissolved in DCM (20 mL), and triethylamine and trifluoromethanesulfonic anhydride (3 eq) were added, respectively. The mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / n-hexane 1:5) to obtain the yellow solid compound PY-810 (0.9 g). LCMS(ESI):m / z,370.1 [M+1] + .

[0179] Procedure 10: Preparation of N-(4-(3-(benzyloxy)propane-1-in-1-yl)-3-fluoro-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-811) Compound 4-acetamido-2-fluoro-5-oxy-5,6,7,8-tetrahydronaphthyl-1-yl-trifluoromethanesulfonate (PY-810) (420 mg) was dissolved in DMF (10 mL), and triethylamine (2 eq), propynyl benzyl ether (3 eq), Pd(PPh3)2Cl2 (0.2 eq), and CuI (0.1 eq) were added. The mixture was stirred under a nitrogen atmosphere at 80°C for 12 hours. The solution was diluted with 100 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 45% to 85%) to obtain the yellow solid compound PY-811 (250 mg). LCMS (ESI): m / z, 366.1 [M+1] + .

[0180] Procedure 11: Preparation of N-(3-fluoro-4-(3-hydroxypropyl)-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-812) Compound N-(4-(3-(benzyloxy)propa-1-in-1-yl)-3-fluoro-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-811) (250 mg) was dissolved in MeOH (10 mL), palladium-carbon (0.1 eq) was added, and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the yellow solid compound PY-812 (150 mg). LCMS (ESI): m / z, 280.2 [M+1] + .

[0181] Procedure 12: Preparation of 8-amino-6-fluoro-5-(3-hydroxypropyl)-3,4-dihydronaphthalene-1(2H)-one (PY-813) Compound N-(3-fluoro-4-(3-hydroxypropyl)-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-812) (150 mg) was dissolved in 6N HCl (2 mL) and EtOH (2 mL), stirred at 60°C for 3 hours, filtered, and concentrated under reduced pressure to obtain the yellow solid compound PY-813 (125 mg). LCMS (ESI): m / z, 238.1 [M+1] + .

[0182] Procedure 13: Preparation of (S)-9-ethyl-5-fluoro-9-hydroxy-4-(3-hydroxypropyl)-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-8) Compounds 8-amino-6-fluoro-5-(3-hydroxypropyl)-3,4-dihydronaphthalene-1(2H)-one (PY-813) (125 mg, 0.53 mmol) and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione (Haoyuan Pharmaceutical, 152 mg, 0.58 mmol, 1.1 eq) were dissolved in xylene (10 mL), and PPTS (pyridine p-toluenesulfonate) (40 mg, 0.16 mmol, 0.3 eq) was added. The mixture was stirred under a nitrogen atmosphere at 120°C for 12 hours. The solution was concentrated under reduced pressure, and the residue was separated and purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 45% to 85%), then freeze-dried to obtain the yellow solid compound PY-8 (42 mg, yield 17%). LCMS (ESI): m / z, 456.2 [M+1] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.72 (d, J = 11.2 Hz, 1H), 7.30 (s, 1H), 6.51 (s, 1H), 5.43 (s, 2H), 5.24 (s, 2H), 4.60 (t, J = 5.2 Hz, 1H), 3.49 (q, J = 6.0 Hz, 2H), 3.16 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 8.0 Hz, 2H), 2.08 (t, J = 6.0 Hz, 2H), 1.88-1.87 (m, 2H), 1.69 (p, J = 6.4 Hz, 2H), 0.88 (t, J = 7.2 Hz, 3H).

[0183] Preparation Example 13: Preparation of (S)-9-ethyl-5-fluoro-9-hydroxy-4-propyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-8B) TIFF2026510566000150.tif130139

[0184] Step 1: Preparation of N-(3-bromo-5-fluorophenyl)acetamide (PY-8a) 3-Bromo-5-fluoroaniline (50 g, 0.263 mol) was dissolved in dichloromethane (700 mL), triethylamine (53.2 g, 0.526 mol) was added at room temperature, and acetic anhydride (40.3 g, 0.395 mol) was slowly added dropwise under an ice bath. The mixture was allowed to react at room temperature for 2 hours. Water (400 mL) was added, the aqueous phase was extracted with dichloromethane (200 mL), the organic phase was combined, and the mixture was sequentially washed with saturated sodium chloride solution (300 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurryed with n-heptane and filtered to obtain N-(3-bromo-5-fluorophenyl)acetamide (54 g, yield: 88.4%).

[0185] Step 2: Preparation of (E)-4-(3-acetamido-5-fluorophenyl)butane-3-enoic acid tert-butyl ester (PY-8b) N-(3-bromo-5-fluorophenyl)acetamide (PY-8a) (54 g, 0.2327 mol) was dissolved in N,N-dimethylformamide (700 mL), and bis(tri-tert-butylphosphine)palladium (5.97 g, 11.64 mmol), tris(o-methylphenyl)phosphine (7.07 g, 23.27 mmol), N-methyldicyclohexylamine (100 g, 0.5119 mol), and 1-buten-4-ate tert-butyl ester (66.1 g, 0.4654 mol) were added sequentially. After submerging the mixture three times with nitrogen gas, the mixture was reacted at 100°C for 16 hours. Extraction was performed by adding ethyl acetate (600 mL) and water (1 L), the aqueous phase was further extracted with ethyl acetate (300 mL), the organic phase was combined, and the mixture was sequentially washed with saturated sodium chloride solution (500 mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-heptane (0-30%)) to obtain (E)-4-(3-acetamido-5-fluorophenyl)butane-3-enoic acid tert-butyl ester (65 g, yield: 95.3%).

[0186] Step 3: Preparation of 4-(3-acetamido-5-fluorophenyl)butanoate (PY-8c) (E)-4-(3-acetamido-5-fluorophenyl)butane-3-enoate tert-butyl ester (PY-8b) (65 g, 0.2218 mol) was dissolved in methanol (1.3 L), purged once with nitrogen gas, then Pd / C (33 g, 0.3101 mol) was added, purged once more with nitrogen gas, then purged twice with hydrogen gas, and the mixture was reacted at room temperature for 16 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography (eluent: acetonitrile / purified water (0-90%)) to obtain 4-(3-acetamido-5-fluorophenyl)butanoate (PY-8c) (55 g, yield: 84%).

[0187] Step 4: Preparation of 4-(5-acetamido-2-bromo-3-fluorophenyl)butanoate (PY-8d) 4-(3-acetamido-5-fluorophenyl)butanoate (PY-8c) (55 g, 0.1864 mol) was dissolved in N,N-dimethylformamide (600 mL), and after dividing the solution and adding NBS (36.5 g, 0.2051 mol) under an ice bath, the mixture was stirred at room temperature for 1 hour, then ethyl acetate (300 mL) and water (400 mL) were added for extraction. The aqueous phase was further extracted once with ethyl acetate (100 mL), the organic phases were combined, and the mixture was sequentially washed with saturated sodium chloride solution (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-heptane (0-30%)) to obtain 4-(5-acetamido-2-bromo-3-fluorophenyl)butanoate (59 g, yield: 84.6%).

[0188] Procedure 5: Preparation of 4-(5-acetamido-2-bromo-3-fluorophenyl)butanoic acid (PY-8e) 4-(5-acetamido-2-bromo-3-fluorophenyl)butanoate (PY-8d) (59 g, 0.1577 mol) was dissolved in dichloromethane (300 mL), and HCl / dioxane (400 mL, 1.6 mol) was added dropwise under an ice bath. The mixture was reacted at room temperature for 16 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain 4-(5-acetamido-2-bromo-3-fluorophenyl)butanoic acid (42 g, yield: 83.7%).

[0189] Step 6: Preparation of N-(4-bromo-3-fluoro-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-8g) 4-(5-acetamido-2-bromo-3-fluorophenyl)butanoic acid (PY-8e) (42 g, 0.1321 mol) and Eaton's reagent (210 g) were added to a 1 L three-necked flask, and after submerging three times with nitrogen gas, the mixture was reacted at 85°C for 1 hour. The reaction mixture was slowly added dropwise to water (2 L) under an ice bath, filtered, the filter cake was thoroughly rinsed with water, and the filtrate was concentrated under reduced pressure until dry. The filtrate was then purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane (0-30%)) to obtain the crude product (30 g). The crude product was further slurryed in an ethyl acetate (10 mL) / petroleum ether (100 mL) system, filtered, and N-(4-bromo-3-fluoro-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (20 g, yield 50.4%). LCMS (ESI): m / z, 300.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 12.35 (s, 1H), 8.61 (d, J = 11.6 Hz, 1H), 3.07 (t, J = 6.0 Hz, 2H), 2.69 (dd, J = 7.2 Hz, 2H), 2.24 (s, 3H), 2.11 (p, J = 6.4 Hz, 2H).

[0190] Step 7: Preparation of N-(4-(3-(benzyloxy)propane-1-in-1-yl)-3-fluoro-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-8h) Under a nitrogen atmosphere, N-(4-bromo-3-fluoro-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-8g) (1.8g, 6.0 mmol) was dissolved in anhydrous DMF (50 mL), and (propa-2-ene-1-oxy)methyl)benzene (4.34 mL, 29.99 mmol), cuprous iodide (228.4 mg, 1.2 mmol), bis(triphenylphosphine)palladium(II) dichloride (841.9 mg, 1.2 mmol), and triethylamine (3.33 mL, 23.99 mmol) were sequentially added. The resulting mixture was purged three times with nitrogen gas, then heated to 100°C and reacted with stirring for 16 hours. The reaction mixture was concentrated until dry, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane 1:20 to 1:5) to obtain compound PY-8h (1.0 g, yield 45.6%), a yellow solid. LCMS: m / z = 366.1 [M+1] + Rt = 1.108.

[0191] Step 8: Preparation of N-(3-fluoro-8-oxo-4-propyl-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-8i) Compound PY-8h (2.5 g, 6.84 mmol) was dissolved in methanol (20 mL) and tetrahydrofuran (20 mL), palladium-carbon (4.0 g) was added, and the mixture was purged three times with hydrogen gas. The mixture was then heated to 45°C and stirred for 4 hours. After filtering the reaction mixture, it was directly concentrated, and the crude product was used directly in the next step. LCMS: m / z = 264.1 [M+1]+; Rt = 1.056.

[0192] Procedure 9: Preparation of 8-amino-6-fluoro-5-propyl-3,4-dihydronaphthalene-1(2H)-one (PY-8j) Compound PY-8i (1.91 g, 6.84 mmol) was dissolved in 6 M hydrochloric acid (20 mL) and ethanol (20 mL), and the mixture was heated to 60°C and reacted with stirring for 1 hour. The reaction mixture was concentrated until dry, and the crude product was used directly in the next step.

[0193] Procedure 10: Preparation of (S)-9-ethyl-5-fluoro-9-hydroxy-4-propyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-8B) Under a nitrogen atmosphere, compound PY-8j (960 mg, 1.0 eq) and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione (PY-8f) (Haoyuan Pharmaceutical) (1.17 g, 1.1 eq) were dispersed in toluene (25 mL), pyridinium p-toluenesulfonate (508 mg, 0.5 eq) were added, and the mixture was heated to 120 °C and reacted with stirring for 16 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10:1) to obtain compound PY-8B (340 mg, yield 18%), a brown solid. LCMS: m / z = 449.2 [M+H] + Rt = 3.313 min. 1 1H NMR (400 MHz, DMSO-d 6) δ 7.72 (d, J = 11.4 Hz, 1H), 7.30 (s, 1H), 6.52 (s, 1H), 5.43 (s, 2H), 5.23 (s, 2H), 3.15 (q, J = 5.6 Hz, 4H), 2.81 (t, J = 7.7 Hz, 2H), 2.08 (t, J = 5.9 Hz, 2H), 1.94-1.78 (m, J = 7.1 Hz, 2H), 1.58 (h, J = 7.4 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[0194] Preparation Example 14: Preparation of (S)-9-ethyl-5-fluoro-9-hydroxy-4-(2-hydroxyethoxy)-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-9) TIFF2026510566000151.tif51120 To 2 ml aqueous solutions of compound PY-13 (20 mg), tetrabutylammonium bromide (TBAB) (15.3 mg, 1 eq), palladium chloride catalyst (1.7 mg, 0.2 eq), 250 ml of ethylene oxide, and potassium carbonate (16.4 mg, 2.5 eq) were added, respectively. The reaction was carried out at 25°C for 16 hours, and the reaction solution was purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: SHIMADZU, model number LC-20AP. Column: Welch Xtimate C18 250×30mm×10μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: elution from 12% to 42%), lyophilized, and obtained the crude product, a white solid compound PY-9. This white solid compound was further separated and purified by thin-layer chromatography to obtain compound PY-9 (3.03 mg). LCMS (ESI): m / z, 467.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 12.5 Hz, 1H), 7.29 (s, 1H), 6.51 (s, 1H), 5.43 (s, 2H), 5.25 (s, 2H), 4.93 (t, J = 5.4 Hz, 1H), 4.14 (t, J = 4.9 Hz, 2H), 3.73 (q, J = 5.1 Hz, 2H), 3.16 (dt, J = 11.1, 6.1 Hz, 4H), 2.02 (dt, J = 12.6, 6.6 Hz, 2H), 1.86 (h, J = 7.0 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H); 19 F NMR (377 MHz, DMSO-d6) δ -123.40.

[0195] Preparation Example 15: Preparation of (S)-9-ethyl-5-fluoro-9-hydroxy-4-(hydroxymethyl)-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-10) TIFF2026510566000152.tif84150

[0196] Procedure 1: Preparation of 8-amino-5-bromo-6-fluoro-3,4-dihydronaphthalene-1(2H)-one (PY-10b) To a solution of compound PY-8g (2g, 6.66 mmol, 1eq) in ethanol (6mL), 6N HCl (6mL) was added and the mixture was reacted at 80°C with stirring for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, diluted with 20mL of water, the pH was neutralized with sodium bicarbonate solution, extracted with dichloromethane (30mL x 3), the organic phases were combined, washed with saturated brine (30mL), dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the yellow solid crude product compound 8-amino-5-bromo-6-fluoro-3,4-dihydronaphthalene-1(2H)-one (PY-10b) (1.52g, yield: 88%; purity: 91%). LCMS (ESI): m / z, 258 [M+1] + , 260 [M+1] + .

[0197] Procedure 2: Preparation of (S)-4-bromo-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-10d) Compound PY-8f (1.55 g, 5.89 mmol, 1 eq) and PPTS (1.48 g, 5.89 mmol, 1 eq) were added to a toluene (20 mL) solution of compound PY-10b (1.52 g, 5.89 mmol, 1 eq) and reacted under a nitrogen atmosphere at 120°C with stirring. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the yellow solid compound PY-10d (1.3 g, yield: 45%; purity: 88%). LCMS (ESI): m / z, 485 [M+H] + , 487 [M+H] + .

[0198] Step 3: Preparation of (S)-9-ethyl-5-fluoro-9-hydroxy-4-(hydroxymethyl)-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-10) To a solution of compound PY-10d (1.30 g, 2.68 mmol, 1 eq) in dioxane (5 mL), (tributyltin)methanol (2.84 g, 8.84 mmol, 3.3 eq) and Xphos Pd G2 (210.77 mg, 267.87 μmol, 0.1 eq) were added, respectively. The mixture was reacted under a nitrogen atmosphere at 90°C with stirring, concentrated under reduced pressure, diluted with water and dichloromethane (50 mL / 50 mL), and a solid precipitated. The mixture was filtered, the filter cake was collected separately, the filtrate was extracted with dichloromethane (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue and filter cake were purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the yellow solid compound PY-10 (649 mg, yield: 55.5%, purity: 100%). LCMS (ESI): m / z, 437 [M+H] + .

[0199] Preparation Example 16: Preparation of (S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-carboxylic acid (PY-10A) and (S)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-10B) TIFF2026510566000153.tif26106 TIFF2026510566000154.tif53144

[0200] Procedure 1: Preparation of N-(3-fluoro-4-formyl-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-10-1) At 0°C, H2SO4 (4.34g, 44.21mmol, 5.2eq) was added to a chloroform (100mL) solution of N-(3-fluoro-4-methyl-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (2g, 8.5 mmol, 1.0eq) and MnO2 (11.09g, 127.52 mmol, 15eq) and slowly cooled to room temperature, allowing the reaction to proceed for 16 hours. After filtration, the pH was neutralized with sodium bicarbonate solution, and the mixture was extracted with dichloromethane (30mL x 3). The mixture was concentrated to obtain a brown solid crude product (2.1g), which was used directly in the next step without purification. LCMS (ESI): m / z, 250.1 [M+1] + .

[0201] Procedure 2: Preparation of 4-acetamido-2-fluoro-5-oxo-5,6,7,8-tetrahydronaphthyl-1-carboxylic acid (PY-10-2) At 25°C, dimethyl dibutylene (1.55g, 22.07 mmol, 10eq) was added to a methanol / water = 1 / 1 (30ml) solution of compound N-(3-fluoro-4-formyl-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (1.1g, 2.21 mmol, 1eq), sodium chlorite (1.20g, 13.24 mmol, 6eq), and sodium dihydrogen phosphate (534mg, 4.41 mmol, 2eq). The mixture was then reacted at 50°C for 2 hours with stirring. The pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (30 mL x 3), and the raw material was recovered. The aqueous phase was adjusted to 2 with 2N HCl, extracted with ethyl acetate (30 mL x 3), and concentrated to obtain compound PY-10-2 (324 mg, yield: 55.36%). LCMS (ESI): m / z, 266.0[M+1] + .

[0202] Step 3: Preparation of 4-amino-2-fluoro-5-oxo-5,6,7,8-tetrahydronaphthyl-1-carboxylic acid (PY-10-3) Compound 4-acetamido-2-fluoro-5-oxo-5,6,7,8-tetrahydronaphthyl-1-carboxylic acid (415 mg, 1.67 mmol, 1 eq) was added to a solution of NaOH (5 M, 15 mL) and reacted with stirring at 80°C for 2 hours. The pH was adjusted to 2 with 2N dilute hydrochloric acid, and the organic phase was extracted with ethyl acetate (30 mL x 3) to obtain compound PY-10-3 (320 mg, yield: 85.6%). LCMS (ESI): m / z: 224.0[M+1] + .

[0203] Procedure 4: Preparation of (S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-carboxylic acid (PY-10A) and (S)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-10B) Compound 4-amino-2-fluoro-5-oxo-5,6,7,8-tetrahydronaphthyl-1-carboxylic acid (364.64 mg, 1.43 mmol, 1 eq) and Compound (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione (377.42 mg, 1.43 mmol, 1 eq) and PPTS (360.29 mg, 1.43 mmol, 1 eq) The compound PY-10A was dissolved in toluene (15 mL) solution, stirred at 120°C for 16 hours, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 10:1 to 5:1) to obtain a crude product, a brownish oily compound. This was separated by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Oriendo, model number Lab311-DJ-R2. Column: YMC-Triart Prep C18 250×30 mm×10 μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: elution from 30% to 60%), lyophilized, and compound PY-10A (18.19 g, yield: 2.82%), LCMS (ESI): m / z: 451.1 [M+1]. + , and compound PY-10B (46 mg, yield: 7.9%), LCMS (ESI): m / z: 407.1 [M+1] + I obtained it.

[0204] Preparation Example 17: Preparation of (S)-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[d]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)methyl(2-hydroxyethyl)carbamate (PY-10Car) TIFF2026510566000155.tif51157

[0205] Procedure 1: Preparation of (S)-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)methyl(4-nitrophenyl)carbonate (PY-10 Cara) At room temperature, compound PY-10 (8.0 mg, 0.018 mmol, 1.0 eq), bis(4-nitrophenyl) carbonate (44.6 mg, 0.147 mmol, 8.0 eq), and N,N-diisopropylethylamine (28.4 mg, 0.220 mmol, 12.0 eq) were added to a solution of N,N-dimethylformamide (2 mL) and stirred at 50°C for 16 hours. Complete reaction was confirmed by LC-MS. The reaction mixture was concentrated under reduced pressure and purified by thin-layer chromatography (eluent: dichloromethane / methanol (15 / 1)) to obtain the yellow oily compound PY-10 Car-a (18 mg, excess weight, yield not calculated). LCMS (ESI): m / z, 602.3 [M+H] + .

[0206] Procedure 2: Preparation of (S)-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[d]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)methyl(2-hydroxyethyl)carbamate (PY-10Car) At room temperature, compound PY-10 Car-a (18.0 mg, impurity), aminoethanol (1.83 mg, 0.030 mmol), and N,N-diisopropylethylamine (11.6 mg, 0.090 mmol) were added to a solution of N,N-dimethylformamide (1 mL) and stirred at 25°C for 0.5 hours. Complete reaction was confirmed by LC-MS. The reaction mixture was prepared by preparative high-performance liquid chromatography (preparative chromatography manufacturer: Luna, model number Lab311-ISCO-R4. Column: Phenomenex Luna C18 250 × 50 mm × 10 μm. Mobile phase: water (0.225% formic acid)-acetonitrile, water elution ratio: elution from 12% to 42%), and the eluate was lyophilized to obtain a white solid product PY-10 Car (4.14 mg, 7.56 μmol, 2-step yield: 42%). LCMS (ESI): m / z, 524.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.79 (d, J = 11.2 Hz, 1H), 7.32 (s, 1H), 7.19 (t, J = 5.6 Hz, 1H), 6.54 (s, 1H), 5.44 (s, 2H), 5.27 (d, J = 4.4 Hz, 3H), 4.63 (t, J = 5.6 Hz, 1H), 3.30 - 3.23 (m, 5H), 3.18 (s, 2H), 3.04 (q, J = 6.0 Hz, 2H), 2.08 (s, 2H), 1.86 (dt, J = 15.2, 7.2 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H).

[0207] Preparation Example 18: Preparation of (S)-9-ethyl-5-fluoro-9-hydroxy-4-methoxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-11) TIFF2026510566000156.tif56143

[0208] Procedure 1: Preparation of 8-amino-6-fluoro-5-methoxy-3,4-dihydronaphthalene-1(2H)-one (PY-111) At 100°C, compound N-(3-fluoro-4-methoxy-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-88) (100 mg) was stirred with HCl (7N, 10 ml) for 2 hours. The reaction was quenched by slowly adding saturated NaHCO3 solution (10 mL), the pH was adjusted to neutral (pH 7), and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the yellow solid compound PY-111 (66 mg, 79%). LCMS (ESI): m / z, 210.1 [M+H] + .

[0209] Procedure 2: Preparation of (S)-9-ethyl-5-fluoro-9-hydroxy-4-methoxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-11) Compound 8-amino-6-fluoro-5-methoxy-3,4-dihydronaphthalene-1(2H)-one (PY-111) (20 mg) was added to toluene (10 mL) solvent with PPTS (0.67 eq, 16 mg) and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione (1 eq, 25 mg), and the mixture was reacted at 140°C for 16 hours. The solution was concentrated under reduced pressure, toluene was removed, 5 ml of DMF was added, and the solution was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 45% to 85%) to obtain the white solid compound PY-11 (8.4 mg, yield 20%). LCMS (ESI): m / z, 437.2 [M+H] + . 11H NMR (400 MHz, DMSO-d 6 ) δ 7.85 (d, J = 12.5 Hz, 1H), 7.30 (s, 1H), 6.52 (s, 1H), 5.43 (s, 2H), 5.25 (s, 2H), 3.94 (s, 3H), 3.14 (dt, J = 11.2, 6.0 Hz, 4H), 2.05 (q, J = 6.4, 5.8 Hz, 2H), 1.88 (dq, J = 14.4, 7.2 Hz, 2H), 0.88 (t, J = 7.2 Hz, 3H).

[0210] Preparation Example 19: Preparation of (1S,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methoxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-10,13-dione and (1R,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methoxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-12A and PY-12B) TIFF2026510566000157.tif80139

[0211] Procedure 1: Preparation of (E)-N-(3-fluoro-7-(hydroxyimino)-4-methoxy-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-121) At 0°C, 10 mL of a tetrahydrofuran solution of compound N-(3-fluoro-4-methoxy-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-88) (200 mg) was mixed with potassium tert-butoxide tetrahydrofuran (3 eq) solution and tert-butyl nitrite, respectively. The mixture was stirred at 0°C for 1 hour, diluted with 30 mL of water, and extracted three times with ethyl acetate at 10 mL intervals. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 45% to 85%) to obtain the yellow solid compound PY-121 (180 mg). LCMS (ESI): m / z, 281.1 [M+1] + .

[0212] Step 2: Preparation of N,N'-(3-fluoro-4-methoxy-8-oxy-5,6,7,8-tetrahydronaphthyl-1,7-diacyl)diethylamide (PY-122) At room temperature, 180 mg of compound (E)-N-(3-fluoro-7-(hydroxyimino)-4-methoxy-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-121) was added to 1 mL of acetic anhydride and 2 mL of acetic acid, and zinc powder (35 mg) was added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with 100 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 45% to 85%) to obtain the white solid compound PY-122 (150 mg). LCMS (ESI): m / z, 309.1 [M+1] + .

[0213] Step 3: Preparation of N-(8-amino-6-fluoro-5-methoxy-1-oxy-1,2,3,4-tetrahydronaphthyl-2-yl)acetamide (PY-123) Compound N,N'-(3-fluoro-4-methoxy-8-oxy-5,6,7,8-tetrahydronaphthyl-1,7-diacyl)diethylamide (PY-122) (150 mg) 6N was dissolved in HCl (2 mL) and EtOH (2 mL) and stirred at 60°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain 115 mg of crude product, which was used directly in the following procedure. LCMS (ESI): m / z, 267.1 [M+1] + .

[0214] Step 4: Preparation of N-(9S)-9-ethyl-5-fluoro-9-hydroxy-4-methoxy-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-1-yl)acetamide (PY-124) To a toluene solution of N-(8-amino-6-fluoro-5-methoxy-1-oxy-1,2,3,4-tetrahydronaphthyl-2-yl)acetamide (PY-123) (80 mg), (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione (Kogen Pharmaceutical) (92 mg, 1 eq) and PPTS (24 mg, 0.5 eq) were added and the mixture was stirred at 120°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 45% to 85%) to obtain a yellow solid mixture PY-124 (55 mg). LCMS (ESI): m / z, 494.2 [M+1] + .

[0215] Procedure 5: Preparation of (1S,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methoxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-10,13-dione and (1R,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methoxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-12A and PY-12B) N-(9S)-9-ethyl-5-fluoro-9-hydroxy-4-methoxy-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4:6,7]indolidine[1,2-b]quinoline-1-yl)acetamide (PY-124) (55 mg) was dissolved in 3 ml of 6N hydrochloric acid and stirred at 85°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% HCOOH)-acetonitrile, eluting from 45% to 85%). The mixture was then freeze-dried to obtain compound PY-12A (4.55 mg) and compound PY-12B (6.24 mg), respectively. PY-12A (LCMS retention time 0.651min): LCMS (ESI): m / z, 452.2 [M+1] + Rt = 0.651. 1 1H NMR (400 MHz, DMSO-d 6) δ 7.87 (d, J = 12.4 Hz, 1H), 7.30 (s, 1H), 6.53 (s, 1H), 5.62 (d, J = 19.2 Hz, 1H), 5.46 - 5.29 (m, 3H), 4.38 (s, 1H), 3.95 (s, 3H), 3.28 - 3.03 (m, 4H), 2.08 (s, 2H), 1.87 (dd, J = 9.2, 7.2 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H). PY-12B (LCMS retention time 0.677min): LCMS (ESI): m / z, 452.2 [M+1] + Rt = 0.677. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.66 (s, 2H), 8.01 (d, J = 12.4 Hz, 1H), 7.34 (s, 1H), 6.57 (s, 1H), 5.90 (d, J = 19.2 Hz, 1H), 5.60-5.30 (m, 3H), 5.08 (s, 1H), 4.00 (d, J = 1.2 Hz, 3H), 3.15 (t, J = 12.8 Hz, 3H), 2.12 (t, J = 13.6 Hz, 1H), 1.97-1.76 (m, J = 7.2 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H).

[0216] Preparation Example 20: Preparation of (S)-9-ethyl-5-fluoro-4,9-dihydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-13) TIFF2026510566000158.tif59150

[0217] Procedure 1: Preparation of N-(3-fluoro-4-hydroxy-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-131) To a DCM solution of compound N-(3-fluoro-4-methoxy-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-88) (200 mg), AlCl3 (3 eq) was added and the mixture was reacted at 60°C for 2 hours. The reaction was quenched by slowly adding saturated NaHCO3 solution (10 mL) to adjust the pH to 3-4, extracted with ethyl acetate (3 × 30 mL), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the yellow solid compound PY-131 (130 mg, 68%). LCMS (ESI): m / z, 238.0 [M+H] + , 260.1 [M+Na].

[0218] Step 2: Preparation of 8-amino-6-fluoro-5-hydroxy-3,4-dihydronaphthalene-1(2H)-one (PY-132) At 100°C, a solution of compound N-(3-fluoro-4-hydroxy-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-131) (70 mg) in HCl (12N, 3.5 mL) was stirred for 16 hours. The reaction was quenched by slowly adding saturated NaHCO3 solution (10 mL) to adjust the pH to 3-4, extracted with ethyl acetate (30 × 3 mL), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. MeCN (5 mL) was added, and the mixture was separated by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 45% to 85%) to obtain the yellow solid compound PY-132 (12 mg, 20%). LCMS (ESI): m / z, 196.1 [M+H] + .

[0219] Step 3: Preparation of (S)-9-ethyl-5-fluoro-4,9-dihydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-13) To a solution of 8-amino-6-fluoro-5-hydroxy-3,4-dihydronaphthalene-1(2H)-one (PY-132) (15 mg) in toluene (10 mL), PPTS (0.67 eq, 12.9 mg) and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione (1 eq, 20.2 mg) were added, and the mixture was reacted at 140 °C for 16 hours. Toluene was removed under reduced pressure, 5 mL of DMF was added, and the mixture was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase: water (0.225% HCOOH)-acetonitrile, eluting from 45% to 85%) to obtain the white solid compound PY-13 (3.2 mg). LCMS (ESI): m / z, 423.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.77 (d, J = 11.9 Hz, 1H), 7.26 (s, 1H), 6.50 (s, 1H), 5.42 (s, 2H), 5.22 (s, 2H), 3.11 (t, J = 6.1 Hz, 2H), 3.03 (t, J = 6.2 Hz, 2H), 2.01 (q, J = 6.2 Hz, 2H), 1.87 (dq, J = 14.5, 7.1 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0220] Preparation Example 21: Preparation of (S)-4,11-diethyl-8,10-difluoro-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H)-dione (PY-14) TIFF2026510566000159.tif81157

[0221] Procedure 1: Preparation of 1-(2,4-difluoro-3-methoxyphenyl)propa-1-one (PY-14-c) At -70°C, n-BuLi (1.07g, 10.41mL, 16.65 mmol, 1.2eq, 1.60M) was slowly added dropwise to 20mL of anhydrous THF solvent containing compound 1,3-difluoro-2-methoxybenzene (PY-14-a) (2g, 13.88 mmol, 1eq), and the mixture was stirred for 0.5 hours under the same temperature conditions. Compound N-methoxy-N-methylpropionamide (PY-14-b) (4.55g, 34.69 mmol, 2.5eq) was added, and the mixture was stirred at -70°C for 0.5 hours. The low-temperature bath was removed, the mixture was heated to 25°C, and stirred for 16 hours. Product formation was confirmed by LC-MS, the reaction was quenched with 5 mL of saturated ammonium chloride solution at room temperature, the organic phase was extracted with 3 × 10 mL of ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to obtain a pale yellow oily title compound (1.6 g, yield: 54%). LCMS (ESI): m / z, 214.9 [M+H] + .

[0222] Procedure 2: Preparation of 1-(2,4-difluoro-3-methoxy-6-nitrophenyl)propa-1-one (PY-14-d) At -40°C, 1-(2,4-difluoro-3-methoxyphenyl)propa-1-one (2.20 g, 10.99 mmol, 1 eq) was added to 22 mL of H2SO4 solvent, to which fuming nitric acid (699.74 mg, 95%, 474.82 μL, 10.55 mmol, 0.96 eq) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into ice water, the reaction plasma was washed with 10 mL of anhydrous ethanol, and the organic phase was extracted by adding DCM (100 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1), dried, and a pale yellow oily compound, 1-(2,4-difluoro-3-methoxy-6-nitrophenyl)propa-1-one (1.2 g, yield: 34%), was obtained. LCMS (ESI): m / z, 246.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.24 - 8.13 (m, 1H), 4.16 (t, J = 2.1 Hz, 3H), 2.89 - 2.81 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H).

[0223] Step 3: Preparation of 1-(6-amino-2,4-difluoro-3-methoxyphenyl)propa-1-one (PY-14-e) To 10 mL of anhydrous ethanol solvent containing 1-(2,4-difluoro-3-methoxy-6-nitrophenyl)propa-1-one (PY-14-d) (200 mg, 815.73 μmol, 1 eq), iron powder (250.57 mg, 31.88 μL, 4.49 mmol, 5.5 eq), water (339.85 mg, 339.85 μL, 18.86 mmol, 23.12 eq), and concentrated hydrochloric acid (16.36 mg, 37.39 μL, 448.65 μmol, 0.55 eq, 12 M) were added, and the mixture was reacted under a nitrogen atmosphere at 80°C with stirring for 16 hours. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain the white solid compound 1-(6-amino-2,4-difluoro-3-methoxyphenyl)propa-1-one (141 mg, yield: 80%). LCMS (ESI): m / z, 216.1 [M+H] + .

[0224] Step 4: Preparation of 1-(6-amino-2,4-difluoro-3-hydroxyphenyl)propa-1-one (PY-14-f) 1-(6-amino-2,4-difluoro-3-methoxyphenyl)propa-1-one (PY-14-e) (300 mg, 1.39 mmol, 1 eq) was added to 10 mL of DCM solvent with AlCl3 (557.61 mg, 4.18 mmol, 3 eq), and the mixture was reacted under a nitrogen atmosphere at 70°C with stirring for 4 hours. The reaction was quenched with 100 mL of saturated ammonium chloride solution, the organic phase was extracted with 2 × 100 mL of DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the yellow solid crude product, compound 1-(6-amino-2,4-difluoro-3-hydroxyphenyl)propa-1-one (165 mg; yield of crude product is not calculated). LCMS (ESI): m / z, 202.0 [M+H] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.06 (s, 1H), 6.42 (dd, J = 13.0, 2.1 Hz, 1H), 3.45 (s, 2H), 2.87-2.82 (m, 2H), 1.05 (t, J = 7.2 Hz, 3H).

[0225] Step 5: Preparation of (S)-4,11-diethyl-8,10-difluoro-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H)-dione (PY-14) To 10 mL of toluene solvent containing 1-(6-amino-2,4-difluoro-3-hydroxyphenyl)propa-1-one (PY-14-f) (30 mg, 149.13 μmol, 1 eq), PPTS (25.11 mg, 99.92 μmol, 0.67 eq) and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione (Kogen Pharmaceutical) (30 mg, 149.13 μmol, 1 eq) were added, respectively, and the mixture was reacted under a nitrogen atmosphere at 130°C with stirring for 16 hours. The reaction product was purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: SHIMADZU, model number LC-20AP. Column: YMC-Triart Prep C18 250×30mm×10μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: eluted from 12% to 42%), lyophilized, and obtained a yellow solid (35.55 mg, 55.65%). LCMS (ESI): m / z, 429.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.84 (d, J = 11.4 Hz, 1H), 7.26 (s, 1H), 6.52 (s, 1H), 5.43 (s, 2H), 5.31 (s, 2H), 3.22 - 3.15 (m, 2H), 1.86 (hept, J = 7.1 Hz, 2H), 1.32 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H).

[0226] Preparation Example 22: Preparation of (S)-4-(aminomethyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-16) TIFF2026510566000160.tif86144

[0227] Procedure 1: Preparation of N-(4-((benzylamino)methyl)-3-fluoro-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-16d) To a solution of compound N-(3-fluoro-4-formyl-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (1.22 g, 8.5 mmol, 1 eq) and benzylamine (642.29 μL) in DCM (110 mL), NaBH(OAc)3 (2.06 g, 9.79 mmol, 2 eq) was added. The mixture was reacted at room temperature with stirring for 12 hours. Water (100 mL) was added to quench the reaction, and the mixture was extracted three times with DCM (50 mL). The organic phases were combined, washed with saturated saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether: 1 / 5-1 / 2) to obtain a brownish oily substance, N-(4-((benzylamino)methyl)-3-fluoro-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-16d) (499.5 mg, yield: 30%). LCMS (ESI): m / z, 341[M+H] + .

[0228] Procedure 2: Preparation of 8-amino-5-((benzylamino)methyl)-6-fluoro-3,4-dihydronaphthalene-1(2H)-one (PY-16e) Compound N-(4-((benzylamino)methyl)-3-fluoro-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (499.5 mg, 1.47 mmol, 1 eq) was mixed with 6N HCl (3 mL) and EtOH (3 mL), and the mixture was reacted at 60°C with stirring for 3 hours. The mixture was then concentrated under reduced pressure to obtain the brownish oily crude product 8-amino-5-((benzylamino)methyl)-6-fluoro-3,4-dihydronaphthalene-1(2H)-one (PY-16e) (517.9 mg). LCMS (ESI): m / z, 341[M+H] + .

[0229] Step 3: Preparation of (S)-4-((benzylamino)methyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-16g) To a toluene (15 mL) solution of compound 8-amino-5-((benzylamino)methyl)-6-fluoro-3,4-dihydronaphthalene-1(2H)-one (517.9 mg, 1.22 mmol, 1 eq) and compound (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione (Kogen Pharmaceutical) (319.87 mg, 1.22 mmol, 1 eq), PPTS (305.35 mg, 1.22 mmol, 1 eq) was added and the mixture was reacted at 120°C with stirring for 12 hours. Water (100 mL) was added to quench the mixture, and it was extracted three times with DCM (50 mL). The organic phases were combined, washed with saturated saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol: 12 / 1-11 / 1) to obtain a brownish oily substance (S)-4-((benzylamino)methyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-16g) (466mg, yield: 73%). LCMS (ESI): m / z, 526[M+H] + .

[0230] Step 4: Preparation of (S)-4-(aminomethyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-16) Under a hydrogen gas atmosphere, the compound (S)-4-((benzylamino)methyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (218 mg, 414.78 μmol, 1 eq) was dissolved in MeOH (10 mL) and Pd / C (100 mg, 939.67 μmol, 2.27 eq) and Pd(OH)2(100 (mg, 712.1 μmol, 1.72 eq) was added, and the mixture was reacted at room temperature with stirring for 5 hours. After filtering out palladium carbon through diatomaceous earth, the mixture was concentrated to obtain the brown solid product (S)-4-(aminomethyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-16) (296.6 mg, yield: 82%). LCMS (ESI): m / z, 436[M+H] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.27 (s, 1H), 7.75 (d, J = 11.2 Hz, 1H), 7.31 (s, 1H), 6.54 (s, 1H), 5.44 (s, 2H), 5.24 (s, 2H), 4.00 (s, 2H), 3.25 (t, J = 5.8 Hz, 2H), 3.16 (t, J = 6.2 Hz, 2H), 2.09 (t, J = 6.2 Hz, 2H), 1.87 (hept, J = 7.0 Hz, 2H), 0.88 (t, J = 7.2 Hz, 3H); 19 F NMR (377 MHz, DMSO-d6) δ-113.60.

[0231] Preparation Example 23: Preparation of 2-hydroxyethyl(S)-((9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)methyl)carbamate (PY-16Car) TIFF2026510566000161.tif2661 TIFF2026510566000162.tif47157

[0232] Procedure 1: Preparation of 2-((tert-tert-butyldimethylsilyl)oxy)ethyl(4-nitrophenyl)carboxylate (PY-16Carb) At 0°C, tert-butyldimethylhydroxyethoxysilane (2.0 g, 11.34 mmol, 1.0 eq) was added to a solution of bis(4-nitrophenyl) carbonate (NPC) (5.18 g, 17.01 mmol, 1.5 eq) and N,N-diisopropylethylamine (DIPEA, 4.40 g, 34.03 mmol, 3.0 eq) in tetrahydrofuran (120 mL), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (0-10%)) to obtain the yellow oily compound PY-16Carb (2.70 g, 7.91 mmol, yield: 70%). 1 H NMR (400 MHz, CHCl3-d) δ 8.28 (d, J = 9.2 Hz, 2H), 7.38 (d, J = 9.2 Hz, 2H), 4.36 (dd, J = 5.6, 4.1 Hz, 2H), 3.91 (dd, J = 5.6, 4.1 Hz, 2H), 0.91 (s, 9H), 0.10 (s, 6H).

[0233] Procedure 2: Preparation of 2-((tert-tert-butyldimethylsilyl)oxy)ethyl(S)-((9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)methyl)carbamate (PY-16Carc) At room temperature, compound 2-((tert-tert-butyldimethylsilyl)oxy)ethyl(4-nitrophenyl)carboxylate (35.75 mg, 0.105 mmol, 1.2 eq), compound (S)-4-(aminomethyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (38.0 mg, 0.087 mmol, 1.0 eq), and N,N-diisopropylethylamine (33.84 mg, 0.262 mmol, 3.0 eq) were added to a solution of N,N-dimethylformamide (2 mL) and stirred at 25°C for 1 hour. The reaction mixture was used directly in the following procedure. LCMS (ESI): m / z, 638.3 [M+H] + .

[0234] Procedure 3: Preparation of 2-hydroxyethyl(S)-((9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)methyl)carbamate (PY-16Car) MeOH (2 mL) and 4N hydrochloric acid were added to the reaction mixture from the previous step, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: Luna, model number Lab311-ISCO-R4. Column: Phenomenex Luna C18 250 × 50 mm × 10 μm. Mobile phase: water (0.225% formic acid)-acetonitrile, water elution ratio: elution from 12% to 42%), and the eluate was freeze-dried to obtain a white solid product PY-16Car (20.4 mg, 0.039 mmol, 2-step yield: 45%). LCMS (ESI): m / z, 524.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 11.2 Hz, 1H), 7.65 (t, J = 5.6 Hz, 1H), 7.31 (s, 1H), 6.52 (s, 1H), 5.43 (s, 2H), 5.24 (s, 2H), 4.71 (t, J = 5.2 Hz, 1H), 4.43 (d, J = 5.2 Hz, 2H), 3.96 (t, J = 5.2 Hz, 2H), 3.52 (q, J = 5.2 Hz, 2H), 3.24 (t, J = 6.0 Hz, 2H), 3.15 (t, J = 6.4 Hz, 2H), 2.12 - 2.02 (m, 2H), 1.87 (hept, J = 7.2 Hz, 2H), 0.88 (t, J = 7.2 Hz, 3H).

[0235] Preparation Example 24: Preparation of (S)-4-(2-aminoethoxy)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[d]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-17) TIFF2026510566000163.tif50150

[0236] Procedure 1: Preparation of (S)-(2-((9-ethyl-5-fluoro-9-hydroxy-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[d]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)oxy)ethyl)carbamate tert-butyl ester (PY-17-a) To a solution of compound PY-13 (41 mg, 38.63 μmol, 1.0 eq) in DMF solvent, potassium carbonate (10.7 mg, 77.26 μmol, 2.0 eq) was added and the mixture was stirred at 25°C for 0.5 hours. At the same temperature, tert-butyl (2-bromoethyl)carbamate (21.6 mg, 91.6 μmol, 2.5 eq) was added and the mixture was stirred at 25°C for 16 hours. The reaction product was purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: SHIMADZU, model number LC-20AP. Column: YMC-Triart Prep C18 250 × 30 mm × 10 μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: elution from 12% to 42%), lyophilized, and obtained the gray solid compound PY-17-a (5 mg, yield: 23%). LCMS (ESI): m / z, 566.2 [M+H] + .

[0237] Procedure 2: Preparation of (S)-4-(2-aminoethoxy)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[d]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-17) Under ice bath conditions, TFA (0.5 mL) was slowly added dropwise to DCM (5 mL) solvent of compound PY-17-a (7 mg, 12.38 μmol, 1.0 eq). The mixture was then heated naturally to 25°C under the same ice bath conditions and stirred for 16 hours. The reaction product was purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: SHIMADZU, model number LC-20AP. Column: YMC-Triart Prep C18 250 × 30 mm × 10 μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: elution from 12% to 42%), lyophilized, and obtained a white solid compound PY-17 (1.97 mg, yield: 34%). LCMS (ESI): m / z, 466.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.06 (s, 3H), 7.90 (d, J = 12.3 Hz, 1H), 7.30 (s, 1H), 6.52 (s, 1H), 5.44 (s, 2H), 5.27 (s, 2H), 4.27 (t, J = 5.1 Hz, 2H), 3.17 (t, J = 6.1 Hz, 5H), 2.06 (t, J = 6.2 Hz, 2H), 1.87 (p, J = 6.8 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0238] Preparation Example 25: Preparation of (S)-9-ethyl-5-fluoro-9-hydroxy-4-(2-hydroxyethyl)-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-18) TIFF2026510566000164.tif101144

[0239] Procedure 1: Preparation of N-(4-(2-(benzyloxy)ethyl)-3-fluoro-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-18c) Under a nitrogen atmosphere, compound N-(4-bromo-3-fluoro-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (200 mg) was sequentially added to a mixed solvent of toluene (12.5 mL) and water (volume ratio 4:1), with the addition of compound (2-(benzyloxy)ethyl)trifluoroborate potassium (532 mg, 3.3 eq), potassium carbonate (3 eq), palladium acetate (30 mg), and S-Phos ligand (88 mg). The mixture was then mixed with ) and reacted under a nitrogen atmosphere at 100°C with stirring for 16 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane 1:20 to 1:8) to obtain the white solid compound N-(4-(2-(benzyloxy)ethyl)-3-fluoro-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-18c) (140 mg, yield: 59%). LCMS (ESI): m / z, 356 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.29 (d, J = 13.3 Hz, 1H), 5.10 (t, J = 5.3 Hz, 1H), 4.50 (dd, J = 5.4, J = 2.2 Hz, 2H), 3.10 (t, J = 6.2 Hz, 2H), 2.67 (dd, J = 7.3, J =5.8 Hz, 2H), 2.16 (s, 3H), 1.99 (p, J = 6.3 Hz, 2H).

[0240] Step 2: Preparation of N-(3-fluoro-4-(2-hydroxyethyl)-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-18d) Compound N-(4-(2-(benzyloxy)ethyl)-3-fluoro-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (140 mg) was added to methanol (10 mL) solvent with palladium-carbon (0.25 eq) and Pd(OH)2 (0.25 eq) catalysts, respectively, and the reaction was carried out under a hydrogen gas atmosphere at 25°C for 16 hours. After filtering the catalyst from the reaction solution, the mixture was concentrated under reduced pressure and dried to obtain the bluish-white solid crude product, compound N-(3-fluoro-4-(2-hydroxyethyl)-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-18d) (100 mg; yield of crude product was not calculated). LCMS (ESI): m / z, 266 [M+H] + ,288 [M+Na] + .

[0241] Step 3: Preparation of 8-amino-6-fluoro-5-(2-hydroxyethyl)-3,4-dihydronaphthalene-1(2H)-one (PY-18e) 80 mg of compound N-(3-fluoro-4-(2-hydroxyethyl)-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide was added to 4 mL of 6 N HCl and reacted at 40°C for 3 hours. The reaction solution was cooled to room temperature, diluted with water, and the pH was adjusted to 3-5 with 2 N dilute hydrochloric acid. The organic phase was extracted with ethyl acetate, and the organic phase was further washed with saturated brine. Anhydrous sodium sulfate was added and dried, and the mixture was concentrated under reduced pressure to obtain the yellow solid compound 8-amino-6-fluoro-5-(2-hydroxyethyl)-3,4-dihydronaphthalene-1(2H)-one (PY-18e) (30 mg, yield: 37%). LCMS (ESI): m / z, 224 [M+H] + .

[0242] Step 4: Preparation of (S)-9-ethyl-5-fluoro-9-hydroxy-4-(2-hydroxyethyl)-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-18) Under a nitrogen atmosphere, compound 8-amino-6-fluoro-5-(2-hydroxyethyl)-3,4-dihydronaphthalene-1(2H)-one (30 mg) was added to toluene (5 ml) solvent, along with PPTS (0.67 eq, 18.8 mg) and compound (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione (1 eq, 29.4 mg) (Haoyuan Pharmaceutical). The mixture was reacted at 130°C with stirring for 16 hours, followed by preparative high-performance liquid chromatography (Preparative chromatograph manufacturer: SHIMADZU, model number LC-20AP. Column: Synergi Max-RP). The sample was prepared in 280 × 30 mm × 10 μm. Separation was performed using water (0.225% HCOOH)-acetonitrile as the mobile phase (elution ratio of water: elution from 12% to 42%), and the sample was freeze-dried to obtain the yellow solid compound (S)-9-ethyl-5-fluoro-9-hydroxy-4-(2-hydroxyethyl)-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-18) (6.0 mg, yield: 12%). LCMS (ESI): m / z, 451 [M+H] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.71 (dd, J = 11.3, 6.3 Hz, 1H), 7.33 - 7.28 (m, 1H), 6.54 (s, 1H), 5.43 (s, 2H), 5.23 (d, J = 11.2 Hz, 2H), 4.88 (t, J = 5.3 Hz, 1H), 3.61 (d, J = 6.5 Hz, 2H), 3.20 - 3.12 (m, 4H), 3.01 (d, J = 6.6 Hz, 2H), 2.07 (s, 2H), 1.87 (hept, J = 7.0 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -112.5.

[0243] Preparation Example 26: Preparation of (S)-4-(3-aminopropyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-19) TIFF2026510566000165.tif83157

[0244] Procedure 1: (S,E)-(3-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)allyl)carbamate tert-butyl ester (PY-19c) and (S,E)- Preparation of a mixed intermediate of (3-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)propa-1-en-1-yl)carbamate tert-butyl ester (PY-19c') Compound (S)-4-bromo-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (20 mg) was dissolved in toluene (5 mL) and bis(tert-butylphosphine)palladium (0.1 eq, 2.1 mg), tri(o-tolyl)phosphine (0.2 eq, 2.5 mg), DIPEA (6 eq, 41 μL), and compound allylcarbamate tert-butyl ester (2.5 eq, 17.8 mg) were added to it, respectively. The mixture was reacted at 120°C with stirring, and the reaction solution was concentrated. After that, it was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1 to 10:1) under reduced pressure. Concentrated, 10 mg of the compound (S,E)-(3-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)allyl)carbamate tert-butyl ester (PY-19c) and (S,E)-(3-( A mixture of 9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)propa-1-en-1-yl)carbamate tert-butyl ester (PY-19c') was obtained (yield: 43%; purity: 77%).

[0245] Procedure 2: Preparation of (S)-(3-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)propyl)carbamate tert-butyl ester (PY-19d) Mixture (S,E)-(3-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)allyl) tert-butyl ester (PY-19c) and (S,E)-(3-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)propa-1-en-1-yl) tert-butyl ester (PY-19c) To 30 mg of Pd(S)-(3-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)propyl)carbamate tert-butyl ester (PY-19d) (19.6 mg, yield: 65%), the crude product was used directly in the following procedure. LCMS (ESI): m / z, 564.3 [M+1] + .

[0246] Step 3: Preparation of (S)-4-(3-aminopropyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-19) Under ice bath conditions, 16.3 mg of compound (S)-(3-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)propyl)carbamate tert-butyl ester (purity: 82%) was slowly added to 2.4 mL of dichloromethane solvent, and the mixture was heated to 25°C and reacted with stirring for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1 to 8:1) to obtain the crude product. This product was then purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: SHIMADZU, model LC-20AP. Column: Welch Xtimate C18 250×50mm×10μm. Mobile phase: water (0.225% FA)-ACN, water elution ratio: 12% to 42%), lyophilized, and compound (S)-4-(3-aminopropyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-19) (2.53 mg, yield: 21%). LCMS (ESI): m / z, 473.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.75 (d, J = 11.4 Hz, 1H), 7.30 (s, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 5.25 (s, 2H), 3.16 (d, J = 6.5 Hz, 6H), 2.88 (s, 2H), 2.82 (s, 2H), 2.08 (t, J = 6.2 Hz, 2H), 1.87 (p, J = 7.0 Hz, 2H), 1.76 (s, 2H), 0.88 (t, J = 7.3 Hz, 3H); 19F NMR (377 MHz, DMSO-d6) δ -113.12.

[0247] Preparation Example 27: Preparation of (S)-4-(2-aminoethyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-20) TIFF2026510566000166.tif65157

[0248] Procedure 1: Preparation of (S)-(2-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)ethyl)benzylcarbamate (PY-20a) Compound PY-10d (90.91 mg, 66%, 123.63 μmol, 1 eq) was dissolved in dioxane (4 mL) / water (1 mL), and potassium benzyloxycarbonylaminoethyltrifluoroborate (148.91 mg, 494.53 μmol, 4 eq), tri-o-toluenephos (18.81 mg, 61.82 μmol, 0.5 eq), and potassium phosphate (78.73 mg, 30.71 μL, 370.90 μmol, 3 eq) were added. The reaction mixture was stirred at 90°C for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, filtered, and the residual solution was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Oriendo, model number BRIX-2860 (R1,4,5,6). Column: Phenomenex Luna C18 250×50mm×10μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: elution from 30% to 60%) to obtain a white solid product PY-20a (10 mg, yield: 13.86%). LCMS (ESI): m / z, 584.2 [M+H] + .

[0249] Procedure 2: Preparation of (S)-4-(2-aminoethyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-20) Compound PY-20a (10 mg, 17.13 μmol, 1 eq) was dissolved in MeCN (0.5 mL), and TMSI (56 mg, 40 μL, 279.87 μmol, 16.334 eq) was added to the solution. The solution was stirred at 25°C for 12 hours. The reaction mixture was purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: Shimadzu, model number LC-20AP. Column: YMC-Triart Prep C18 250 × 30 mm × 10 μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: eluted from 3% to 33%) to obtain a white solid product (5.16 mg, yield: 67%, purity: 97.64%). LCMS (ESI): m / z, 450.2 [M+H] + .

[0250] Preparation Example 28: Preparation of (S)-4-ethyl-8-fluoro-4,9-dihydroxy-11-propyl-1,12-dihydro-14H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H)-dione (PY-21-A) TIFF2026510566000167.tif88139

[0251] Procedure 1: Preparation of 1-(2-amino-4-fluoro-5-methoxyphenyl)butan-1-one (PY-21-Ab) Under ice bath conditions, BCl3 (1 eq, 830.04 mg, 7.08 mmol) was added to anhydrous benzene (10 mL), then a solution of 3-fluoro-4-methoxyaniline (1 eq, 1 g, 7.08 mmol) dissolved in anhydrous benzene (20 mL) was added, and under a nitrogen atmosphere, nitrile (2 eq, 979.24 mg, 14.17 mmol, 1.23 mL) and AlCl3 (1.1053 eq, 1.04 g, 1.04 mol) were sequentially added, and the mixture was reacted at 100°C for 16 hours. After cooling in an ice bath, 2 M hydrochloric acid (50 mL) was slowly added, and the mixture was stirred for a further 1 hour at 80°C. The reaction was quenched with water (100 mL) under an ice bath, the organic phase was extracted with ethyl acetate (2 × 100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain the pale yellow solid compound PY-21-Ab (440 mg, yield: 29%). LCMS (ESI): m / z, 212.1 [M+H] + .

[0252] Procedure 2: Preparation of (S)-4-ethyl-8-fluoro-4-hydroxy-9-methoxy-11-propyl-1,12-dihydro-14H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H)-dione (PY-21-Ad) To a toluene (10 mL) solution of 1-(2-amino-4-fluoro-5-methoxyphenyl)butan-1-one (PY-21-Ab) (1 eq, 62.31 mg, 236.70 μmol), (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione (1 eq, 62.31 mg, 236.70 μmol) and PPTS (1 eq, 59.48 mg, 236.70 μmol, 10 mL) were added, respectively, and the mixture was reacted under a nitrogen atmosphere at 130°C with stirring for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the yellow solid compound PY-21-Ad (80 mg, yield: 77%). LCMS (ESI): m / z, 439.1 [M+H] + .

[0253] Step 3: Preparation of (S)-4-ethyl-8-fluoro-4,9-dihydroxy-11-propyl-1,12-dihydro-14H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H)-dione (PY-21-A) AlCl3 (18.25 mg, 136.84 μmol, 6 eq) was added to a solution of compound PY-21-Ad (10 mg, 22.81 μmol, 1 eq) in DCM (4 mL). The mixture was reacted at 70°C with stirring for 16 hours. The reaction was quenched with saturated ammonium chloride solution (100 mL), the organic phase was extracted with ethyl acetate (2 × 100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: SHIMADZU, model number LC-20AP. Column: YMC-Triart Prep C18 250 × 30 mm × 10 μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: eluted from 12% to 42%), lyophilized, and a white solid compound PY-21-A (4.3 mg, yield: 44%) was obtained. LCMS (ESI): m / z, 425.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.91 (dd, J = 11.9, 2.8 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.26 (s, 1H), 6.49 (s, 1H), 5.43 (s, 2H), 5.27 (d, J = 3.1 Hz, 2H), 3.06 (t, J = 7.9 Hz, 2H), 1.86 (dq, J = 14.1, 7.0 Hz, 2H), 1.73 (p, J = 7.5 Hz, 2H), 1.05 (t, J = 7.3 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[0254] Preparation Example 29: Preparation of (S)-4-(4-aminobutyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-24) TIFF2026510566000168.tif62150

[0255] Procedure 1: Preparation of (S)-(4-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)butan-3-en-1-yl)carbamate tert-butyl ester (PY-24c) Compound (S)-4-bromo-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (200 mg) was dissolved in toluene (15 mL) and bis(tri-tert-butylphosphine)palladium (21 mg, 0.1 eq), tris(o-methylphenyl)phosphine (25 mg, 0.2 eq), DIPEA (410 μL, 6 eq), and butane-3-en-1-ylcarbamate tert-butyl ester (176 mg, 2.5 eq) were added, respectively, and the mixture was reacted at 120 °C with stirring for 16 hours. After concentrating the reaction mixture, it was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1 to 10:1), concentrated under reduced pressure to obtain the crude product (129 mg, yield: 54%), which was used directly in the following procedure. LCMS (ESI): m / z, 576.3 [M+1] + .

[0256] Procedure 2: Preparation of (S)-(4-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)butyl)carbamate tert-butyl ester (PY-24d) To the crude product (S)-(4-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)butan-3-en-1-yl)carbamate tert-butyl ester (6.8 mg), Pd / C (1.3 mg, 0.25 eq) and Pd(OH)2 (1.7 mg, 0.25 eq) were added to methanol (3 mL) solvent, respectively, and under a hydrogen gas atmosphere... The reaction was carried out under gaseous conditions at 25°C with stirring for 16 hours. After filtering the reaction solution, it was concentrated under reduced pressure to obtain the crude product compound (S)-(4-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)butyl)carbamate tert-butyl ester (PY-24d) (6.8 mg, yield: 55%, purity: 63%), which was used directly in the following procedure. LCMS (ESI): m / z, 578.2 [M+1] + .

[0257] Step 3: Preparation of (S)-4-(4-aminobutyl)-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-24) Under ice bath conditions, the compound (S)-(4-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)butyl)carbamate tert-butyl ester (6.8 mg, purity: 63%) was added to dichloromethane (2.1 mL) with TFA (0.7 mL), and the mixture was heated naturally to 25°C and reacted with stirring for 16 hours. Preparative high-performance liquid chromatography (Preparative chromatograph manufacturer: SHIMADZU, model number LC-20AP. Column: Welch Xtimate C18) was used. The sample was prepared in dimensions of 250 × 50 mm × 10 μm. It was purified using water (0.225% FA)-ACN as the mobile phase (elution ratio of water: 12% to 42%), then freeze-dried to obtain 0.35 mg of compound PY-24 (yield: 5.4%). LCMS (ESI): m / z, 473.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.78-7.71 (m, 1H), 7.30 (s, 1H), 6.51 (s, 1H), 5.43 (s, 2H), 5.25 (s, 2H), 3.16 (d, J = 6.0 Hz, 6H), 2.86 (s, 2H), 2.76 (s, 2H), 2.08 (s, 2H), 1.88 (q, J = 7.0 Hz, 2H), 1.59 (s, 2H), 0.88 (t, J = 7.3 Hz, 3H); 19 F NMR (377 MHz, DMSO-d 6 ) δ -112.93.

[0258] Preparation Example 30: Preparation of 2-((9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-1-yl)acetic acid (PY-25) TIFF2026510566000169.tif3034 TIFF2026510566000170.tif57133

[0259] Procedure 1: Preparation of 2-(8-acetamido-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)acetate (PY-251) N-(3-fluoro-4-methyl-8-oxy-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (2 g, 8.5 mmol) was placed in a 100 mL three-necked flask and dissolved in THF (30 mL) under a nitrogen atmosphere. The mixture was cooled to -78 °C, and LDA (10.6 mL, in 2 M THF) was slowly added to the reaction mixture and allowed to react at -78 °C for 1 hour. Next, methyl bromoacetate (1.3 g, 8.5 mmol) was added to the reaction mixture, heated to room temperature, and allowed to react for 16 hours. The reaction mixture was added to water (150 mL), extracted with ethyl acetate (100 mL x 3), washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure, and purified the residue by silica gel column chromatography (80% PE / 20% EA) to obtain the pale yellow solid compound 2-(8-acetamido-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)acetate (PY-251) (800 mg, yield: 30.6%).

[0260] Procedure 2: Preparation of 2-(8-amino-6-fluoro-5-methyl-1-oxy-1,2,3,4-tetrahydronaphthyl-2-yl)acetic acid (PY-252) An aqueous solution of NaOH (2 mL, 2 mol / mL) was added to a solution of compound 2-(8-acetamido-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)acetate (PY-251) (400 mg, 1.3 mol) in EtOH (8 mL), and the reaction was carried out at 75°C for 16 hours. The reaction mixture was adjusted to pH 7-8 with 2N hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (200 mg), which was used directly in the next procedure.

[0261] Procedure 3: Preparation of 2-((9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4:6,7]indolidino[1,2-b]quinoline-1-yl)acetic acid (PY-25) 2-(8-amino-6-fluoro-5-methyl-1-oxy-1,2,3,4-tetrahydronaphthyl-2-yl)acetic acid (PY-252) (200 mg, 0.796 mmol) and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indridine-3,6,10(4H)-trione (251 mg, 0.954 mmol) were placed in a 50 mL three-necked flask, toluene (10 mL, 50V) was added, and then p-toluenesulfonic acid (27.3 mg, 0.159 mmol) and o-cresol (0.6 mL, 3V) were added, and the mixture was reacted at 120-125°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% HCOOH)-acetonitrile, eluting from 45% to 85%) to obtain the yellow powder compound PY-25 (70 mg, yield 18.38%). 1H NMR (400 MHz, DMSO) δ 12.50 (s, 1H), 7.76 (d, J = 11.1 Hz, 1H), 7.31 (s, 1H), 6.51 (s, 1H), 5.44 (s, 2H), 5.36 (s, 2H), 3.83 - 3.74 (m, 1H), 3.19-3.05 (m, 2H), 2.70-2.64 (m, 1H), 2.58-2.53 (m, 1H), 2.38 (s, 3H), 2.23 (d, J = 13.6 Hz, 1H), 2.06-1.95 (m, 1H), 1.87 (tt, J = 14.1, 7.0 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0262] Preparation Example 31: 2-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl)-N-(2-hydroxyethyl)acetamide and 2-((1R Preparation of ,9S)-9-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl)-N-(2-hydroxyethyl)acetamide (PY-25A and PY-25B) Under ice bath conditions, a solution of compound 2-((9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxy-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4]:6,7]indolidino[1,2-b]quinoline-1-yl)acetic acid (PY-25) (18 mg, 37.62 μmol, 1.0 eq) in DMF (3 mL) was mixed with HATU (17 mg, 45.14 μmol, 1.2 eq), DIEPA (20 mg, 150.5 μmol, 4 eq), and ethanolamine (2.3 mg, 37.62 μmol, 1.0 eq), heated to room temperature, and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% HCOOH)-acetonitrile, eluting from 45% to 85%) to obtain the white solid compounds PY-25A (4.01 mg, yield 18%) and PY-25B (6.62 mg, yield 30%). PY-25A (LCMS retention time 1.73min): LCMS (ESI): m / z, 522.3[M+1] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.07 (t, J = 4.0 Hz, 1H), 7.76 (d, J = 12.0 Hz, 1H), 7.30 (s, 1H), 6.51 (s, 1H), 5.44 (s, 2H), 5.34 (s, 2H), 4.67 (t, J = 4.0 Hz, 1H), 3.78-3.77 (m, 1H), 3.44-3.36 (m, 3H), 3.18-3.14 (m, 4H), 2.45-2.44 (m, 1H), 2.39 (s, 3H), 2.13-2.11 (m, 1H), 1.97-1.80 (m, 3H), 0.87 (t, J = 8.0 Hz (3H). PY-25B (LCMS retention time 1.83min): LCMS (ESI): m / z, 522.2[M+1] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (brs, 0.36H, HCOOH), 8.08-8.06 (m, 1H), 7.75 (d, J = 12.0 Hz, 1H), 7.30 (s, 1H), 6.51 (s, 1H), 5.44 (s, 2H), 5.34 (s, 2H), 4.66 (s, 1H), 3.78-3.76 (m, 1H), 3.38-3.36 (m, 2H), 3.15-3.12 (m, , 4H), 2.48 - 2.30 (m, 5H), 2.14 (s, 1H), 1.88-1.85 (m, 3H), 0.87 (t, J = 8.0 Hz, 3H).

[0263] Preparation Example 32: Preparation of (S)-N-((9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)methyl)-2-hydroxyacetamide (PY-26) At 1500°C, N,N-diisopropylethylamine (26.71 mg, 206.68 μmol, 3 eq) and HATU (31.43 mg, 82.67 μmol, 1.2 eq) were added to a solution of compound PY-16 (30 mg, 68.89 μmol, 1 eq) and 2-hydroxyacetic acid (6.29 mg, 82.67 μmol, 1.2 eq) in N,N-dimethylformamide (3 mL). The mixture was then reacted at 25°C for 2 hours. The reaction solution was purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: ISCO, model number ISCO-R1. Column: YMC-Triart Prep C18 250×50mm×7μm. Mobile phase: water (0.225% FA)-acetonitrile, acetonitrile elution ratio: eluted from 28% to 37%) to obtain the white solid compound PY-26 (4.37 mg, yield = 12.8%). LCMS (ESI): m / z, 494.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.06-8.05 (m, 1H), 7.74 (d, J = 12 Hz, 1H), 7.31 (s, 1H), 6.54 (s, 1H), 5.43-5.42 (m, 3H), 5.25 (s, 2H), 4.56 (d, J = 8.0 Hz, 2H), 3.82 (d, J = 8.0 Hz, 2H), 3.26-3.23 (m, 2H), 3.15-3.15 (m, 2H), 2.08-2.05 (m, 2H), 1.90-1.83 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -112.11.

[0264] Preparation Example 33: Preparation of (S)-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)methyl(2-hydroxyethyl)carbamate (PY-27) TIFF2026510566000173.tif47150

[0265] Procedure 1: Preparation of (S)-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)methyl(4-nitrophenyl)carbonate (PY-27a) At room temperature, compound PY-10 (8.0 mg, 0.018 mmol, 1.0 eq), bis(4-nitrophenyl) carbonate (44.6 mg, 0.147 mmol, 8.0 eq), and N,N-diisopropylethylamine (28.4 mg, 0.220 mmol, 12.0 eq) were added to N,N-dimethylformamide (2 mL) and stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (eluent: dichloromethane / methanol (15 / 1)) to obtain the yellow oily compound PY-27a (18 mg). LCMS (ESI): m / z, 602.3 [M+H] + .

[0266] Procedure 2: Preparation of (S)-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)methyl(2-hydroxyethyl)carbamate (PY-27) At room temperature, compound PY-27a (18.0 mg, impurity), aminoethanol (1.83 mg, 0.030 mmol), and N,N-diisopropylethylamine (11.6 mg, 0.090 mmol) were added to N,N-dimethylformamide (1 mL) and stirred at 25°C for 0.5 hours. The reaction mixture was purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: Luna, model number Lab311-ISCO-R4. Column: Phenomenex Luna C18 250 × 50 mm × 10 μm. Mobile phase: water (0.225% formic acid)-acetonitrile, water elution ratio: elution from 12% to 42%), lyophilized, and obtained a white solid product PY-27 (4.14 mg, 7.56 µl, two-step yield: 42%). LCMS (ESI): m / z, 524.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 11.2 Hz, 1H), 7.32 (s, 1H), 7.19 (t, J = 5.6 Hz, 1H), 6.54 (s, 1H), 5.44 (s, 2H), 5.27 (d, J = 4.4 Hz, 3H), 4.63 (t, J = 5.6 Hz, 1H), 3.30-3.23 (m, 5H), 3.18 (s, 2H), 3.04 (q, J = 6.0 Hz, 2H), 2.08 (s, 2H), 1.86 (dt, J = 15.2, 7.2 Hz, 2H), 0.87 (t, J = 7.2 Hz (3H).

[0267] Preparation Example 34: Preparation of (S)-4-ethyl-8,10-difluoro-4,9-dihydroxy-11-(4-hydroxybutyl)-1,12-dihydro-14H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H)-dione (PY-29) and preparation of (S)-4-ethyl-8,10-difluoro-4-hydroxy-11-(4-hydroxybutyl)-9-methoxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H)-dione (PY-29B) TIFF2026510566000174.tif118150

[0268] Procedure 1: Preparation of 2,4-difluoro-3-methoxybenzaldehyde (PY-29a) At -78°C, 1,3-difluoro-2-methoxybenzene (2.8 g) was added to THF (20 mL) solvent, n-BuLi (9.3 mL, 2.5 M, 1.2 eq) was added, and the mixture was stirred at the same temperature for 0.5 hours. Then, DMF (9.15 mL, 6 eq) was added, and the mixture was stirred for another 0.5 hours. The low-temperature reaction bath was removed, and the mixture was reacted at 15°C for 1 hour. The reaction was quenched with 4 M HCl (6 mL), extracted with ethyl acetate (3 × 50 mL), and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate 20:1 to 10:1) to obtain the yellow oily compound PY-29a (1.8 g, yield: 53%). LCMS (ESI): m / z, 173 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.96-9.56 (m, 1H), 7.83-7.43 (m, 1H), 7.30 (b, 1H), 4.22-3.90 (m, 3H).

[0269] Procedure 2: Preparation of 2,4-difluoro-3-methoxy-6-nitrobenzaldehyde (PY-29b-1) Compound 2,4-difluoro-3-methoxybenzaldehyde (1.78 g) was dissolved in sulfuric acid (20.3 mL) and fuming nitric acid (446 μL, 0.96 eq) was added, and the mixture was reacted at 25°C for 1 hour. The reaction mixture was poured into ice water, filtered by suction under pressure, washed with water, and dried to obtain a yellow solid compound 2,4-difluoro-3-methoxy-6-nitrobenzaldehyde (PY-29b-1) (925 mg, yield: 40%). 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.21 (dd, J = 11.1, 2.0 Hz, 1H), 4.13 (t, J = 1.9 Hz, 3H).

[0270] Step 3: Preparation of 6-amino-2,4-difluoro-3-methoxybenzaldehyde (PY-29c) To ethanol (30 mL) solvent of compound 2,4-difluoro-3-methoxy-6-nitrobenzaldehyde (925 mg), iron powder (5.5 eq, 1.31 g), water (23.12 eq, 1.77 mL), and hydrochloric acid (0.55 eq, 71 μL) were added, respectively. The mixture was reacted at 80°C with stirring for 16 hours, and the formation of the product was confirmed by LC-MS. The reaction mixture was cooled to room temperature, filtered under pressure, and concentrated to obtain the crude product. This crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate 10:1 to 5:1), dried, and obtained as a green solid 6-amino-2,4-difluoro-3-methoxybenzaldehyde (PY-29d) (488 mg, 61% yield). LCMS (ESI): m / z, 187.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.48 (s, 2H), 6.44 (dd, J = 13.4, 2.0 Hz, 1H), 3.77 (s, 3H).

[0271] Step 4: Preparation of (S)-4-ethyl-8,10-difluoro-4-hydroxy-9-methoxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H)-dione (PY-29d) Compound 6-amino-2,4-difluoro-3-methoxybenzaldehyde (PY-29c) (150 mg) was dissolved in toluene (10 mL) and PPTS (134.9 mg, 0.67 eq) and compound PY-8f (253.2 mg, 1.2 eq) were added, respectively. The reaction was carried out under a nitrogen atmosphere at 130°C with stirring for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate 5:1 to 0:1) to obtain the yellow solid compound PY-29d (233 mg, yield: 67%; purity: 78%). LCMS (ESI): m / z, 415 [M+H] + .

[0272] Step 5: Preparation of (S)-11-(4-(benzyloxy)butyl)-4-ethyl-8,10-difluoro-4-hydroxy-9-methoxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H)-dione)(PY-29f) Compound PY-29d (193 mg, 78% purity) was dissolved in glacial acetic acid (14.6 mL), and concentrated sulfuric acid (3.6 mL) was slowly added under ice bath conditions. In another reaction flask, ferrous sulfate (66.2 mg, 1.2 eq) and deionized water (2.6 mL) were added, and under the same temperature, the ferrous sulfate solution was added to the solution of compound PY-29d, followed by the sequential addition of 5-(benzyloxy)pentanal (PY-29e) (349 mg, 5 eq) and hydrogen peroxide (54.4 μL). The mixture was reacted under ice bath conditions with stirring for 45 minutes. The reaction mixture was poured into ice water, the organic phase was extracted with ethyl acetate (50 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the crude product, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1 to 4:1) to obtain compound PY-29f (230 mg, 64% purity). LCMS (ESI): m / z, 577.3 [M+H] + .

[0273] Procedure 6: Preparation of (S)-4-ethyl-8,10-difluoro-4-hydroxy-11-(4-hydroxybutyl)-9-methoxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H)-dione (PY-29B) To a methanol (10 ml) solution of compound PY-29f (497 mg), palladium carbon (78 mg, 0.25 eq) and Pd(OH)2 (51.4 mg, 0.25 eq) were added, respectively, and the mixture was reacted at 30°C with stirring for 16 hours. After filtration, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1 to 10:1) to obtain compound PY-29B (55 mg, yield: 38%; purity: 78%). LCMS (ESI): m / z, 487.1 [M+H] + .

[0274] Procedure 7: Preparation of (S)-4-ethyl-8,10-difluoro-4,9-dihydroxy-11-(4-hydroxybutyl)-1,12-dihydro-14H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H)-dione (PY-29) At 90°C, AlCl3 compound (79 mg, 6 eq) was added to 4 mL of DCM solvent containing compound PY-29B (48 mg, 78% purity) in 2-hour intervals. The reaction mixture was purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: SHIMADZU, model LC-20AP; column: YMC-Triart Prep C18 250 × 30 mm × 10 μm; mobile phase: water (0.225% HCOOH)-acetonitrile; water elution ratio: elution from 12% to 42%), lyophilized, and obtained a white solid compound PY-29 (6.77 mg, yield: 14.5%). LCMS (ESI): m / z, 473.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 6.8 Hz, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.76 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 7.5 Hz, 2H), 7.55 (t, J = 6.2 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 4.33 - 4.20 (m, 4H), 4.11 (p, J = 7.0 Hz, 1H), 3.67 (d, J = 6.2 Hz, 2H), 1.95 (dt, J = 12.6, 6.3 Hz, 1H), 1.38 (d, J = 1.9 Hz, 9H), 1.24 (d, J = 7.2 Hz, 3H), 0.86 (dd, J = 19.2, 6.7 Hz, 6H); 19 F NMR (377 MHz, DMSO-d6) δ -125.50 (d, J = 13.5 Hz).

[0275] Preparation Example 35: Preparation of (S)-4-ethyl-8,10-difluoro-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H)-dione (PY-29A) TIFF2026510566000175.tif55134

[0276] Procedure 1: Preparation of (S)-4-ethyl-8,10-difluoro-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H)-dione (PY-29A) To a 3 mL solution of compound PY-29d (29.5 mg, 55.51 μmol, 1.0 eq, 78% purity) in DCM, AlCl3 (22.2 mg, 166.52 μmol, 3.0 eq) was added and the mixture was reacted at 70°C for 2 hours. The reaction product was purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: SHIMADZU, model number LC-20AP. Column: YMC-Triart Prep C18 250 × 30 mm × 10 μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: elution from 12% to 42%), lyophilized, and obtained a white solid compound PY-29A (1.46 mg, yield: 4.9%). LCMS (ESI): m / z, 401.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.77 (d, J = 11.9 Hz, 1H), 7.25 (s, 1H), 6.52 (s, 1H), 5.42 (s, 2H), 5.23 (s, 2H), 1.86 (p, J = 7.0 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0277] Preparation Example 36: Preparation of (S)-4-(aminomethyl)-5-chloro-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro-10h,13h-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-36) TIFF2026510566000176.tif3053 TIFF2026510566000177.tif63150

[0278] Step 1: Preparation of N-(3-bromo-5-chlorophenyl)acetamide (PY-36b) 3-Bromo-5-chloroaniline (PY-36a) (5.00 g, 24.2 mmol, 1.0 eq) and triethylamine (4.90 g, 48.4 mmol, 6.74 mL, 2.0 eq) were added to dichloromethane (50.0 mL), the mixture was purged three times with nitrogen gas, and acetyl chloride (2.85 g, 36.3 mmol, 2.58 mL, 1.5 eq) was added at 0°C. The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. At 0°C, water (30.0 mL) was added dropwise to the reaction mixture, a precipitate formed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the white solid compound N-(3-bromo-5-chlorophenyl)acetamide (5.90 g, yield 97%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.26 (s, 1H), 7.77 (d, J = 1.2 Hz, 1H), 7.68 (d, J = 1.2 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 2.05 (s, 3H).

[0279] Step 2: Preparation of (E)-4-(3-acetamido-5-chlorophenyl)butane-3-enoic acid tert-butyl ester (PY-36c) N-(3-bromo-5-chlorophenyl)acetamide (5.00 g, 20.1 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (30 mL), and 1-buten-4-category tert-butyl ester (4.29 g, 30.2 mmol, 4.89 mL, 1.5 eq), tris(o-methylphenyl)phosphine (306.2 mg, 1.01 mmol, 0.05 eq), triethylamine (4.07 g, 40.2 mmol, 5.60 mL, 2.0 eq), bis(tri-tert-butylphosphine)palladium (103 mg, 201.2 μmol, 0.01 eq), and N-methyldicyclohexylamine (7.86 g, 40.2 mmol, 8.54 mL, 2.0 eq) were added. The mixture was reacted under a nitrogen atmosphere at 100 °C for 4 hours. The reaction mixture was cooled to room temperature, water (50.0 mL) was added, and the mixture was extracted twice with ethyl acetate (25.0 mL). The organic phase was washed three times with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate = 15 / 1-3 / 2 to obtain (E)-4-(3-acetamido-5-chlorophenyl)butane-3-enoic acid tert-butyl ester (5.10 g, 16.5 mmol, yield 82.09%), a white solid. LCMS: RT = 0.634 min, MS (ESI) m / z = 254.0 [M+H] + .

[0280] Step 3: Preparation of 4-(3-acetamido-5-chlorophenyl)butanoate (PY-36d) (E)-4-(3-acetamido-5-chlorophenyl)butane-3-enoate tert-butyl ester (5.00 g, 16.1 mmol, 1.0 eq) was added to methanol (50.0 ml), and tris(triphenylphosphine)rhodium chloride (I) (1.49 g, 1.61 mmol, 0.1 eq) was added under an argon gas atmosphere. The reaction was carried out at 25°C under hydrogen gas (30 Psi) for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product 4-(3-acetamido-5-chlorophenyl)butanoate (3.60 g, 11.5 mmol, yield 71.42%), a white solid. 1 HNMR(400MHz, CDCl3) δ ppm 7.41 (s, 1 H), 7.13-7.08 (m, 2 H), 6.85 (s, 1 H), 2.52 (t, J = 7.2 Hz, 2 H), 2.15 (t, J = 7.6 Hz, 1 H), 2.10 (s, 1 H), 1.83-1.81 (m, 2 H), 1.38 (s, 9 H).

[0281] Step 4: Preparation of 4-(5-acetamido-2-bromo-3-chlorophenyl)butanoate (PY-36e) 4-(3-acetamido-5-chlorophenyl)butanoate (100 mg, 320.7 μmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5.00 mL), and NBS (68.5 mg, 385 μmol, 1.2 eq) was slowly added. The mixture was reacted at 25°C for 1 hour. Water (10.0 mL) was added dropwise to the reaction mixture, and the mixture was extracted twice with ethyl acetate (10.0 mL). The organic phase was washed three times with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product 4-(5-acetamido-2-bromo-3-chlorophenyl)butanoate (120 mg, 96.0%), a white solid. LCMS: RT = 2.885 min, MS(ESI) m / z = 336.1 [M+H] + .

[0282] Procedure 5: Preparation of 4-(5-acetamido-2-bromo-3-chlorophenyl)butanoic acid (PY-36f) 4-(5-acetamido-2-bromo-3-chlorophenyl)butanoate (100 mg, 256 μmol, 1.0 eq) was dissolved in dichloromethane (2.00 mL), and trifluoroacetic acid (2.00 mL) was slowly added dropwise at 0°C. The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was concentrated directly under reduced pressure to obtain a solid, and dichloromethane (8.00 mL) was added, the mixture was stirred, and filtered to obtain the crude product 4-(5-acetamido-2-bromo-3-chlorophenyl)butanoic acid (60.0 mg, 70.0%), a white solid. 1HNMR (400MHz, CDCl3) δ ppm 12.09 (br, 1H), 10.19 (s, 1 H), 7.87 (d, J = 2.4 Hz, 1 H), 7.37 (d, J = 2.4 Hz, 1 H), 2.72 (t, J = 7.6 Hz, 2 H), 2.28 (t, J = 7.2 Hz, 2 H), 2.04 (s, 3 H), 1.78 (t, J = 7.6 Hz, 2 H).

[0283] Step 6: Preparation of N-(4-bromo-3-chloro-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-36g) 4-(5-acetamido-2-bromo-3-chlorophenyl)butanoic acid (1.80 g, 5.38 mmol, 1.0 eq) was dissolved in Eaton's reagent (113.6 g, 477.3 mmol, 75.00 mL, 88.73 eq) and reacted under a nitrogen atmosphere at 100°C for 1 hour. The reaction mixture was cooled to room temperature, slowly added to cold water, thoroughly quenched, and filtered to obtain a solid. The solid was dissolved in dichloromethane (10.0 mL) and concentrated, then slurryed with a mixed solvent (petroleum ether / ethyl acetate = 10 / 1), filtered, and obtained N-(4-bromo-3-chloro-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (1.20 g, 3.79 mmol, yield 70.45%), a yellow solid. LCMS: RT = 0.961 min, MS(ESI) m / z = 317.9 [M+H] + . 1 HNMR (400MHz, CDCl3) δ ppm 12.11 (s, 1H), 8.86 (s, 1 H), 3.03 (t, J = 6.0 Hz, 2 H), 2.61 (t, J = 6.4 Hz, 2 H), 2.16 (s, 3 H), 2.04 (t, J = 6.4 Hz, 2H).

[0284] Procedure 7: Preparation of 8-amino-5-bromo-6-chloro-3,4-dihydronaphthalene-1(2H)-1-one (PY-36h) N-(4-bromo-3-chloro-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (900 mg, 2.84 mmol, 1.0 eq) was dissolved in ethanol (15 mL), hydrochloric acid solution (5 mL, 6 mol / mL) was added at room temperature, and the mixture was stirred at 80°C for 3 hours. The reaction mixture was cooled to room temperature, concentrated, and the concentrate was adjusted to pH 8-9 with saturated sodium bicarbonate solution. It was extracted twice with ethyl acetate (10 mL), the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 8-amino-5-bromo-6-chloro-3,4-dihydronaphthalen-1(2H)-1-one (700 mg, 2.55 mmol, yield 89.8%), a yellow solid. LCMS: RT = 0. 942 min, MS(ESI) m / z = 275.8 [M+H] + .

[0285] Procedure 8: Preparation of (S)-4-bromo-5-chloro-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro-10h,13h-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-36i) 8-amino-5-bromo-6-chloro-3,4-dihydronaphthalene-1(2H)-1-one (574 mg, 2.09 mmol, 1.1 eq) and compound PY-8f (500 mg, 1.90 mmol, 1.0 eq) were dissolved in toluene (10 mL), and p-toluenesulfonic acid (36.1 mg, 0.19 mmol, 0.1 eq) was added. The mixture was reacted under a nitrogen atmosphere at 110°C for 16 hours. The reaction mixture was cooled to room temperature, a solid precipitated, filtered, and dried to obtain the crude product PY-36i, a yellow solid (850 mg, 1.69 mmol, yield 89.4%). LCMS: RT = 2.233 min, MS(ESI) m / z = 503.3 [M+H] + .

[0286] Procedure 9: Preparation of (S)-(5-chloro-9-ethyl-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1h,12h-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)methyl)carbamate tert-butyl ester (PY-36j) Compound PY-36i (400 mg, 0.80 mmol, 1.0 eq), potassium N-Boc-aminomethyltrifluoroborate (948 mg, 4.00 mmol, 5.0 eq), n-butyl-bis(1-adamantyl)phosphine (375 mg, 0.40 mmol, 0.5 eq), potassium carbonate (221 mg, 1.60 mmol, 2.0 eq), and palladium acetate (53.88 mg, 0.24 mmol, 0.3 eq) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), and stirred under a nitrogen atmosphere at 80°C for 2 hours. The reaction mixture was cooled to room temperature, concentrated, water (10 mL) was added to the concentrate, and extracted twice with ethyl acetate (10 mL). The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reverse-phase chromatography (column: Xtimate C18 150 × 40 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 26%-66% B, 36 min) to obtain compound PY-36j (54.2 mg, 0.095 mmol, yield 11.87%), a white solid. LCMS: RT = 2.127 min, MS(ESI) m / z = 552.5 [M+H] + .

[0287] Procedure 10: Preparation of (S)-4-(aminomethyl)-5-chloro-9-ethyl-9-hydroxy-1,2,3,9,12,15-hexahydro-10h,13h-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-36) Compound PY-36j (52.4 mg, 0.095 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added at 0°C, and the mixture was reacted at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase chromatography (column: Xtimate C18 150 × 40 mm × 10 μm; mobile phase: [water (TFA)-ACN]; gradient: 0%-38% B, 30 min) to obtain compound PY-36 (4.55 mg, 0.01 mmol, yield 10.53%), a white solid. LCMS: RT = 1.566 min, MS(ESI) m / z = 452.2 [M+H] + . 1 HNMR (400MHz, DMSO-d 6 ) δ ppm 8.23 ​​(s, 1 H), 8.19 (s, 2 H), 7.34 (s, 1 H), 6.55 (s, 1 H), 5.45 (s, 2 H), 5.30 (s, 2 H), 4.41 (s, 2 H), 3.20-3.18 (m , 4 H), 2.12 (t, J = 4.8 Hz, 2 H), 1.90-1.86 (m, 2 H), 0.88 (t, J = 7.2 Hz, 3 H).

[0288] Preparation Example 37: Preparation of (S)-5-chloro-9-ethyl-9-hydroxy-4-(hydroxymethyl)-1,2,3,9,12,15-hexahydro-10h,13h-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-37) Compound PY-36i (200 mg, 0.40 mmol, 1.0 eq) and (tributyltinyl)methanol (192 mg, 0.60 mmol, 1.5 eq) were dissolved in 1,4-dioxane (5 mL), and the catalyst chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II)(XPhos Pd G2) (31.4 mg, 0.04 mmol, 0.1 eq) was added. The reaction was carried out under a nitrogen atmosphere at 90°C for 4 hours. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, diluted with water, extracted twice with ethyl acetate (10 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reverse-phase chromatography (column: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase [water (FA)-ACN]; gradient: 6%-46% B, 25 min) to obtain compound PY-37 (2.08 mg, 0.005 mmol, yield 1.25%), a white solid. LCMS: RT = 1.475 min, MS(ESI) m / z = 453.3 [M+H] + . 1 HNMR (400MHz, DMSO-d 6 ) δ ppm 8.10 (s, 1 H), 7.32 (s, 1 H), 6.53 (s, 1 H), 5.44 (s, 2 H), 5.28 (s, 2 H), 5.19 (t, J = 5.2 Hz , 1 H), 4.83 (d, J = 5.2 Hz , 2 H), 3.17 (t, J = 7.6 Hz, 2 H), 2.09 (t, J = 7.6 Hz, 2 H), 1.89-1.84 (m, 2 H), 1.15-1.14 (m, 2 H), 0.88 (t, J = 7.2 Hz, 3 H).

[0289] Preparation Example 38: Preparation of (S)-9-ethyl-9-hydroxy-4-(hydroxymethyl)-1,2,3,9,12,15-hexahydro-10h,13h-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-37A) Compound PY-36i (200 mg, 0.40 mmol, 1.0 eq) and (tributyltinyl)methanol (192 mg, 0.60 mmol, 1.5 eq) were dissolved in 1,4-dioxane (5 mL), and the catalyst chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II)(XPhos Pd G2) (31.4 mg, 0.04 mmol, 0.1 eq) was added. The reaction was carried out under a nitrogen atmosphere at 90°C for 4 hours. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, diluted with water, extracted twice with ethyl acetate (10 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reverse-phase chromatography (column: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; gradient: 6%-46% B, 25 min) to obtain compound PY-37A (2.23 mg, 0.005 mmol, yield 1.25%), a white solid. LCMS: RT = 1.233 min, MS(ESI) m / z = 419.4 [M+H] + . 1 HNMR (400MHz, DMSO-d 6) δ ppm 7.99 (d, J = 8.8 Hz 1 H), 7.90 (d, J = 8.8 Hz 1 H), 7.32 (s, 1 H), 6.51 (s, 1 H), 5.44 (s, 2 H), 5.33 (t, J = 4.4 Hz , 1 H), 5.27 (s, 2 H), 4.73 (d, J = 5.2 Hz, 2 H), 3.19-3.16 (m, 1 H), 3.10-3.07 (m, 1 H), 2.08 (t, J = 3.2 Hz, 2 H), 1.90-1.86 (m, 2 H), 1.15-1.13 (m, 2 H), 0.89 (t, J = 7.2 Hz, 3 H).

[0290] Preparation Example 39: Preparation of (S)-5-chloro-9-ethyl-4,9-dihydroxy-1,2,3,9,12,15-hexahydro-10h,13h-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-38) TIFF2026510566000180.tif79133

[0291] Procedure 1: Preparation of (S)-5-chloro-9-ethyl-9-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,9,12,15-hexahydro-10h,13h-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-38a) Compound PY-36i (400 mg, 0.80 mmol, 1.0 eq), bispinacol borate (305 mg, 1.20 mmol, 1.5 eq), potassium acetate (235 mg, 2.40 mmol, 3.0 eq), and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (176 mg, 0.24 mmol, 0.3 eq) were dissolved in 1,4-dioxane (10 mL) and stirred under a nitrogen atmosphere at 90°C for 5 hours. The reaction mixture was cooled to room temperature, concentrated, water (10 mL) was added to the concentrate, and extracted twice with ethyl acetate (10 mL). The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (PE / EA = 1 / 4) to obtain compound PY-38a (70.2 mg, 0.13 mmol, yield 16.25%), a yellow solid. LCMS: RT = 2.391 min, MS(ESI) m / z = 549.3 [M+H] + .

[0292] Procedure 2: Preparation of (S)-5-chloro-9-ethyl-4,9-dihydroxy-1,2,3,9,12,15-hexahydro-10h,13h-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-38) Compound PY-38a (70.2 mg, 0.13 mmol, 1.0 eq) was dissolved in tetrahydrofuran (0.2 mL) and water (0.2 mL), and sodium perborate tetrahydrate (44.15 mg, 0.39 mmol, 3.0 eq) was added at 0°C. The reaction was carried out at 25°C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (0.2 mL), and purified by reverse-phase chromatography (column: Xtimate C18 150 × 40 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 10%-50% B, 36 min) to obtain compound PY-38 (0.82 mg, 0.002 mmol, yield 1.53%), a white solid. LCMS: RT = 1.491 min, MS(ESI) m / z = 439.3 [M+H] + . 1HNMR (400MHz, DMSO-d 6 ) δ ppm 8.36 (s, 0.16 H), 8.03 (s, 1 H), 7.23 (s, 1 H), 6.49 (s, 1 H), 5.42 (s, 2 H), 5.21 (s, 2 H), 3.10 -3.07 (m, 2 H), 3.02 (t, J = 5.6 Hz, 2 H), 2.01 (t, J = 6.4 Hz, 2 H), 1.88-1.85 (m, 2 H), 1.24 (s, 1 H), 0.88 (t, J = 7.6 Hz, 3 H).

[0293] Preparation Example 40: Preparation of PY-41A and PY-41B TIFF2026510566000181.tif149150

[0294] Procedure 1: Preparation of compounds PY-41A-a and PY-41A-b Compound N-(8-amino-5-bromo-6-fluoro-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)acetamide (PY-Uc) (see Preparation Example 44 for preparation method) (140 mg, 444.25 μmol, 1 eq) was dissolved in toluene (10 mL), and (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione (PY-8f) (116.95 mg, 444.25 μmol, 1 eq) and PPTS (111.64 mg, 444.25 μmol, 1 eq) were added. The reaction mixture was stirred at 125 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (preparative chromatography manufacturer: Shimadzu, model number LC-20AP. Column: YMC-Triart Prep C18 250×50mm×7μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: eluted from 21% to 51%) to obtain two brownish isomer solids, PY-41-a (54 mg, yield: 22.41%) and PY-41-b (54 mg, yield: 22.41%), respectively. LCMS (ESI): m / z, 542.2 [M+H]+ .

[0295] Step 2: Preparation of compound PY-41A Compound PY-41A-a (15 mg, 27.66 μmol, 1 eq) was dissolved in dioxane (2 mL), hydroxymethyltributylstannane (26.64 mg, 82.97 μmol, 3 eq) and XPhos Pd G2 (4.35 mg, 5.53 μmol, 0.2 eq) were added, the reaction mixture was purged three times with nitrogen gas, and the mixture was stirred under a nitrogen atmosphere at 90°C for 12 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Oriendo, model number BRIX-2860 (R1,4,5,6), column: Phenomenex Luna C18 250×50mm×10μm, mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: eluted from 14% to 24%) to obtain a white solid PY-41A (1.10 mg, yield: 8.06%). LCMS (ESI): m / z, 494.2 [M+H] + .

[0296] Step 3: Preparation of compound PY-41B Compound PY-41A-b (15 mg, 27.66 μmol, 1 eq) was dissolved in dioxane (2 mL), hydroxymethyltributylstannane (26.64 mg, 82.97 μmol, 3 eq) and XPhos Pd G2 (4.35 mg, 5.53 μmol, 0.2 eq) were added, the reaction mixture was purged three times with nitrogen gas, and the mixture was stirred under a nitrogen atmosphere at 90°C for 12 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (preparative chromatograph manufacturer: Oriendo, model number BRIX-2860 (R1,4,5,6), column: Phenomenex Luna C18 250×50mm×10μm, mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: eluted from 12% to 42%) to obtain a white solid product PY-41B (1.02 mg, yield: 7.47%). LCMS (ESI): m / z, 494.1 [M+H]+ .

[0297] Preparation Example 41: Preparation of ((9S)-9-ethyl-5-fluoro-9-hydroxy-4-(hydroxymethyl)-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[d]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl)carbamate ethyl ester (PY-42) Compound PY-UA (see Preparation Example 44 for preparation method) (10.53 mg, 95%, 22.15 μmol, 1 eq) was dissolved in DCM (5 mL), TEA (4.48 mg, 6.16 μL, 44.30 μmol, 2 eq) was added, and ethyl chloroformate (4.81 mg, 4.24 μL, 44.30 μmol, 2 eq) was added at 0°C. The reaction mixture was stirred at 0°C for 8 hours. The reaction mixture was diluted with DCM (10 mL), washed with water (10 mL), dried the organic phase, filtered, and purified by high-performance liquid chromatography (preparative chromatograph manufacturer: Oriendo, model number BRIX-2860 (R1,4,5,6). Column: Welch Xtimate C18 250 × 30 mm × 10 μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: elution from 20% to 50%) to obtain a white solid product PY-42 (1.12 mg, yield: 9.66%, Purity: 90%). LCMS (ESI): m / z, 524.2 [M+H] + .

[0298] Preparation Example 42: Preparation of N-((9S)-9-ethyl-5-fluoro-9-hydroxy-4-(hydroxymethyl)-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[d]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl)-2-hydroxyacetamide (PY-43) TIFF2026510566000183.tif72150

[0299] Procedure 1: Preparation of 2-((tert-butyldimethylsilyl)oxy)-N-((9S)-9-ethyl-5-fluoro-9-hydroxy-4-(hydroxymethyl)-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[d]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl)acetamide (PY-43-b) Compound PY-UA (5 mg, 100%, 11.08 μmol, 1 eq) was dissolved in DMF (1 mL), and DIPEA (2.86 mg, 3.66 μL, 22.15 μmol, 2 eq) and 2,5-dioxopyrrolidine-1-yl-2-((tert-butyldimethylsilyl)oxy)acetate (PY-43-a) (3.82 mg, 13.29 μmol, 1.2 eq) were added. The reaction mixture was stirred at 20°C for 12 hours. The reaction solution was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Oriendo, model number BRIX-2860 (R1,4,5,6). Column was GS-120-10-C18AP. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: eluted from 30% to 60%) to obtain a white solid product (2 mg, yield: 28.95%). LCMS (ESI): m / z, 624.2 [M+H] + .

[0300] Procedure 2: Preparation of N-((9S)-9-ethyl-5-fluoro-9-hydroxy-4-(hydroxymethyl)-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[d]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl)-2-hydroxyacetamide (PY-43) Compound PY-43-b (2 mg, 3.21 μmol, 1 eq) was dissolved in THF (1 mL), and HCl (116.91 μg, 500 μL, 3.21 μmol, 1 eq) was added. The reaction mixture was stirred at 15°C for 2 hours. The reaction mixture was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Oriendo, model number BRIX-2860 (R1,4,5,6). Column: Welch Xtimate C18 250 × 30 mm × 10 μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: elution from 12% to 42%) to obtain the yellow solid product PY-43 (1.10 mg, yield: 67.33%, purity: 100%). LCMS (ESI): m / z, 510.2 [M+H] + .

[0301] Preparation Example 43: Preparation of (S)-4-amino-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-A) TIFF2026510566000184.tif2549 TIFF2026510566000185.tif89124

[0302] Procedure 1: Preparation of 6,8-difluoro-5-nitro-1,2,3,4-tetrahydronaphthyl-1-one (PY-Ab) To a solution of 6,8-difluoro-3,4-dihydronaphthalene-1(2H)-one (PY-Aa) (1.0 g) in sulfuric acid (6 mL), potassium nitrate (546 mg, 0.96 eq) was added and the mixture was reacted for 2 hours with stirring under an ice bath. The reaction solution was poured into ice water, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, compound PY-Ab (800 mg, purity 41%). 1H NMR (400 MHz, DMSO-d6) δ 7.20 - 7.07 (m, 1H), 2.96 (q, J = 6.0 Hz, 2H), 2.61 (ddd, J = 27.9, 7.3, 5.8 Hz, 2H), 2.12 - 2.00 (m, 2H).

[0303] Step 2: Preparation of 6,8-difluoro-5-amino-1,2,3,4-tetrahydronaphthyl-1-one (PY-Ac) 6,8-difluoro-5-nitro-1,2,3,4-tetrahydronaphthyl-1-one (800 mg) was mixed with ethanol (9 mL) and water (volume ratio 8:1) to which iron powder (894 mg, 8 eq) and ammonium chloride (321 mg, 3 eq) were added, respectively. The mixture was reacted at 80°C with stirring for 2 hours. After filtering the iron powder from the reaction solution, it was directly concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether 1:1) to obtain 6,8-difluoro-5-amino-1,2,3,4-tetrahydronaphthyl-1-one (PY-Ac) (176 mg, yield: 45%). LCMS (ESI): m / z, 198.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.03 (t, J = 11.4 Hz, 1H), 5.02 (s, 2H), 2.70 (t, J = 6.2 Hz, 2H), 2.08 (s, 1H), 2.00 (p, J = 6.4 Hz, 2H).

[0304] Step 3: Preparation of N-(2,4-difluoro-5-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-Ad) To a solution of 6,8-difluoro-5-amino-1,2,3,4-tetrahydronaphthyl-1-one (600 mg) in dichloromethane (25 mL), acetic anhydride (343 μL, 1.2 eq) and triethylamine (508 μL, 1.2 eq) were added, respectively, and the mixture was reacted at 60°C with stirring for 36 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1) to obtain N-(2,4-difluoro-5-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-Ad) (483 mg, yield: 66%, purity: 95%). LCMS (ESI): m / z, 240.1 [M+H] + .

[0305] Step 4: Preparation of N-(4-amino-2-fluoro-5-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-Ae) In a sealed tube, 1.43 g of N-(2,4-difluoro-5-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-Ad) was added to 30 mL of DMSO, 35 mL of aqueous ammonia was added, and the mixture was stirred at 100°C for 16 hours. 50 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1) to obtain N-(4-amino-2-fluoro-5-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-Ae) (1.01 g, yield: 72%, purity: 94%). LCMS (ESI): m / z, 237.2 [M+H] + .

[0306] Step 5: Preparation of (S)-N-(9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)acetamide (PY-Ag) To a solution of N-(4-amino-2-fluoro-5-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (1.01 g) in toluene (50 mL), compounds PY-8f (1.3 g, 1.2 eq) and PPTS (691 mg, 0.67 eq) were added, respectively, and the mixture was reacted at 130°C with stirring for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 10:1) to obtain compound PY-Ag (584 mg, yield: 30%, purity: >99%). LCMS (ESI): m / z, 464.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.80 (d, J = 11.0 Hz, 1H), 7.31 (s, 1H), 6.52 (s, 1H), 5.44 (s, 2H), 5.25 (s, 2H), 3.16 (t, J = 6.1 Hz, 2H), 2.98 (t, J = 6.0 Hz, 2H), 2.14 (s, 3H), 2.06 - 1.99 (m, 2H), 1.87 (p, J = 7.1 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0307] Procedure 6: Preparation of (S)-4-amino-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-10,13-dione (PY-A) To a solution of compound PY-Ag (78 mg) in ethanol (6 mL), 12N hydrochloric acid (6 mL) was added and the mixture was reacted at 60°C with stirring for 16 hours. The mixture was purified by preparative high-performance liquid chromatography (preparative chromatography manufacturer: SHIMADZU, model number LC-20AP. Column: YMC-Triart Prep C18 250 × 30 mm × 10 μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: elution from 21% to 51%), and then lyophilized to obtain compound PY-A (43.9 mg, yield: 61%, purity: 98%). LCMS (ESI): m / z, 422.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 12.5 Hz, 1H), 7.20 (s, 1H), 6.47 (s, 1H), 5.76 (s, 2H), 5.41 (s, 2H), 5.18 (s, 2H), 3.06 (t, J = 6.1 Hz, 2H), 2.84 (t, J = 6.1 Hz, 2H), 2.02 (t, J = 6.2 Hz, 2H), 1.86 (dq, J = 14.4, 7.0 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H); 19 F NMR (377 MHz, DMSO-d6) δ -125.24.

[0308] Preparation Example 44: Preparation of PY-UA and PY-UB TIFF2026510566000186.tif139150

[0309] Procedure 1: Preparation of (E)-N-(4-bromo-3-fluoro-7-(hydroxyimino)-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-Ua) At 0°C under a nitrogen atmosphere, tert-butoxide potassium (3.36g, 29.99mL, 29.99 mmol, 3eq, 1M present in THF) and tert-butyl nitrite (3.09g, 3.60mL, 29.99 mmol, 3eq) were added dropwise to a solution of N-(4-bromo-3-fluoro-8-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)acetamide (PY-8g) (3g, 10 mmol, 1eq) in anhydrous THF (150mL), and the mixture was reacted at 0-10°C for 1.5 hours. At 0°C, water (200 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound PY-Ua (3.20 g, crude product, yield: 48.63%, purity: 50%), which is a yellow solid crude product. LCMS (ESI): m / z, 329.0 [M+1] + .

[0310] Step 2: Preparation of compound N,N'-(4-bromo-3-fluoro-8-oxo-5,6,7,8-tetrahydronaphthyl-1,7-diyl)diacetylamide (PY-Ub) To a solution of compound PY-Ua (3.20 g, 50%, 4.86 mmol, 1 eq) in acetic acid (40 mL) and acetic anhydride (20 mL), zinc powder (4.77 g, 668.47 μL, 72.92 mmol, 15 eq) was added and the mixture was reacted at 15-20°C for 16 hours. The reaction solution was concentrated to remove the acetic acid, and the residue was poured into a mixed solution of ethyl acetate (50 mL) and water (50 mL). The mixed solution was stirred for 10 minutes, filtered through diatomaceous earth, and the filtrate was separated using a separatory funnel. The aqueous phase was extracted twice with ethyl acetate (50 mL x 2), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the yellow solid compound PY-Ub (1.15 g, yield: 55.63%, purity: 84%). LCMS (ESI): m / z, 357 [M+H] + , 359 [M+H] + .

[0311] Step 3: Preparation of N-(8-amino-5-bromo-6-fluoro-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)acetamide (PY-Uc) Compound PY-Ub (1.15 g, 84%, 2.70 mmol, 1 eq) was dissolved in ethanol (15 mL), and HCl (3.28 g, 15 mL, 90 mmol, 33.2776 eq, 6 M) was added. The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was concentrated, most of the solvent was removed, neutralized with sodium bicarbonate (30 mL), extracted with DCM (20 mL x 2), dried on the organic phase, filtered, concentrated under reduced pressure, and then used directly in the next step. The resulting product was a brownish solid (700 mg, yield: 68.99%). LCMS (ESI): m / z, 315.0 [M+H] + .

[0312] Step 4: Preparation of N-((9S)-4-bromo-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[d]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl)acetamide (PY-Ud) Compound PY-Uc (700 mg, 2.22 mmol, 1 eq) was dissolved in toluene (50 mL). (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione (PY-8f) (877.11 mg, 3.33 mmol, 1.5 eq) and PPTS (558.20 mg, 2.22 mmol, 1 eq) were added to the solution, and the solution was stirred at 125°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain a brown solid product (1 g, yield: 83.01%, purity: 75%). LCMS (ESI): m / z, 542.1 [M+H] + .

[0313] Step 5: Preparation of N-((9S)-9-ethyl-5-fluoro-9-hydroxy-4-(hydroxymethyl)-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[d]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-1-yl)acetamide (PY-Ue) Compound PY-Ud (300 mg, 75%, 414.85 μmol, 1 eq) was dissolved in dioxane (10 mL) solution, and (tributyltin)methanol (399.62 mg, 1.24 mmol, 3 eq) and XPhos Pd G2 (65.28 mg, 82.97 μmol, 0.2 eq) were added. After purging the reaction mixture with nitrogen gas, the mixture was stirred under a nitrogen atmosphere at 90°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain a white solid product (120 mg, yield: 58.6%). LCMS (ESI): m / z, 494.1 [M+H] + .

[0314] Step 6: Preparation of compounds PY-UA and PY-UB Compound PY-Ue (50 mg, 101.32 μmol, 1 eq) was dissolved in HCl (6N, 6 mL), DIPEA was added, and the reaction mixture was stirred at 85°C for 6 hours. The reaction mixture was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Oriendo, model R-120 g. Column: Phenomenex Luna C18 250 × 50 mm × 10 μm. Mobile phase: water (0.225% HCOOH)-acetonitrile, water elution ratio: eluted from 20% to 20%), yielding two white isomer solids, PY-UA (62 mg, yield: crude product yield not calculated) and PY-UB (16 mg, yield: 34.98%). LCMS (ESI): m / z, 452.2 [M+H] + .

[0315] Preparation Example 45: Preparation of (S)-7-ethyl-7-hydroxy-14-(3-hydroxypropyl)-10,13-dihydro-11H-[1,3]dioxol[4,5-g]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-8,11(7H)-dione (PY-Y) TIFF2026510566000187.tif3439 TIFF2026510566000188.tif74129

[0316] Procedure 1: Preparation of 6-aminobenzo[d][1,3]dioxol-5-carbaldehyde (PY-Y2) Iron powder (3.94 g, 70.47 mmol, 5.5 eq) and ammonium chloride (3.77 g, 70.47 mmol, 5.5 eq) were added to ethanol (30.0 mL) and water (3.00 mL). 6-nitrophenyl[d][1,3]oxol-5-carbaldehyde (2.50 g, 12.81 mmol, 1 eq) was added, and the reaction mixture was allowed to react at 80°C for 4 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in water and dichloromethane (100 mL). The organic phase was washed with saturated sodium bicarbonate (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (SiO2, DCM:MeOH=1:0, Rf (P) The compound was purified using a solution of 0.39 to obtain 6-aminobenzo[d][1,3]dioxol-5-carbaldehyde (1.27 g, yield: 59.83%). LCMS: RT = 0.996 min, MS(ESI) m / z = 166.1 [M+H] + .

[0317] Procedure 2: Preparation of (S)-7-ethyl-7-hydroxy-10,13-dihydro-11h-[1,3]dioxol[4,5-g]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-8,11(7H)-dione (PY-Y3) Compound PY-8f (2.00 g, 7.60 mmol, 1 eq) and 6-aminobenzo[d][1,3]dioxol-5-carbaldehyde (1.25 g, 7.60 mmol, 1 eq) were dissolved in toluene (160 ml), and p-toluenesulfonic acid monohydrate (144.52 mg, 759.75 μmol, 0.1 eq) was added. The reaction mixture was stirred at 125 °C for 16 hours, then cooled to 25 °C, filtered, and the filter cake was washed with tetrahydrofuran (10 mL) and dried under reduced pressure to obtain compound PY-Y3 (1.51 g, yield: 50.65%). LCMS: RT = 1. 271 min, MS(ESI) m / z = 393.2 [M+H] + .

[0318] Step 3: Preparation of (S)-7-ethyl-7-hydroxy-14-(3-hydroxypropyl)-10,13-dihydro-11H-[1,3]dioxol[4,5-g]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-8,11(7H)-dione (PY-Y) Compound PY-Y3 (400 mg, 795.19 μmol, 1 eq) and iron sulfate heptahydrate (353.72 mg, 1.27 mmol, 1.6 eq) were dissolved in water (10 mL), and 98% sulfuric acid (4.59 g, 46.83 mmol, 2.50 mL, 58.89 eq) was added while stirring. After stirring thoroughly for 10 minutes, 4-hydroxybutyraldehyde (343.3 mg, 3.90 mmol, 5 eq) was added dropwise at 0°C, and then hydrogen peroxide (1.26 g, 11.10 mmol, 1.07 mL, 30% purity, 13.96 eq) was added dropwise to water (20 mL), and the reaction mixture was stirred at 0-5°C for 1 hour. The reaction mixture was poured into ice water, adjusted to pH=8.0 with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL x 5), concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Xtimate C18 150 × 40 mm × 10 μm; mobile phase: [water (0.1% FA) - acetonitrile]; gradient: 10%-44% acetonitrile, 36 min) to obtain compound PY-Y (99.5 mg, 99.6% purity). LCMS: RT = 1. 890 min, MS(ESI) m / z = 451.3 [M+H] + . 1 HNMR (400MHz, DMSO-d 6) δ ppm 7.63 (s, 1 H), 7.50 (s, 1 H), 7.24 (s, 1 H), 6.50 (s, 1 H), 6.29 (s, 2 H), 5.42 (s, 2 H), 5.25 (s, 2 H), 4.68 (t, J = 5.2 Hz, 1 H), 3.49 (t, J = 5.6 Hz, 2 H), 3.15 (t, J = 6.8 Hz, 2 H), 2.53 (t, J = 1.6 Hz, 1 H), 2.33 (t, J = 1.6 Hz, 1 H), 1.81 - 1.88 (m, 2 H), 0.88 (t, J = 7.2 Hz, 3 H).

[0319] Preparation example 46:N 2 -(6-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)hexanoyl)-N 6 Preparation of -(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoyl)-L-lysine (A) TIFF2026510566000189.tif3850

[0320] Route 1: TIFF2026510566000190.tif65150

[0321] Step 1: N 2 -(benzyloxy)carbonyl)-N 6 Preparation of -(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoyl)-L-lysine (Ac) At room temperature, (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyrano-2-one (Aa) (1.27 g, 7.13 mmol) and ((benzyloxy)carbonyl)-L-lysine (Ab) (2 g, 7.13 mmol) were dissolved in methanol (30 mL), and triethylamine (1.44 g, 14.27 mmol) was added. The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was separated by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 45% to 85%) to obtain the white solid compound Ac (2.5g, yield 76.43%). LCMS: [M+H] + = 459.1.

[0322] Step 2: N 6 Preparation of -(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoyl)-L-lysine (Ad) At room temperature, compound N 2 -(benzyloxy)carbonyl)-N 6 -(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoyl)-L-lysine (Ac) (2.5 g, 5.45 mmol) was dissolved in methanol (40 mL), and 10% wet palladium carbon (250 mg) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 6 hours under a hydrogen gas atmosphere. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with water, and the filtrate was freeze-dried to obtain the white solid compound Ad (1.6 g, yield: 88.96%). LCMS: [M+H] + = 325.1. 1 1H NMR (400 MHz, DMSO-d 6) δ 4.16-4.19 (d, J = 9.4 Hz, 1H), 3.93-3.97 (t, J = 9.4 Hz, 1H), 3.72 - 3.50 (m, 5H), 3.10-3.20 (m, 2H), 1.68-1.79 (m, 2H), 1.40-1.55 (m, 2H), 1.20-1.35 (m, 2H).

[0323] Step 3: N 2 -(6-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)hexanoyl)-N 6 Preparation of -(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoyl)-L-lysine (A) At room temperature, compound N 6 -(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoyl)-L-lysine (Ad) (1.6 g, 4.93 mmol) was dissolved in N,N-dimethylformamide (30 mL), and 2,5-dioxopyrrolidine-1-yl-6-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)hexanoate (Ae) (1.52 g, 4.93 mmol) and DIEA (1.27 g, 9.87 mmol) were added, respectively. The reaction mixture was stirred at 70°C under a nitrogen atmosphere for 16 hours. The reaction mixture was filtered and separated by preparative high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% trifluoroacetic acid)-acetonitrile, eluting from 45% to 85%) to obtain white solid linker A (400 mg, yield: 15.67%). LCMS: [M+H] + = 517.9. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 6.97 (s, 2H), 5.32 (m, 1H), 4.59 - 4.30 (m, 2H), 4.17 - 3.99 (m, 1H), 3.96-3.91 (m, 1H), 3.89-3.81 (m, 1H), 3.57-3.5 (m, 1H), 3.48-3.39 (m, 2H), 3.34 (s, 4H), 3.12 - 2.89 (m, 2H), 2.05 (t, J = 6.4Hz,2H), 1.82 - 0.95 (m, 13H).

[0324] Route 2: TIFF2026510566000191.tif25145

[0325] Step 1: N 2 -(tert-butyloxycarbonyl)-N 6 Preparation of -(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoyl)-L-lysine (Ag) (tert-butyloxycarbonyl)-L-lysine (Af) (5g, 0.02mol) and (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyrano-2-one (Aa) (3.6g, 0.02mol) were dissolved in MeOH (80mL), TEA (4.1g, 0.04mol) was added, and the mixture was reacted at 70°C for 16 hours. The reaction mixture was concentrated, MTBE (50ml x 3) was added, and the mixture was concentrated under reduced pressure. The mixture was then slurryed with petroleum ether to obtain a crude product (8g), which was a white foamy crude product (the product is a salt of an acidic compound and TEA). The yield was not calculated. LCMS (ESI): m / z, 425.2[M+H] + , 447.2[M+Na] + . 1H NMR (400 MHz, DMSO) δ 7.50 (brs, 1H), 5.61 (d, J = 4.0 Hz, 1H), 4.27 (s, 1H), 4.13 (s, 1H), 4.10-3.85 (m,1H), 3.85-3.66 (m, 4H), 3.28-3.15 (m, 2H), 1.80-1.55 (m, 2H),1.55-1.48 (m, 2H), 1.50-1.21 (m, 11H).

[0326] Step 2: N 6 Preparation of -(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoyl)-L-lysine (Ad) N 2 -(tert-butyloxycarbonyl)-N 6 -(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoyl)-L-lysine (Ag) (7g) was dissolved in DCM (35mL), TFA (35mL) was added, and the mixture was reacted at 10-15°C for 16 hours. The reaction mixture was concentrated, DCM (50mL x 3) was added, and the mixture was concentrated under reduced pressure. Water was added to clarify the solution, and the mixture was freeze-dried to obtain the crude product (8g, 100%), which was a yellow, viscous substance. 1 H NMR (400 MHz, DMSO) δ 9.26 (s, 1H), 8.26 (d, J = 25.1 Hz, 3H), 7.69 (dd, J = 37.2, 31.4 Hz, 1H), 3.99 (d, J = 3.7 Hz, 1H), 3.94 - 3.84 (m, 2H), 3.58 (dd, J = 13.3, 3.7 Hz, 1H), 3.51 - 3.45 (m, 2H), 3.40-3.34 (m, 1H), 3.09 (qt, J = 15.7, 7.9 Hz, 2H), 1.84 - 1.67 (m, 2H), 1.60 - 1.27 (m, 4H), 1.18 (t, J = 7.3 Hz, 5H).

[0327] The rest of the procedure was the same as in route 1, and linker A was obtained.

[0328] Preparation Example 47: Preparation of the antibody tag 2-(2-aminoethoxy)-N-(3-azidopropyl)acetamide hydrochloride (TS-1) TIFF2026510566000192.tif1754 TIFF2026510566000193.tif20145

[0329] Step 1: Preparation of (2-(2-(3-azidopropyl)amino)-2-oxoethoxy)carbamate tert-butyl ester (TS-13) To a 4.5 mL solution of 2-(2-(tert-butyloxycarbonyl)amino)ethoxy)acetic acid (TS-12) (Haoyuan Pharmaceutical, 450.0 mg, 2.0 mmol, 1.0 eq) in dichloromethane, 3-azidopropylamine (205.4 mg, 2.0 mmol, 1.0 eq), DIEA (662.6 mg, 5.1 mmol, 2.5 eq), and T3P (2.3 g, 3.7 mmol, 1.8 eq) were sequentially added. After reacting at room temperature with stirring for 16 hours, the mixture was diluted with dichloromethane (30 mL), and the organic phase was washed with water (20 mL). The aqueous phase was extracted once with dichloromethane (30 mL), the organic phase was combined, and the mixture was washed with saturated saline solution (20 mL). The organic phase was dried, filtered, and concentrated. The residue was purified by silica gel column flash chromatography (eluent: ethyl acetate / n-hexane 1:20 to 1:1) to obtain a colorless oily compound TS-13,492 mg (yield 79%). LCMS (ESI): m / z, 302 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 6.84 (s, 1H), 4.88 (s, 1H), 3.95 (s, 2H), 3.56 (t, J = 5.2 Hz, 2H), 3.41 - 3.31 (m, 6H), 1.81 (q, J = 6.7 Hz, 2H), 1.44 (s, 9H).

[0330] Step 2: Preparation of 2-(2-aminoethoxy)-N-(3-azidopropyl)acetamide hydrochloride (TS-1) In a three-necked flask, the compound tert-butyl(2-(2-((3-azidopropyl)amino)-2-oxoethoxy)ethyl)carbamate (TS-13) (482.0 mg, 1.6 mmol, 1.0 eq) and methanol (5 mL) were added. At 0°C, a 1,4-dioxane solution in 6 M HCl (1.6 mL) was slowly added dropwise, and the temperature was reduced to below 5°C. The mixture was heated to room temperature and stirred for 16 hours, after which the reaction system was concentrated. The residue was purified by high-performance liquid chromatography (Oriendo, BRIX-2860; column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase: water (0.1% HCl)-acetonitrile, water elution ratio: elution from 55% to 85%), lyophilized, and a colorless oily compound TS-1, 94.8 mg (yield 24.7%) was obtained. LCMS (ESI): m / z, 202 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.67 - 1.72 (m, J=6.85 Hz, 2 H), 2.97 - 3.04 (m, J=5.30 Hz, 2 H), 3.15 - 3.20 (q, J=6.71 Hz, 2 H), 3.34- 3.37 (t, J=6.82 Hz, 2 H), 3.62 - 3.64 (t, J=5.00 Hz, 2 H), 3.91 (s, 2 H), 8.21 - 8.30 (m, 3 H).

[0331] Example 1: Preparation of compound LY-1 TIFF2026510566000194.tif140150

[0332] Procedure 1: Preparation of methyl-L-phenylalanylglycine tert-butyl ester (LY-1c) ((benzyloxy)carbonyl)-L-phenylalanine (LY-1a) (3.0 g, 10.0 mmol) was dissolved in DMF (50 mL), and glycine tert-butyl hydrochloride (1.9 g, 10.1 mmol), HOBt (0.68 g, 5.0 mmol), EDCI (2.3 g, 12.0 mmol), and DIPEA (3.87 g, 30.0 mmol) were added sequentially. The mixture was stirred under a nitrogen atmosphere at room temperature for 18 hours. The mixture was diluted with water (80 mL), extracted twice with DCM (100 mL), the organic phases were combined, washed with saturated saline, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane 1:20~1:5) to obtain compound LY-1c (3.5 g, yield 85%), a colorless oil.

[0333] Step 2: Preparation of L-phenylalanylglycine tert-butyl ester (LY-1d) Methyl-L-phenylalanylglycine tert-butyl ester (LY-1c) (3.0 g, 7.3 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added at 0°C. The mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. It was concentrated under reduced pressure. The product was used directly in the next step without purification. A pale yellow solid was obtained.

[0334] Step 3: Preparation of ((9H-fluoren-9-yl)methoxy)carbonyl)glycyl-L-phenylalanylglycine (LY-1f) L-phenylalanylglycine tert-butyl ester (LY-1d) (1.39 g, 5 mmol) and LY-1e (1.49 g, 5 mmol) were dissolved in DMF (50 mL), and HOBt (0.68 g, 5.0 mmol), EDCI (1.9 g, 10.0 mmol), and DIPEA (3.87 g, 30.0 mmol) were added sequentially. The mixture was stirred under a nitrogen atmosphere at room temperature for 18 hours. The pH was adjusted to 1-2 with dilute hydrochloric acid (30 mL), and the mixture was extracted twice with DCM (100 mL). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane 1:20 to 1:5) to obtain compound LY-1f (3.1 g, yield 84%, 2 steps), a white solid. LCMS (ESI): m / z, 502.4 [M+H] + .

[0335] Step 4: Preparation of (9H-fluoren-9-yl)methyl-(2-(1-(2-(4-(hydroxymethyl)phenyl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropane-2-yl)amino)-2-oxoethyl)carbamate (LY-1g) The compound ((9H-fluoren-9-yl)methoxy)carbonyl)glycyl-L-phenylalanylglycine (2.5 g, 5 mmol) was dissolved in DMF (20 mL), and HATU (2.3 g, 6.0 mmol), DIPEA (1.9 g, 15.0 mmol), and 4-aminobenzyl alcohol (0.74 g, 6 mmol) were added sequentially. The mixture was stirred under a nitrogen atmosphere at room temperature for 10 hours. The mixture was diluted with water (50 mL), extracted twice with DCM (100 mL), the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane 1:20 to 1:5) to obtain compound LY-1 g (2.8 g, yield 92%), a white solid. LCMS (ESI): m / z, 607.2 [M+H] + .

[0336] Step 5: Preparation of (9H-fluoren-9-yl)methyl-(2-(1-(2-(4-(4-(nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropane-2-yl)amino)-2-oxoethyl)carbamate (LY-1h) (9H-fluoren-9-yl)methyl-(2-(1-(2-(4-(hydroxymethyl)phenyl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropane-2-yl)amino)-2-oxoethyl)carbamate (LY-1g) (2.0g, 3.3 mmol) and bis(4-nitrophenyl) carbonate (2g, 6.6 mmol) were dissolved in DMF (20 mL), and DIPEA (0.43 g, 3.3 mmol) was added. The mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The mixture was diluted with water (30 mL), extracted twice by DCM, the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane 1:20 to 1:5) to obtain compound LY-1h (0.92 g, yield 36%), a white solid.

[0337] Step 6: Preparation of compounds (LY-1i) and (LY-1j) (9H-fluoren-9-yl)methyl-(2-(1-(2-(4-(4-(nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropane-2-yl)amino)-2-oxoethyl)carbamate (LY-1h) (397 mg, 0.54 mmol) and exatecan mesylate (300 mg, 0.56 mmol) were dissolved in DMF (2 mL), and HOBt (73 mg, 0.54 mmol), pyridine (425 mg, 5.38 mmol), and DIPEA (208 mg, 1.61 mmol) were added. The mixture was stirred overnight at room temperature to obtain LY-1i. NMM (109 mg, 1.08 mmol) was added and the mixture was stirred for 8 hours at room temperature. The reaction mixture was separated by preparative HPLC (column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: water (0.225% HCOOH)-acetonitrile, eluting from 45% to 85%) to obtain compound LY-1j (123 mg, yield 21%), a white solid. LCMS (ESI): m / z, 1068.5 [M+H] + .

[0338] Step 7: Preparation of compound (LY-1) To a solution of Linker A (11.2 mg, 0.022 mmol, 1.2 eq) in anhydrous tetrahydrofuran (7 mL), HATU (10.3 mg, 0.027 mmol, 1.5 eq), DIPEA (7.0 mg, 0.054 mmol, 3.0 eq), and LY-1j (15 mg, 0.018 mmol, 1 eq) were sequentially added. The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was separated and purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase: water (0.225% HCOOH)-acetonitrile, eluting from 45% to 85%), and lyophilized to obtain the yellow solid target compound LY-1 (9.4 mg, yield 38%). LCMS (ESI): m / z, 1345.6 [M+H] + , 673.5 [1 / 2M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.40 (s, 1H), 8.10 (dd, J = 20.8, 8.0 Hz, 3H), 7.94 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 10.8 Hz, 1H), 7.66 - 7.53 (m, 3H), 7.37 (d, J = 8.2 Hz, 2H), 7.31 (s, 1H), 7.27 - 7.22 (m, 3H), 7.18 (t, J = 4.4 Hz, 1H), 6.98 (d, J = 2.2 Hz, 2H), 6.53 (s, 1H), 5.44 (s, 2H), 5.35 (s, 1H), 5.29 (s, 3H), 5.08 (s, 2H), 4.50 (dd, J = 13.6, 8.4 Hz, 5H), 4.18 - 4.07 (m, 1H), 3.96 (s, 1H), 3.93 - 3.83 (m, 3H), 3.72 (s, 1H), 3.64 - 3.51 (m, 2H), 3.46 (s, 2H), 3.23 (s, 4H), 3.05 (dt, J = 15.2, 7.2 Hz, 5H), 2.90 - 2.77 (m, 2H), 2.38 (d, J = 1.9 Hz, 3H), 2.25 - 2.01 (m, 5H), 1.92 - 1.82 (m, 2H), 1.58 (s, 2H), 1.49 - 1.33 (m, 6H), 1.26 - 1.10 (m, 4H), 0.87 (t, J = 7.3 Hz, 3H).

[0339] Example 2: Preparation of compound LY-2 TIFF2026510566000195.tif3497 TIFF2026510566000196.tif154144

[0340] Procedure 1: Preparation of ((9H-fluoren-9-yl)methoxy)carbonyl)glycyl-L-pentanoyl-L-alanine tert-butyl ester (LY-2b) (((9H-fluoren-9-yl)methoxy)carbonyl)glycyl-L-valine (LY-2a) (8g, 20.2 mmol) and tert-butylaminoacetate (3.66g, 20.2 mmol) were added to a 250 mL three-necked flask, DMF (80 mL) was added, and DIEA (7.8 g, 60.6 mmol) was added dropwise under a nitrogen atmosphere, and the mixture was stirred for 5 minutes. Then, a solution of HATU (9.2 g, 24.2 mmol) in DMF (30 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was slowly poured into water (800 mL), stirred for 30 minutes, filtered, and the solid was dissolved in DCM (200 mL). After washing once with water, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily substance (9.5 g, yield: 90%). 1 H NMR (400 MHz, DMSO) δ 8.32 (d, J = 6.7 Hz, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 7.3 Hz, 3H), 7.51 (t, J = 6.0 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 4.19 (m , 5H), 3.66 (d, J = 5.1 Hz, 2H), 1.95 (m, 1H), 1.37 (s, 9H), 1.23 (d, J = 7.2 Hz, 3H), 0.85 (dd, J = 18.7, 6.8 Hz, 6H).

[0341] Step 2: Preparation of ((9H-fluoren-9-yl)methoxy)carbonyl)glycyl-L-valyl-L-alanine (LY-2c) ((9H-fluoren-9-yl)methoxy)carbonyl)glycyl-L-pentanoyl-L-alanine tert-butyl ester (LY-2b) (6g, 11.47 mmol) was dissolved in DCM (30 mL), and TFA (20 mL) was added dropwise under a nitrogen atmosphere. The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated to a small volume, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and impurities were extracted by adding DCM (100 mL). The pH was then adjusted to 1-2 with 1N HCl, and the mixture was extracted with EA (200 mL x 2). The organic phase was washed with water (100 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid (4.8 g, yield: 89%). 1 H NMR (400 MHz, DMSO) δ 7.88 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 7.4 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.3 Hz, 2H), 4.21 (m, 5H), 3.65 (s, 2H), 1.92 (m, 1H), 1.26 (d, J = 7.3 Hz, 3H), 0.84 (dd, J = 20.8, 6.7 Hz, 6H).

[0342] Step 3: Preparation of (9H-fluoren-9-yl)methyl(2-((S)-1-((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-2-oxoethyl)carbamate (LY-2d) ((9H-fluoren-9-yl)methoxy)carbonyl)glycyl-L-valyl-L-alanine (LY-2c) (2.5 g, 5.35 mmol) and aminobenzyl alcohol (645 mg, 5.24 mmol) were added to a reaction flask, dissolved in DMF (25 mL), and under a nitrogen atmosphere, 2,6-dimethylpyridine (1.72 g, 16 mmol) was added, followed by stirring for 5 minutes. A solution of HATU (2.44 g, 6.4 mmol) in DMF (8 mL) was added dropwise, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was poured into water (200 mL), extracted with EA (200 mL x 2), the organic phase was washed with dilute hydrochloric acid, the organic phase was washed with sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid (2.4 g, yield: 80%). 1 H NMR (400 MHz, DMSO) δ 7.90 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 4.48 - 4.35 (m, 3H), 4.25 (dd, J = 21.4, 6.6 Hz, 4H), 3.70 (d, J = 2.4 Hz, 2H), 2.00 - 1.95 (m, 1H), 1.33 (d, J = 7.1 Hz, 3H), 0.87 (dd, J = 19.4, 6.8 Hz, 6H). ...

Claims

1. A compound represented by general formula (A) or a pharmaceutically acceptable salt thereof, Here, Dr is selected from the following structures: R 1 is hydrogen, halogen, hydroxy group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, -NR d R e , -(CH 2 ) m -OH, -(CH 2 ) m -NR d R e , -OC(=O)NR f -(CH 2 ) m -OH, -OC(=O)NR f -(CH 2 ) m -NR d R e , -(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)-NR d R e , -(CH 2 ) m -C(=O)NR f -(CH 2 ) n -OH, -(CH 2 ) m -C(=O)NR f -(CH 2 ) n -NR d R e , -NR f -(CH 2 ) m -OH, -NR f -(CH 2 ) m -NR d R e , -O-(CH 2 ) m -OH, -O-(CH 2 ) m -NR d R e , -NR f C(=O)O-(CH 2 ) m -OH, -NR b C(=O)O-(CH 2 ) m -NR d R e 、 -(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -OH-、 -(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -NR d R e 、 -(CH 2 ) m -OC(=O)NR f -(CH 2 ) n -NR d R e 、 -(CH 2 ) m -OC(=O)NR f -(CH 2 ) n -OH、 -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -NR d R e 、 -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH、 -(CH 2 ) m -NR f C(=O)-G-(CH 2 ) n -OH selected from, the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group may be optionally further substituted by a group selected from any one or more of halogen, deuterium, amino group, alkyl group, hydroxy group, the -(CH 2 )[[ID=]] m - may be optionally substituted by one or more deuterium or halogen, G is selected from a cycloalkylene group, heterocyclylene group, heteroarylene group, arylene group, R 2 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally substituted with one or more groups further selected from halogens. R 3 These include hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, and CH 2 =, -NR d R e ,-(CH 2 ) m -OH, -(CH 2 ) m -NR d R e , -OC(=O)NR f - (CH 2 ) m -OH, -OC(=O)NR f - (CH 2 ) m -NR d R e ,-(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)-NR d R e ,-(CH 2 ) m -C(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -C(=O)NR f - (CH 2 ) n -NR d R e , -NR f - (CH 2 ) m -OH, -NR f - (CH 2 ) m -NR d R e , -NR f -C(=O)R d , -NR f -C(=O)-(CH 2 ) m -R d , -NR f C(=O)O-(CH 2 ) m -R d , -O-(CH 2 ) m -OH、-O-(CH 2 ) m -NR d R e 、-NR f C(=O)O-(CH 2 ) m -OH、-NR f C(=O)NR d -(CH 2 ) m -OH、-NR f C(=O)NR d -(CH 2 ) m -O-(CH 2 ) n -OH、-NR f C(=O)O-(CH 2 ) m -O-(CH 2 ) n -OH、-NR f C(=O)NR d -(CH 2 ) m -O-(CH 2 ) n -NR d R e 、-NR f C(=O)O-(CH 2 ) m -O-(CH 2 ) n -NR d R e 、-NR f C(=O)NR d -(CH 2 ) m -NR d R e 、-NR f C(=O)O-(CH 2 ) m -NR d R e 、-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -OH、-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -NR d R e ,-(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally further substituted with one or more groups selected from halogen, deuterium, amino group, alkyl group, and hydroxyl group. R 4 hydrogen, halogen, hydroxyl group, carboxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, -NR d R e ,-(CH 2 ) m -OH, -(CH 2 ) m -NR d R e , -OC(=O)NR f - (CH 2 ) m -OH, -OC(=O)NR f - (CH 2 ) m -NR d R e ,-(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)-NR d R e ,-(CH 2 ) m -C(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -C(=O)NR f - (CH 2 ) n -NR d R e , -NR f - (CH 2 ) m -OH, -NR f - (CH 2 ) m -NR d R e , -O-(CH 2 ) m -OH, -O-(CH 2 ) m -NR d R e , -NR f C(=O)O-(CH 2 ) m -OH, -NR b C(=O)O-(CH 2 ) m -NR d R e ,-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -OH-, -(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -NR d R e ,-(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-G-(CH 2 ) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, alkynyl group, and cycloalkyl group are optionally further substituted with one or more groups selected from halogen, deuterium, amino group, alkyl group, and hydroxyl group, and the -(CH 2 ) m - is optionally substituted with one or more deuterium or halogens, and G is selected from a cycloalkylene group, a heterocyclylene group, a heteroarylene group, and an arylene group. R 5 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally substituted with one or more groups further selected from halogens. R 6 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally substituted with one or more groups further selected from halogens. R 7 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally substituted with one or more groups further selected from halogens. R d and R e Each is independently selected from hydrogen and alkyl groups. R f is hydrogen, alkyl group, -C(O)R c , -S(O)R c , -S(O) 2 R c Selected from, the alkyl group is optionally further substituted with a cycloalkyl group, where R c It is selected from hydrogen, hydroxyl group, and alkyl group. L 1 is a bond, -(CH 2 ) m -, -O-, -NR a -, -(CH 2 ) m -O-, -(CH 2 ) m -NR a -, -OC(=O)NR b -(CH 2 ) m -O-, -OC(=O)NR b -(CH 2 ) m -NR a -, -(CH 2 ) m -C(=O)O-, -(CH 2 ) m -C(=O)NR a -, -(CH 2 )[[ID=第45行]] m -C(=O)NR b -(CH 2 ) n -O-, -(CH 2 ) m -C(=O)NR b -(CH 2 ) n -NR a -, -NR b -(CH 2 ) m -O-, -NR b -(CH 2 ) m -NR a -, -O-(CH 2 ) m -O-, -O-(CH 2 ) m -NR a -, -NR b C(=O)O-(CH 2 ) m -O-, -NR b C(=O)O-(CH 2 ) m -NR a -, -(CH 2 ) m -NR b C(=O)O-(CH 2 ) n -O-*, -(CH 2 ) m -NR b C(=O)O-(CH 2 ) n -NR a -*, -(CH 2 ) m -OC(=O)NR b - (CH 2 ) n -NR a -*, -(CH 2 ) m -OC(=O)NR b - (CH 2 ) n -O-*, -(CH 2 ) m -NR b C(=O)-(CH 2 ) n -NR a -*, -(CH 2 ) m -NR b C(=O)-(CH 2 ) n -O-* is selected, where * is L 2 This is the connection point to, R a and R b These are, independently, hydrogen, alkyl group, and -C(O)R. c , -S(O)R c , -S(O) 2 R c Selected from, the alkyl group is optionally further substituted with a cycloalkyl group, where R c It is selected from hydrogen, hydroxyl group, and alkyl group. L 2 is to combine, Selected from, where * is L 1 This is the connection point to, L is And, L 3 is an amino acid residue formed from two or more amino acids, and L 3 The structure is optionally selected from one or more of the following structures, L 6 It is selected from one or more of the following structures: Here, R, R aa , R bb Each is independently selected from hydrogen and alkyl groups. L 4 teeth And, Z 1 is selected from a bond, -(CH 2 ), p -(C 2 H 4 O), q -(CH 2 ), p -C(O)NH-, -(CH 2 ), p -O-(CH 2 ), p -C(O)NH-, -(CH 2 ), p -C(O)-L 6 -NH-, -(CH 2 ), p -O-(CH 2 ), p -C(O)-L 6 -NH-, -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, -NH-, -O- and -OC(O)NH- m is an integer from 1 to 6. n is an integer between 1 and 6. s is an integer from 1 to 6. t is an integer between 0 and 10. s 1 s 2 s 3 s 4 Each of these is an integer between 0 and 10, s 5 s 6 Each of these is an integer from 1 to 6, t 1 These are integers from 1 to 6, t 2 is an integer from 0 to 6, t 3 These are integers from 1 to 6, t 4 is an integer between 0 and 10, t 5 is an integer between 0 and 10, p is an integer between 1 and 10. q is an integer between 1 and 10. Q is the linker unit.

2. A compound represented by the general formula (A) described in claim 1 or a pharmaceutically acceptable salt thereof, wherein Dr is selected from the following structures: L 1 is -O-*, -NR a -*, -(CH 2 ) m -O-*, -(CH 2 ) m -NR a -*, -OC(=O)NR b - (CH 2 ) m -O-*, -OC(=O)NR b - (CH 2 ) m -NR a -*, -(CH 2 ) m -C(=O)O-*, -(CH 2 ) m -C(=O)NR a -*, -NR b - (CH 2 ) m -O-*, -NR b - (CH 2 ) m -NR a -*, -O-(CH 2 ) m -O-*, -O-(CH 2 ) m -NR a -*, -NR b C(=O)O-(CH 2 ) m -O-*, -NR b C(=O)O-(CH 2 ) m -NR a -*, -(CH 2 ) m -NR b C(=O)-(CH 2 ) n -NR a -*, -(CH 2 ) m -NR b C(=O)-(CH 2 ) n -O-* is selected, where * is L 2 This is the connection point to, R a is hydrogen, C 1 -C 6 Selected from alkyl groups, R b is hydrogen, alkyl group, -C(O)R c , -S(O)R c , -S(O) 2 R c Selected from, the alkyl group is optionally further substituted with a cycloalkyl group, where R c is hydrogen, hydroxyl group, C 1 -C 6 Selected from alkyl groups, m is an integer from 1 to 6, preferably an integer from 1 to 4, and particularly preferably an integer from 1 to 2. n is an integer from 1 to 6, preferably an integer from 1 to 4, and particularly preferably an integer from 1 to 2. R 1 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 6 Cycloalkyl groups, -NR d R e ,-(CH 2 ) m -OH, -(CH 2 ) m -NR d R e , -OC(=O)NR f - (CH 2 ) m -OH, -OC(=O)NR f - (CH 2 ) m -NR d R e ,-(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)-NR d R e ,-(CH 2 ) m -C(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -C(=O)NR f - (CH 2 ) n -NR d R e , -NR f - (CH 2 ) m -OH, -NR f - (CH 2 ) m -NR d R e , -O-(CH 2 ) m -OH, -O-(CH 2 ) m -NR d R e , -NR f C(=O)O-(CH 2 ) m -OH, -NR b C(=O)O-(CH 2 ) m -NR d R e ,-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -OH-, -(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -NR d R e ,-(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-G-(CH 2 ) n - Selected from OH, the C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 6 Cycloalkyl groups can optionally be further enriched with halogens, deuterium, amino groups, and C 1 -C 6 It is substituted with one or more groups selected from alkyl groups and hydroxyl groups, preferably C 1 -C 6 Alkyl alkyl group, C 1 -C 6 It is an alkoxy group, and the -(CH 2 ) m - is optionally substituted with one or more deuterium or halogens, and G is selected from a cycloalkylene group, a heterocyclylene group, a heteroarylene group, and an arylene group. R 2 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 Selected from the alkynyl group, the C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 The alkynyl group is optionally substituted with one or more groups further selected from halogens, preferably halogens. R d , R e , R f m and n are as defined in claim 1.

3. A compound represented by the general formula (A) described in claim 1 or a pharmaceutically acceptable salt thereof, wherein Dr is selected from the following structures: L 1 The bond is -(CH 2 ) m -*, -O-*, -(CH 2 ) m -O-*, -NR a -*, -(CH 2 ) m -NR a -*, -NR b - (CH 2 ) m -O-*, -NR b - (CH 2 ) m -NR a -*, -O-(CH 2 ) m -O-*, -O-(CH 2 ) m -NR a -*, -(CH 2 ) m -OC(=O)NR b - (CH 2 ) n -NR a -*, -(CH 2 ) m -OC(=O)NR b - (CH 2 ) n -O-*, -(CH 2 ) m -NR b C(=O)-(CH 2 ) n -NR a -*, -(CH 2 ) m -NR b C(=O)-(CH 2 ) n -O-* is selected, where * is L 2 This is the connection point to, R a is hydrogen, C 1 -C 6 Selected from alkyl groups, R b is hydrogen, alkyl group, -C(O)R c , -S(O)R c , -S(O) 2 R c Selected from, the alkyl group is optionally further substituted with a cycloalkyl group, where R c is hydrogen, hydroxyl group, C 1 -C 6 Selected from alkyl groups, m is an integer from 1 to 6, preferably an integer from 1 to 4. n is an integer from 1 to 6, preferably an integer from 1 to 4. R 2 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 Selected from the alkynyl group, the C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 The alkynyl group is optionally substituted with one or more groups further selected from halogens, preferably halogens.

4. A compound represented by the general formula (A) described in claim 1 or a pharmaceutically acceptable salt thereof, wherein Dr is selected from the following structures: L 1 is selected from -O-*, where * is L 2 This is the connection point to, R 2 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 Selected from the alkynyl group, the C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 The alkynyl group is optionally substituted with one or more groups further selected from halogens, preferably halogens. R 3 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, CH 2 =, -NR d R e ,-(CH 2 ) m -OH, -(CH 2 ) m -NR d R e , -OC(=O)NR f - (CH 2 ) m -OH, -OC(=O)NR f - (CH 2 ) m -NR d R e ,-(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)-NR d R e ,-(CH 2 ) m -C(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -C(=O)NR f - (CH 2 ) n -NR d R e , -NR f - (CH 2 ) m -OH, -NR f - (CH 2 ) m -NR d R e , -NR f -C(=O)R d , -NR f -C(=O)-(CH 2 ) m -R d 、-NR f C(=O)O-(CH 2 ) m -R d 、-O-(CH 2 ) m -OH、-O-(CH 2 ) m -NR d R e 、-NR f C(=O)O-(CH 2 ) m -OH、-NR f C(=O)NR d -(CH 2 ) m -OH、-NR f C(=O)NR d -(CH 2 ) m -O-(CH 2 ) n -OH、-NR f C(=O)O-(CH 2 ) m -O-(CH 2 ) n -OH、-NR f C(=O)NR d -(CH 2 ) m -O-(CH 2 ) n -NR d R e 、-NR f C(=O)O-(CH 2 ) m -O-(CH 2 ) n -NR d R e 、-NR f C(=O)NR d -(CH 2 ) m -NR d R e 、-NR f C(=O)O-(CH 2 ) m -NR d R e 、-(CH 2 ) m -NR f C(=O)O-(CH 2 ), n -OH, -(CH 2 ), m -NR f C(=O)O-(CH 2 ), n -NR d R e , -(CH 2 ), m -OC(=O)NR f -(CH 2 ), n -NR d R e , -(CH 2 ), m -OC(=O)NR f -(CH 2 ), n -OH, -(CH 2 ), m -NR f C(=O)-(CH 2 ), n -NR d R e , -(CH 2 ), m -NR[[ID=6S]] f C(=O)-(CH 2 ), n -OH selected from, the C 1 -C 6 alkyl group, C<00009X>-C 6 alkoxy group, C<D000T34>-C 6 alkenyl group, C 2 -C 6 alkynyl group is optionally further substituted by one or more groups selected from halogen, deuterium, amino group, C 1 -C 6 alkyl group, hydroxy group, preferably hydrogen or hydroxy group, R 4 is hydrogen, halogen, hydroxy group, carboxy group, amino group, cyano group, C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, C 3 -C 6 cycloalkyl group, -NR d R e [[ID=2​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ m -NR d R e , -NR f C(=O)O-(CH 2 ) m -OH, -NR b C(=O)O-(CH 2 ) m -NR d R e ,-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -OH-, -(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -NR d R e ,-(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-G-(CH 2 ) n - Selected from OH, the C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 6 Cycloalkyl groups can optionally be further enriched with halogens, deuterium, amino groups, and C 1 -C 6 Substituted with one or more groups selected from alkyl groups and hydroxyl groups, preferably a hydroxyl group, C 1 -C 6 Alkyl alkyl group, C 1 -C 6 It is an alkoxy group, and the -(CH 2 ) m - is optionally substituted with one or more deuterium or halogens, and G is selected from a cycloalkylene group, a heterocyclylene group, a heteroarylene group, and an arylene group. R d , R e , R f m and n are as defined in claim 1.

5. A compound represented by the general formula (A) described in claim 1 or a pharmaceutically acceptable salt thereof, wherein Dr is selected from the following structures: L 1 is, -(CH 2 ) m -O-*, -(CH 2 ) m -NR a - Selected from *, where * is L 2 This is the connection point to, m is an integer from 1 to 6, preferably an integer from 1 to 4. R a is hydrogen, C 1 -C 6 Selected from alkyl groups, R 5 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 Selected from the alkynyl group, the C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 The alkynyl group is optionally substituted with one or more groups further selected from halogens, preferably halogens. R 7 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 Selected from the alkynyl group, the C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 The alkynyl group is optionally further substituted with one or more groups selected from halogens, preferably a hydroxyl group or an amino group.

6. A compound represented by the general formula (A) described in claim 1 or a pharmaceutically acceptable salt thereof, wherein Dr is selected from the following structures: L 1 is selected from -O-*, where * is L 2 This is the connection point to, R 5 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 Selected from the alkynyl group, the C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 The alkynyl group is optionally substituted with one or more groups further selected from halogens, preferably halogens. R 6 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 Selected from the alkynyl group, the C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 The alkynyl group is optionally further substituted with one or more groups selected from halogens, preferably a hydroxyl group or an amino group. R 7 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 Selected from the alkynyl group, the C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 2 -C 6 Alkenyl group, C 2 -C 6 The alkynyl group is optionally further substituted with one or more groups selected from halogens, preferably a hydroxyl group or an amino group.

7. A compound represented by general formula (A) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Dr is They are selected from among them.

8. A compound represented by general formula (A) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein L 1 -NR a -*, -(CH 2 ) m -NR a -*, -OC(=O)NR b - (CH 2 ) m -NR a -*, -(CH 2 ) m -C(=O)NR a -*, -(CH 2 ) m -C(=O)NR b - (CH 2 ) n -NR a -*, -NR b - (CH 2 ) m -NR a -*, -O-(CH 2 ) m -NR a -*, -NR b C(=O)O-(CH 2 ) m -NR a -*, -(CH 2 ) m -NR b C(=O)O-(CH 2 ) n -NR a -*, -(CH 2 ) m -OC(=O)NR b - (CH 2 ) n -NR a - * or - (CH 2 ) m -NR b C(=O)-(CH 2 ) n -NR a - Selected from *, where * is L 2 If it is a connection point to, L 2 is, combine or Selected from, where * is L 1 This is the connection point to, R a , R b m and n are as defined in any one of claims 1 to 7.

9. A compound represented by general formula (A) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein L 1 The bond is -O-*, -(CH 2 ) m -O-*, -NR a -*, -OC(=O)NR b - (CH 2 ) m -O-*, -(CH 2 ) m -C(=O)O-*, -(CH 2 ) m -C(=O)NR b - (CH 2 ) n -O-*, -NR b - (CH 2 ) m -O-*, -O-(CH 2 ) m -O-*, -NR b C(=O)O-(CH 2 ) m -O-*, -(CH 2 ) m -NR b C(=O)O-(CH 2 ) n -O-*, -(CH 2 ) m -OC(=O)NR b - (CH 2 ) n -O-* or -(CH 2 ) m -NR b C(=O)-(CH 2 ) n -O-* is selected, where * is L 2 If it is a connection point to, L 2 is to combine, Selected from, where * is L 1 This is the connection point to, R a , R b m and n are as defined in any one of claims 1 to 7.

10. A compound represented by general formula (A) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein L 3 L is an amino acid residue formed from two or more amino acids selected from phenylalanine, alanine, glycine, valine, leucine, isoleucine, tryptophan, tyrosine, histidine, lysine, citrulline, serine, threonine, cysteine, glutamic acid, glutamine, aspartic acid, asparagine, methionine, and arginine, and L 3 It optionally includes one or more structures selected from the following: And, Here, R, R aa , R bb These are, independently, hydrogen and C 1 -C 6 Selected from alkyl groups, s is an integer between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. s 5 s 6 Each of these is an integer from 1 to 6, preferably from 2 to 6, and particularly preferably from 2 to 4. t is an integer between 0 and 10. t 1 is an integer from 1 to 6, preferably an integer from 1 to 4, also preferably an integer from 2 to 4, and also preferably 1 or 2. t 2 is an integer from 0 to 6, preferably an integer from 1 to 4, and also preferably 1 or 2. t 3 is an integer from 1 to 6, preferably an integer from 1 to 4, and particularly preferably 1 or 2. t 4 is an integer between 0 and 10, t 5 This is an integer between 0 and 10.

11. A compound represented by general formula (A) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein L 3 teeth, And * is L 2 This is a linking site to a carbonyl group or a methylene group. Here, L 1b and L' 1b Each of these is an amino acid residue formed independently from one or more amino acids selected from phenylalanine, alanine, glycine, valine, leucine, isoleucine, tryptophan, tyrosine, histidine, lysine, citrulline, serine, threonine, cysteine, glutamic acid, glutamine, aspartic acid, asparagine, methionine, and arginine. L 1a This is selected from a combination or one or more of the following structures: Here, R is hydrogen and C 1 -C 6 Selected from alkyl groups, preferably hydrogen, R aa , R bb Each of them is independent of C 1 -C 6 Selected from alkyl groups, s is an integer between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. s 5 s 6 Each of these is an integer from 1 to 6, preferably from 2 to 6, and particularly preferably from 2 to 4. t is an integer between 0 and 10. t 1 is an integer from 1 to 6, preferably an integer from 1 to 4, also preferably an integer from 2 to 4, and also preferably 1 or 2. t 2 is an integer from 0 to 6, preferably an integer from 1 to 4, and also preferably 1 or 2. t 3 is an integer from 1 to 6, preferably an integer from 1 to 4, and particularly preferably 1 or 2. t 4 is an integer between 0 and 10, t 5 This is an integer between 0 and 10.

12. A compound represented by general formula (A) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein L 3 teeth, Selected from, Here, L 1b and L' 1b These are amino acid residues formed from one or more amino acids selected from phenylalanine, alanine, glycine, valine, leucine, isoleucine, tryptophan, tyrosine, histidine, lysine, citrulline, serine, threonine, cysteine, glutamic acid, glutamine, aspartic acid, asparagine, methionine, and arginine, respectively. R is hydrogen and C 1 -C 6 Selected from alkyl groups, preferably hydrogen, R aa , R bb Each of them is independent of C 1 -C 6 Selected from alkyl groups, s is an integer between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. s 5 s 6 Each of these is an integer from 1 to 6, preferably from 2 to 6, and particularly preferably from 2 to 4. t is an integer between 0 and 10. t 1 is an integer from 1 to 6, preferably an integer from 1 to 4, also preferably an integer from 2 to 4, and also preferably 1 or 2. t 2 is an integer from 0 to 6, preferably an integer from 1 to 4, and also preferably 1 or 2. t 3 is an integer from 1 to 6, preferably an integer from 1 to 4, and particularly preferably 1 or 2. t 4 is an integer between 0 and 10, t 5 is an integer between 0 and 10, * is L 2 This is the connection point to, This is a linking site to a carbonyl group or a methylene group.

13. A compound represented by general formula (A) according to claim 11 or 12, or a pharmaceutically acceptable salt thereof, wherein L 1b and L' 1b Each of these is an amino acid residue formed from one or more amino acids selected from glycine, phenylalanine, citrulline, leucine, isoleucine, alanine, valine, asparagine, glutamine, arginine, glutamic acid, and lysine, and is preferably an amino acid residue formed from two or more amino acids selected from glycine, phenylalanine, citrulline, valine, lysine, glutamine, glutamic acid, aspartic acid, leucine, and alanine.

14. A compound represented by general formula (A) according to any one of claims 11 to 13 or a pharmaceutically acceptable salt thereof, wherein L 1b and L' 1b is, independently of each other, -Gly-*, -Val-*, -Gly-Phe-Gly-*, -Phe-Gly-*, -Gly-Val-Cit-*, -Val-Cit-*, -Gly-Val-Arg-*, -Val-Arg-*, -Gly-Val-Ala-*, -Val-Ala-*, -Gly-Phe-*, -Phe-Gly-*, -Gly-Gly-Gly-*, Gly-Gly-*, -Gly-Val-Gly-*, -Gly-Ala-Gly-*, -Gly-Phe-Cit-*, -Gly-Phe-Val-*, -Gly-Phe-Ala-*, -Gly-Phe-Lys-*, -Phe-Lys-*, -Gly-Val-*, -Gly-Cit-*, -Gly-Ala-*, -Gly-Gly-Lys-*, Gly-Lys’-*, -Ala-Ala-Ala-*, -Gln-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, -Asp-Val-Cit-*, -Lys-Gly-Val-Ala-*, -Lys-Gly-Val-Cit-*, -Lys-Gly-Gly-Val-Ala-*, -Lys-Gly-Gly-Val-Cit-*, Gly-Gly-Phe-Gly-*, -Lys-Gln-Val-Cit-*, -Lys-Gln-Val-Ala-*, -Lys-Glu-Val-Cit-*, -Lys-Glu-Val-ALA-*, -Lys-Asp-Val-Cit-*, -Lys-Asp-Val-Ala-*, Glu-Val-Cit-*, Glu-Val-Ala-*, -Lys-Val-Ala-*, -Lys-Val-Cit-*, -Val-Lys-Gly-*, -Val-Lys-* selected from, preferably, -Gly-Phe-Gly-*, -Gly-Val-Cit-*, -Val-Cit-*, -Gly-Val-Ala-*, -Val-Ala-*, -Gly-Phe-Gly-*, -Phe-Gly-*, -Gly-Phe-Lys-, -Phe-Lys-*, -Gln-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, -Lys-Gly-Val-Ala-*, -Lys-Gly-Val-Cit-*, -Lys-Gly-Gly-Val-Ala-*, -Lys-Gly-Gly-Val-Cit-*, Gly-Gly-Phe-Gly-*,-Lys-Gln-Val-Cit-*, -Lys-Gln-Val-Ala-*, -Lys-Glu-Val-Cit-*, -Lys-Glu-Val-ALa-*, -Lys-Asp-Val-Cit-*, -Lys-Asp-Val-Ala-* , Glu-Val-Cit-*, Glu-Val-Ala-*, -Lys-Val-Ala-*, -Lys-Val-Cit-*, -Val-Lys-Gly-*, -Val-Lys-*, -Asp-Val-Cit-*, where * is L, 2 This is the connection point.

15. A compound represented by general formula (A) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein L 3 teeth, Selected from, R aa and R bb Each of them is independent of C 1 -C 6 Selected from alkyl groups, * is L 2 This is the connection point to, This is a linking site to a carbonyl group or a methylene group.

16. A compound represented by general formula (A) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein Q is Selected from, preferably, They are selected from among them.

17. A compound represented by general formula (A) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein Z 1 The bond is -(CH 2 ) p -, - (CH 2 ) p -C(O)NH-, -(CH 2 ) p -O-(CH 2 ) p -C(O)NH-, -(CH 2 ) p -C(O)-L 6 -NH-, -(CH 2 ) p -O-(CH 2 ) p -C(O)-L 6 -NH-, -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, and -OC(O)NH-, where p is an integer from 1 to 10, preferably an integer from 1 to 6. s 1 s 2 s 3 s 4 Each of these is an integer between 0 and 10, preferably between 0 and 6, more preferably between 0 and 4, and particularly preferably between 0 and 2. L 6 teeth, Selected from, s is an integer between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. t is an integer between 0 and 10. Preferably, L 6 teeth, That is the case.

18. A compound represented by general formula (A) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z 1 The bond is -(CH 2 ) p -, - (CH 2 ) p -C(O)NH-, -(CH 2 ) p -O-(CH 2 ) p Selected from -C(O)NH-, -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, and -OC(O)NH-, s 1 is an integer between 0 and 6, preferably an integer between 0 and 2. s 2 is an integer between 0 and 6, preferably an integer between 0 and 2. s 3 It is 0, s 4 It is 0, p is an integer between 1 and 10, preferably an integer between 1 and 6.

19. A compound represented by general formula (A) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z 1 is, -(CH 2 ) p -C(O)NH-, -(CH 2 ) p -O-(CH 2 ) p -C(O)NH-, -C(O)NH- s 1 is an integer between 1 and 6, preferably an integer between 2 and 6. s 2 is an integer between 1 and 10, preferably an integer between 2 and 10. s 3 It is 0, s 4 It is 0, p is an integer between 1 and 10, preferably an integer between 1 and 6.

20. A compound represented by general formula (A) according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein Q-L 4 -teeth, Selected from, Here, Z 1 is selected from -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, and -OC(O)NH-, preferably -C(O)NH-, p is an integer between 1 and 10, preferably an integer between 1 and 6. s 1 is an integer between 0 and 6, preferably an integer between 0 and 2. s 2 is an integer between 1 and 10, preferably an integer between 1 and 8. s 3 is an integer between 0 and 6, preferably an integer between 0 and 2. s 4 is an integer between 1 and 6, preferably an integer between 1 and 2. s 7 is an integer from 0 to 6, preferably an integer from 1 to 2. s 8 is an integer between 1 and 4, preferably an integer between 1 and 2. s 9 is an integer between 1 and 10, preferably an integer between 1 and 8. s 10 is an integer between 1 and 4, preferably an integer between 1 and 2.

21. A compound represented by general formula (A) according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein the compound is They are selected from among them.

22. A compound represented by general formula (I) or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, Here, R 8 The group is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally further substituted with one or more groups selected from halogens, preferably halogens. R 9 This includes hydrogen, halogen, hydroxyl group, carboxyl group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, -NR d R e ,-(CH 2 ) m -OH, -(CH 2 ) m -NR d R e , -OC(=O)NR f - (CH 2 ) m -OH, -OC(=O)NR f - (CH 2 ) m -NR d R e ,-(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)-NR d R e ,-(CH 2 ) m -C(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -C(=O)NR f - (CH 2 ) n -NR d R e , -NR f - (CH 2 ) m -OH, -NR f - (CH 2 ) m -NR d R e , -O-(CH 2 ) m -OH, -O-(CH 2 ) m -NR d R e , -NR f C(=O)O-(CH 2 ) m -OH, -NR b C(=O)O-(CH 2 ) m -NR d R e ,-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -NR d R e ,-(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-G-(CH 2 ) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, alkynyl group, and cycloalkyl group are optionally further substituted with one or more groups selected from deuterium, halogen, amino group, alkyl group, and hydroxyl group, preferably a hydroxyl group and C 1 -C 6 Alkyl alkyl group, C 1 -C 6 Alkoxy group, C 3 -C 6 Cycloalkyl groups, -NR d R e ,-(CH 2 ) m -OH, -(CH 2 ) m -NR d R e ,-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -OH, -(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH, -O-(CH 2 ) m -NR d R e , -O-(CH 2 ) m -OH, -(CH 2 ) m -NR f C(=O)-G-(CH 2 ) n -OH and the aforementioned -(CH 2 ) m - is optionally substituted with one or more deuterium or halogens, G is selected from cycloalkylene groups, heterocyclylene groups, heteroarylene groups, and arylene groups. R 10 These include hydrogen, halogen, hydroxyl group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, and CH 2 =, -NR d R e ,-(CH 2 ) m -OH, -(CH 2 ) m -NR d R e , -OC(=O)NR f - (CH 2 ) m -OH, -OC(=O)NR f - (CH 2 ) m -NR d R e ,-(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)-NR d R e ,-(CH 2 ) m -C(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -C(=O)NR f - (CH 2 ) n -NR d R e , -NR f - (CH 2 ) m -OH, -NR f - (CH 2 ) m -NR d R e , -NR f -C(=O)R d , -NR f -C(=O)-(CH 2 ) m -R d , -NR f C(=O)O-(CH 2 ) m -R d , -O-(CH 2 ) m -OH、-O-(CH 2 ) m -NR d R e 、-NR f C(=O)O-(CH 2 ) m -OH、-NR f C(=O)NR d -(CH 2 ) m -OH、-NR f C(=O)NR d -(CH 2 ) m -O-(CH 2 ) n -OH、-NR f C(=O)O-(CH 2 ) m -O-(CH 2 ) n -OH、-NR f C(=O)NR d -(CH 2 ) m -O-(CH 2 ) n -NR d R e 、-NR f C(=O)O-(CH 2 ) m -O-(CH 2 ) n -NR d R e 、-NR f C(=O)NR d -(CH 2 ) m -NR d R e 、-NR f C(=O)O-(CH 2 ) m -NR d R e 、-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -OH、-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -NR d R e ,-(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, or alkynyl group is optionally further substituted with one or more groups selected from halogens, preferably hydrogen, hydroxyl group, amino group, -(CH 2 ) m -OH, -OC(=O)NR f - (CH 2 ) m -OH, -(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)NR f - (CH 2 ) n -OH, -NR f - (CH 2 ) m -OH, -NR f -C(=O)R d , -NR f -C(=O)-(CH 2 ) m -R d , -NR f C(=O)O-(CH 2 ) m -R d , -NR f C(=O)O-(CH 2 ) m -OH, -NR f C(=O)NR d -(CH 2 ) m -OH, -NR f C(=O)NR d -(CH 2 ) m -O-(CH 2 ) n -OH, -NR f C(=O)O-(CH 2 ) m -O-(CH 2 ) n -OH, -NR f C(=O)NR d -(CH 2 ) m -O-(CH 2 ) n -NR d R e 、-NR f C(=O)O-(CH 2 ) m -O-(CH 2 ) n -NR d R e 、-NR f C(=O)NR d -(CH 2 ) m -NR d R e 、-NR f C(=O)O-(CH 2 ) m -NR d R e and R d and R e These are, independently, hydrogen and C 1 -C 6 Selected from alkyl groups, R f is hydrogen, C 1 -C 6 Alkyl alkyl group, -C(O)R c , -S(O)R c , -S(O) 2 R c Selected from, the above C 1 -C 6 Alkyl alkyl groups can be further selected from C 3 -C 6 Substituted by a cycloalkyl group, where R c is hydrogen, hydroxyl group, C 1 -C 6 Selected from alkyl groups, m is an integer from 1 to 6. n is an integer between 1 and 6.

23. A compound represented by the general formula (I) described in claim 22, or its stereoisomer, tautomer, endo compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically usable salt thereof, Here, R 9 is hydrogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, hydroxyl group, carboxyl group, -NR d R e ,-(CH 2 ) m -OH, -(CH 2 ) m -NR d R e ,-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -OH, -(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH, -O-(CH 2 ) m -NR d R e , -O-(CH 2 ) m - Selected from OH, R d and R e These are, independently, hydrogen and C 1 -C 6 Selected from alkyl groups, R f is hydrogen, C 1 -C 6 Selected from alkyl groups, m is an integer from 1 to 6. n is an integer between 1 and 4, preferably 1 or 2.

24. A compound represented by general formula (I) as described in claim 22 or 23, or its stereoisomer, tautomer, endo compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically usable salt thereof, Here, R 10 is hydrogen, hydroxyl group, amino group, CH 2 =, -(CH 2 ) m -OH, -OC(=O)NR f - (CH 2 ) m -OH, -(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)NR f - (CH 2 ) n -OH, -NR f - (CH 2 ) m -OH, -NR f -C(=O)R d , -NR f -C(=O)-(CH 2 ) m -R d , -NR f C(=O)O-(CH 2 ) m -R d , -NR f -C(=O)-(CH 2 ) m -OH, -NR f C(=O)O-(CH 2 ) m - Selected from OH, R d and R e These are, independently, hydrogen and C 1 -C 6 Selected from alkyl groups, R f is hydrogen, C 1 -C 6 Alkyl alkyl group, -C(O)R c , -S(O)R c , -S(O) 2 R c Selected from, the above C 1 -C 6 Alkyl alkyl groups can be further selected from C 3 -C 6 Substituted by a cycloalkyl group, where R c is hydrogen, hydroxyl group, C 1 -C 6 Selected from alkyl groups, m is an integer between 1 and 6, preferably between 1 and 4 or between 4 and 6. n is an integer between 1 and 4, preferably 1 or 2.

25. A compound represented by general formula (I) as described in any one of claims 22 to 24, or a stereoisomer, tautomer, endo compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically usable salt thereof, Here, R 8 It is selected from halogens.

26. A compound represented by general formula (I) as described in any one of claims 22 to 25, selected from the above, or a stereoisomer, tautomer, endo compound, racemic compound, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically usable salt thereof.

27. A compound represented by general formula (II) or its stereoisomers, tautomers, endo compounds, racemic compounds, enantiomers, diastereomers or mixtures thereof, or pharmaceutically usable salts thereof, Here, R 11 The group is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally substituted with one or more groups further selected from halogens, preferably halogens and cyano groups. R 12 hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, -NR d R e ,-(CH 2 ) m -OH, -(CH 2 ) m -NR d R e , -OC(=O)NR f - (CH 2 ) m -OH, -OC(=O)NR f - (CH 2 ) m -NR d R e ,-(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)-NR d R e ,-(CH 2 ) m -C(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -C(=O)NR f - (CH 2 ) n -NR d R e , -NR f - (CH 2 ) m -OH, -NR f - (CH 2 ) m -NR d R e , -O-(CH 2 ) m -OH, -O-(CH 2 ) m -NR d R e , -NR f C(=O)O-(CH 2 ) m -OH, -NR b C(=O)O-(CH 2 ) m -NR a -*, -(CH 2 ) m -NR b C(=O)O-(CH 2 ) n -O-*, -(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -NR d R e ,-(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, or alkynyl group is optionally further substituted with one or more groups selected from halogens, preferably a hydroxyl group, an amino group, or C 1 -C 6 Alkyl alkyl group, -(CH 2 ) m -OH, -(CH 2 ) m -NR d R e And, R 13 hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, -NR d R e ,-(CH 2 ) m -OH, -(CH 2 ) m -NR d R e , -OC(=O)NR f - (CH 2 ) m -OH, -OC(=O)NR f - (CH 2 ) m -NR d R e ,-(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)-NR d R e ,-(CH 2 ) m -C(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -C(=O)NR f - (CH 2 ) n -NR d R e , -NR f - (CH 2 ) m -OH, -NR f - (CH 2 ) m -NR d R e , -O-(CH 2 ) m -OH, -O-(CH 2 ) m -NR d R e , -NR f C(=O)O-(CH 2 ) m -OH, -NR b C(=O)O-(CH 2 ) m -NR a -*, -(CH 2 ) m -NR b C(=O)O-(CH 2 ) n -O-*, -(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -NR d R e ,-(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, or alkynyl group is optionally further substituted with one or more groups selected from halogens, preferably a hydroxyl group or an amino group. R d and R e These are, independently, hydrogen and C 1 -C 6 Selected from alkyl groups, R f is hydrogen, C 1 -C 6 Alkyl alkyl group, -C(O)R c , -S(O)R c , -S(O) 2 R c Selected from, here, R c is hydrogen, hydroxyl group, C 1 -C 6 Selected from alkyl groups, m is an integer from 1 to 6. n is an integer between 1 and 6.

28. A compound represented by the general formula (II) described in claim 27, or its stereoisomer, tautomer, endo compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically usable salt thereof, wherein R 11 The group is selected from halogens and cyano groups.

29. A compound represented by the general formula (II) described in claim 27, or its stereoisomer, tautomer, endo compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically usable salt thereof, wherein R 12 C 1 -C 6 Alkyl alkyl group, -(CH 2 ) m -OH, -(CH 2 ) m -NR d R e Selected from, R d and R e These are, independently, hydrogen and C 1 -C 6 Selected from alkyl groups, m is an integer between 1 and 6.

30. A compound represented by the general formula (II) described in claim 27, or its stereoisomer, tautomer, endo compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically usable salt thereof, wherein R 13 C is a hydroxyl group. 1-6 Selected from alkoxy groups.

31. A compound represented by general formula (II) as described in any one of claims 27 to 30, selected from

31. , or a stereoisomer, tautomer, endo compound, racemic compound, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically usable salt thereof.

32. A ligand-drug conjugate represented by general formula (B) or a pharmaceutically acceptable salt thereof, Here, Dr is selected from the following structures: R 1 hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, -NR d R e ,-(CH 2 ) m -OH, -(CH 2 ) m -NR d R e , -OC(=O)NR f - (CH 2 ) m -OH, -OC(=O)NR f - (CH 2 ) m -NR d R e ,-(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)-NR d R e ,-(CH 2 ) m -C(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -C(=O)NR f - (CH 2 ) n -NR d R e , -NR f - (CH 2 ) m -OH, -NR f - (CH 2 ) m -NR d R e , -O-(CH 2 ) m -OH, -O-(CH 2 ) m -NR d R e , -NR f C(=O)O-(CH 2 ) m -OH, -NR b C(=O)O-(CH 2 ) m -NR d R e ,-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -OH-, -(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -NR d R e ,-(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-G-(CH 2 ) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group is optionally further substituted with a group selected from one or more halogens, deuterium, amino groups, alkyl groups, and hydroxyl groups, and the -(CH 2 ) m - is optionally substituted with one or more deuterium or halogens, and G is selected from a cycloalkylene group, a heterocyclylene group, a heteroarylene group, and an arylene group. R 2 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally substituted with one or more groups further selected from halogens. R 3 These include hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, and CH 2 =, -NR d R e ,-(CH 2 ) m -OH, -(CH 2 ) m -NR d R e , -OC(=O)NR f - (CH 2 ) m -OH, -OC(=O)NR f - (CH 2 ) m -NR d R e ,-(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)-NR d R e ,-(CH 2 ) m -C(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -C(=O)NR f - (CH 2 ) n -NR d R e , -NR f - (CH 2 ) m -OH, -NR f - (CH 2 ) m -NR d R e , -NR f -C(=O)R d , -NR f -C(=O)-(CH 2 ) m -R d , -NR f C(=O)O-(CH 2 ) m -R d , -O-(CH 2 ) m -OH、-O-(CH 2 ) m -NR d R e 、-NR f C(=O)O-(CH 2 ) m -OH、-NR f C(=O)NR d -(CH 2 ) m -OH、-NR f C(=O)NR d -(CH 2 ) m -O-(CH 2 ) n -OH、-NR f C(=O)O-(CH 2 ) m -O-(CH 2 ) n -OH、-NR f C(=O)NR d -(CH 2 ) m -O-(CH 2 ) n -NR d R e 、-NR f C(=O)O-(CH 2 ) m -O-(CH 2 ) n -NR d R e 、-NR f C(=O)NR d -(CH 2 ) m -NR d R e 、-NR f C(=O)O-(CH 2 ) m -NR d R e 、-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -OH、-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -NR d R e ,-(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally further substituted with one or more groups selected from halogen, deuterium, amino group, alkyl group, and hydroxyl group. R 4 hydrogen, halogen, hydroxyl group, carboxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, -NR d R e ,-(CH 2 ) m -OH, -(CH 2 ) m -NR d R e , -OC(=O)NR f - (CH 2 ) m -OH, -OC(=O)NR f - (CH 2 ) m -NR d R e ,-(CH 2 ) m -C(=O)OH, -(CH 2 ) m -C(=O)-NR d R e ,-(CH 2 ) m -C(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -C(=O)NR f - (CH 2 ) n -NR d R e , -NR f - (CH 2 ) m -OH, -NR f - (CH 2 ) m -NR d R e , -O-(CH 2 ) m -OH, -O-(CH 2 ) m -NR d R e , -NR f C(=O)O-(CH 2 ) m -OH, -NR b C(=O)O-(CH 2 ) m -NR d R e ,-(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -OH-, -(CH 2 ) m -NR f C(=O)O-(CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -NR d R e ,-(CH 2 ) m -OC(=O)NR f - (CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-(CH 2 ) n -NR d R e ,-(CH 2 ) m -NR f C(=O)-(CH 2 ) n -OH, -(CH 2 ) m -NR f C(=O)-G-(CH 2 ) n -OH is selected, and the alkyl group, alkoxy group, alkenyl group, alkynyl group, and cycloalkyl group are optionally further substituted with one or more groups selected from halogen, deuterium, amino group, alkyl group, and hydroxyl group, and the -(CH 2 ) m - is optionally substituted with one or more deuterium or halogens, and G is selected from a cycloalkylene group, a heterocyclylene group, a heteroarylene group, and an arylene group. R 5 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally substituted with one or more groups further selected from halogens. R 6 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally substituted with one or more groups further selected from halogens. R 7 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, alkyl group, alkoxy group, alkenyl group, and alkynyl group, and the alkyl group, alkoxy group, alkenyl group, and alkynyl group are optionally substituted with one or more groups further selected from halogens. R d and R e Each is independently selected from hydrogen and alkyl groups. R f is hydrogen, alkyl group, -C(O)R c , -S(O)R c , -S(O) 2 R c Selected from, the alkyl group is optionally further C 3 -C 6 Substituted by a cycloalkyl group, where R c It is selected from hydrogen, hydroxyl group, and alkyl group. L 1 is a bond, -(CH 2 ) m -, -O-, -NR a -, -(CH 2 ) m -O-, -(CH 2 ) m -NR a -, -OC(=O)NR b -(CH 2 ) m -O-, -OC(=O)NR b -(CH 2 ) m -NR a -, -(CH 2 ) m -C(=O)O-, -(CH 2 ) m -C(=O)NR a -, -(CH 2 ) m -C(=O)NR b -(CH 2 ) n -O-, -(CH 2 ) m -C(=O)NR b -(CH 2 ) n -NR a -, -NR b -(CH 2 ) m -O-, -NR b -(CH 2 ) m -NR a -, -O-(CH 2 ) m -O-, -O-(CH 2 ) m -NR a -, -NR b C(=O)O-(CH 2 ) m -O-, -NR b C(=O)O-(CH 2 ) m -NR a -, -(CH 2 ) m -NR b C(=O)O-(CH​​​-O-*, -(CH 2 ) m -NR b C(=O)O-(CH 2 ) n -NR a -*, -(CH 2 ) m -OC(=O)NR b - (CH 2 ) n -NR a -*, -(CH 2 ) m -OC(=O)NR b - (CH 2 ) n -O-*, -(CH 2 ) m -NR b C(=O)-(CH 2 ) n -NR a -*, -(CH 2 ) m -NR b C(=O)-(CH 2 ) n -O-* is selected, where * is L 2 This is the connection point to, R a and R b These are, independently, hydrogen, alkyl group, and -C(O)R. c , -S(O)R c , -S(O) 2 R c Selected from, the alkyl group is optionally further substituted with a cycloalkyl group, where R c It is selected from hydrogen, hydroxyl group, and alkyl group. L 2 is to combine, Selected from, where * is L 1 This is the connection point to, L' is, And, Q' is, Selected from, Here, * is L 4 This is the connection point to, This is the connection point to PC, L 3 is an amino acid residue formed from two or more amino acids, and L 3 The structure is optionally selected from one or more of the following structures, L 6 It is selected from one or more of the following structures: Here, R, R aa , R bb Each is independently selected from hydrogen and alkyl groups. L 4 teeth, And, Z 1 is selected from bonding, -(CH 2 ), p -(C 2 H 4 O)-, q -(CH 2 ), p -C(O)NH-, -(CH 2 ), p -O-(CH 2 ), p -C(O)NH-, -(CH 2 ), p -C(O)-L 6 -NH-, -(CH 2 ), p -O-(CH 2 ), p -C(O)-L 6 -NH-, -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, -NH-, -O- and -OC(O)NH-. m is an integer from 1 to 6. n is an integer from 1 to 6. s is an integer from 1 to 6. t is an integer between 0 and 10. s 1 s 2 s 3 s 4 Each of these is an integer between 0 and 10, s 5 s 6 Each of these is an integer from 1 to 6, t 1 These are integers from 1 to 6, t 2 is an integer from 0 to 6, t 3 These are integers from 1 to 6, t 4 is an integer between 0 and 10, t 5 is an integer between 0 and 10, p is an integer between 1 and 10. q is an integer between 1 and 10. v is between 1 and 10, and v can be a decimal or an integer. Pc is an antibody or its antigen-binding fragment, or a modified antibody. The modified antibody is Pc'-((L 5 ) w -F) x It has a structure, and here, Pc' is an antibody, L 5 It is a linker, w is either 0 or 1, F is a click probe or sulfhydryl group or its precursor that can bind to Q' after a reaction such as a metal-free click reaction, and preferably F is an azide group. x is an integer between 1 and 8.

33. A ligand-drug complex represented by general formula (B) as described in claim 32, or a pharmaceutically acceptable salt thereof, wherein L 3 teeth, Selected from, R is hydrogen and C 1 -C 6 Selected from alkyl groups, preferably hydrogen, R aa , R bb Each of them is independent of C 1 -C 6 Selected from alkyl groups, s is an integer between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. s 5 s 6 Each of these is an integer from 1 to 6, preferably from 2 to 6, and particularly preferably from 2 to 4. t is an integer between 0 and 10. t 1 is an integer from 1 to 6, preferably an integer from 1 to 4, also preferably an integer from 2 to 4, and also preferably 1 or 2. t 2 is an integer from 0 to 6, preferably an integer from 1 to 4, and also preferably 1 or 2. t 3 is an integer from 1 to 6, preferably an integer from 1 to 4, and particularly preferably 1 or 2. t 4 is an integer between 0 and 10, t 5 is an integer between 0 and 10, * is L 2 This is the connection point to, This is a linking site to a carbonyl group or a methylene group. L 1b and L' 1b Each of these is an amino acid residue formed from one or more amino acids selected from glycine, phenylalanine, citrulline, leucine, isoleucine, alanine, valine, asparagine, glutamine, arginine, glutamic acid, and lysine, and preferably an amino acid residue formed from two or more amino acids selected from glycine, phenylalanine, citrulline, valine, lysine, glutamine, glutamic acid, leucine, and alanine. Preferably, L 1b and L' 1b is, independently of each other, -Gly-*, -Val-*, -Gly-Phe-Gly-*, -Phe-Gly-*, -Gly-Val-Cit-*, -Val-Cit-*, -Gly-Val-Arg-*, -Val-Arg-*, -Gly-Val-Ala-*, -Val-Ala-*, -Gly-Phe-*, -Phe-Gly-*, -Gly-Gly-Gly-*, Gly-Gly-*, -Gly-Val-Gly-*, -Gly-Ala-Gly-*, -Gly-Phe-Cit-*, -Gly-Phe-Val-*, -Gly-Phe-Ala-*, -Gly-Phe-Lys-*, -Phe-Lys-*, -Gly-Val-*, -Gly-Cit-*, -Gly-Ala-*, -Gly-Gly-Lys-*, Gly-Lys’-*, -Ala-Ala-Ala-*, -Gln-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, -Asp-Val-Cit-*, -Lys-Gly-Val-Ala-*, -Lys-Gly-Val-Cit-*, -Lys-Gly-Gly-Val-Ala-*, -Lys-Gly-Gly-Val-Cit-*, Gly-Gly-Phe-Gly-*, -Lys-Gln-Val-Cit-*, -Lys-Gln-Val-Ala-*, -Lys-Glu-Val-Cit-*, -Lys-Glu-Val-ALA-*, -Lys-Asp-Val-Cit-*, -Lys-Asp-Val-Ala-*, Glu-Val-Cit-*, Glu-Val-Ala-*, -Lys-Val-Ala-*, -Lys-Val-Cit-*, -Val-Lys-Gly-*, -Val-Lys-* selected from, preferably, -Gly-Phe-Gly-*, -Gly-Val-Cit-*, -Val-Cit-*, -Gly-Val-Ala-*, -Val-Ala-*, -Gly-Phe-Gly-*, -Phe-Gly-*, -Gly-Phe-Lys-, -Phe-Lys-*, -Gln-Val-Ala-*, -Gln-Val-Cit-*, -Asp-Val-Ala-*, -Lys-Gly-Val-Ala-*, -Lys-Gly-Val-Cit-*, -Lys-Gly-Gly-Val-Ala-*, -Lys-Gly-Gly-Val-Cit-*, Gly-Gly-Phe-Gly-*,-Lys-Gln-Val-Cit-*, -Lys-Gln-Val-Ala-*, -Lys-Glu-Val-Cit-*, -Lys-Glu-Val-ALa-*, -Lys-Asp-Val-Cit-*, -Lys-Asp-Val-Ala-* , Glu-Val-Cit-*, Glu-Val-Ala-*, -Lys-Val-Ala-*, -Lys-Val-Cit-*, -Val-Lys-Gly-*, -Val-Lys-*, -Asp-Val-Cit-*, where * is L, 2 This is the connection point.

34. A ligand-drug complex represented by general formula (B) as described in claim 32, or a pharmaceutically acceptable salt thereof, wherein L' is, And, Q' is, Selected from, Here, * is L 4 This is the connection point to, This is the connection point to PC, L 3 This is an amino acid residue formed from two or more amino acids selected from glycine, phenylalanine, citrulline, leucine, isoleucine, alanine, valine, asparagine, glutamine, arginine, glutamic acid, and lysine, and preferably an amino acid residue formed from two or more amino acids selected from glycine, phenylalanine, citrulline, valine, lysine, glutamine, glutamic acid, leucine, and alanine. L 4 teeth, And, Z 1 The bond is -(CH 2 ) p -, - (CH 2 ) p -C(O)NH-, -(CH 2 ) p -O-(CH 2 ) p -C(O)NH-, -(CH 2 ) p -C(O)-L 6 -NH-, -(CH 2 ) p -O-(CH 2 ) p -C(O)-L 6 Selected from -NH-, -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, -NH-, -O-, and -OC(O)NH-, s 1 is an integer between 1 and 6, preferably an integer between 2 and 6. s 2 is an integer between 1 and 10, preferably an integer between 2 and 10. s 3 It is 0, s 4 It is 0, p is an integer between 1 and 10, preferably an integer between 1 and 6. L 6 teeth, Selected from, s is an integer between 1 and 6, preferably between 2 and 6, and particularly preferably between 2 and 4. t is an integer between 0 and 10. Preferably, L 6 teeth, That is the case.

35. A ligand-drug complex represented by general formula (B) according to any one of claims 32 to 34 or a pharmaceutically acceptable salt thereof, wherein L 5 teeth, And, Z 2 and Z 3 Each of these is independently selected from -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, -NH-, -O-, and -OC(O)NH-, preferably -C(O)NH-, r 1 is an integer from 1 to 8, preferably an integer from 1 to 6, and particularly preferably an integer from 1 to 3. r 2 is an integer from 1 to 6, preferably an integer from 1 to 4, and particularly preferably an integer from 1 to 2. r 3 is an integer between 0 and 6, preferably between 0 and 4, and particularly preferably between 0 and 2. r 4 is an integer between 0 and 6, preferably between 0 and 4, and particularly preferably between 0 and 2. r 5 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably between 1 and 2.

36. A ligand-drug complex represented by general formula (B) as described in any one of claims 32 to 35, or a pharmaceutically acceptable salt thereof, wherein when w is 0, F is a sulfhydryl group, and when w is 1, F is a click probe that can bind to Q' after a reaction such as a metal-free click reaction, preferably F is an azide group.

37. A ligand-drug complex represented by general formula (B) according to any one of claims 32 to 36, or a pharmaceutically acceptable salt thereof, wherein Pc is a modified antibody, and the modified antibody has the following structure: Here, Pc' is an antibody, Z 2 and Z 3 Each of these is independently selected from -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, -NH-, -O-, and -OC(O)NH-, preferably -C(O)NH-, r 1 is an integer from 1 to 8, preferably an integer from 1 to 6, and particularly preferably an integer from 1 to 3. r 2 is an integer from 1 to 6, preferably an integer from 1 to 4, and particularly preferably an integer from 1 to 2. r 3 is an integer between 0 and 6, preferably between 0 and 4, and particularly preferably between 0 and 2. r 4 is an integer between 0 and 6, preferably between 0 and 4, and particularly preferably between 0 and 2. r 5 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably between 1 and 2.

38. A ligand-drug conjugate represented by general formula (B) according to any one of claims 32 to 37 or a pharmaceutically acceptable salt thereof, wherein Pc is a modified antibody and Pc-Q' is Selected from the structure, Pc' is an antibody, Z 2 and Z 3 Each of these is independently selected from -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, -NH-, -O-, and -OC(O)NH-, preferably -C(O)NH-, r 1 is an integer from 1 to 8, preferably an integer from 1 to 6, and particularly preferably an integer from 1 to 3. r 2 is an integer from 1 to 6, preferably an integer from 1 to 4, and particularly preferably an integer from 1 to 2. r 3 is an integer between 0 and 6, preferably between 0 and 4, and particularly preferably between 0 and 2. r 4 is an integer between 0 and 6, preferably between 0 and 4, and particularly preferably between 0 and 2. r 5 is an integer between 1 and 6, preferably between 1 and 4, and particularly preferably between 1 and 2.

39. A ligand-drug complex represented by general formula (B) according to any one of claims 32 to 38, selected from the above, or a pharmaceutically acceptable salt thereof, Here, v is between 1 and 10, and v can be a decimal or an integer. Pc is an antibody or its antigen-binding fragment, Pc' is an antibody.

40. A ligand-drug conjugate represented by general formula (B) as described in any one of claims 32 to 39, or a pharmaceutically acceptable salt thereof, wherein the antibody is selected from mouse antibodies, chimeric antibodies, humanized antibodies and fully human antibodies, and preferably the antibody or its antigen-binding fragment is an anti-HER2 (ErbB2) antibody, an anti-EGFR antibody, an anti-B7-H3 antibody, an anti-c-Met antibody, an anti-HER3 (ErbB3) antibody, an anti-HER4 (ErbB4) antibody, an anti-ROR1 antibody, an anti-CLDN6 antibody, Anti-CLDN9 antibody, anti-CLDN18.2 antibody, anti-NaPi-2b antibody, anti-TNF-α antibody, anti-ENPP3 antibody, anti-DLL3 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD28 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD37 antibody, anti-C D38 antibody, anti-CD44 antibody, anti-CD45 antibody, anti-CD47 antibody, anti-CD48 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD98 antibody, anti-CD105 antibody, anti-CEA antibody, anti-EphA2 antibody, anti-MUCI antibody, anti-Lewis Selected from Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-CD79 antibody, anti-TROP-2 antibody, anti-CD79B antibody, anti-Mesothelin antibody, anti-Nectin-4 antibody, anti-TPBG antibody, or its antigen-binding fragment.

41. A ligand-drug conjugate represented by general formula (B) according to any one of claims 32 to 40 or a pharmaceutically acceptable salt thereof, wherein the antibody or antigen-binding fragment is selected from trastuzumab, cetuximab, pertuzumab, nimotuzumab, enoblituzumab, emibetuzumab, inotuzumab, pinatuzumab, brentuximab, gemtuzumab, bivatuzumab, lorvotuzumab or an antigen-binding fragment thereof.

42. A ligand-drug complex represented by general formula (B) according to any one of claims 32 to 41, selected from the above, or a pharmaceutically acceptable salt thereof, Here, v is an integer or decimal number between 1 and 10, preferably an integer or decimal number between 2 and 8.

43. A pharmaceutical composition comprising a ligand-drug complex represented by general formula (B) as described in any one of claims 32 to 42 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

44. Use in the preparation of ligand-drug conjugates a compound represented by general formula (A) as described in any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, or a compound represented by general formula (I) as described in any one of claims 22 to 26 or a stereoisomer, tautomer, endoform, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a compound represented by general formula (II) as described in any one of claims 27 to 31 or a stereoisomer, tautomer, endoform, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

45. The use of a ligand-drug conjugate represented by general formula (B) as described in any one of claims 32 to 42 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in claim 43, in the preparation of a drug for treating a tumor or cancer, wherein the cancer includes breast cancer, ovarian cancer, soft tissue sarcoma, liposarcoma, lung cancer, non-small cell lung cancer, gastric cancer, melanoma, head and neck cancer, cervical cancer, and prostate cancer.

46. The use of a compound represented by general formula (I) as described in any one of claims 22 to 26 or its stereoisomer, tautomer, endoform, racemate, enantiomer, diastereomer or mixed form thereof, or a pharmaceutically usable salt thereof, in the preparation of a drug for treating a tumor or cancer, preferably the use of a compound represented by general formula (II) as described in any one of claims 27 to 31 or its stereoisomer, tautomer, endoform, racemate, enantiomer, diastereomer or mixed form thereof, or a pharmaceutically usable salt thereof, wherein the cancer includes breast cancer, ovarian cancer, soft tissue sarcoma, liposarcoma, lung cancer, non-small cell lung cancer, gastric cancer, melanoma, head and neck cancer, cervical cancer, and prostate cancer.

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