Pentacyclic active compounds and their complexes and their use

Abstract

This disclosure relates to pentacyclic active compounds, their complexes, and their uses. The compounds and complexes of this disclosure exhibit excellent tumor cell inhibitory activity, stability, and efficacy in animal vivo.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims priority to a prior application filed with the China National Intellectual Property Administration on August 18, 2023, patent application number 202311046439.3, with the title of invention "Pentacyclic active compounds, and their complexes and uses." The entire text of the said application is incorporated into this application by reference.

[0002] [Technical field] This disclosure relates to the pharmaceutical technology field, specifically to pentacyclic active compounds, their complexes, and their uses. [Background technology]

[0003] The concept of antibody-drug conjugates (ADCs) has a long history. In the early 20th century, Nobel laureate Professor Paul Ehrlich first proposed the concept of a "magic bullet," a conjugate in which a cytotoxic small molecule drug is bound to an antibody via a rationally constructed linker, enabling the selective delivery of effective cytotoxic drugs to tumors. Currently available ADC drugs are based on this theory. With the continued expansion of targets and indications, ADCs are leading a new era of targeted cancer therapy and are expected to replace conventional chemotherapy drugs in the future.

[0004] ADC drugs are composed of an antibody linked to a small molecule cytotoxic drug using a specific linker. Their main components include an antibody (mAb), a linker, and a small molecule cytotoxic drug (payload). Once an ADC enters the bloodstream, its antibody component recognizes its target and can bind to tumor cells that highly express cell surface antigens. When the ADC-antigen complex enters the tumor cell via endocytosis, its cytotoxic payload (drug) is released through lysosomal degradation, killing the tumor cell by damaging its DNA or inhibiting cell division.

[0005] In 1958, an attempt was made to treat leukemia by conjugating anti-mouse leukocyte immunoglobulin with methotrexate. In 2000, the U.S. Food and Drug Administration (FDA) approved Mylotarg, the first ADC drug, for the treatment of adult acute myeloid leukemia, marking the beginning of the era of ADC-based cancer targeted therapy. Mylotarg was a first-generation ADC drug, but it was withdrawn from the market due to severe and fatal liver damage and a lack of significant improvement in survival rates. The shortcomings of first-generation ADC drugs included the fact that the antibodies were mouse antibodies, their cytotoxicity was insufficient, and their expression sites were low.

[0006] The first ADC drug approved for breast cancer was trastuzumab emtansine, which became the starting point for the development of second-generation ADCs. Benzuximab vedotin is the most successful ADC drug in the field of hematological malignancies, primarily targeting classical Hodgkin lymphoma and anaplastic large cell lymphoma. The advantages of second-generation ADCs include the diversification of target antigens and their humanized antibody status, while the disadvantages include extremely low or high drug load, a narrow treatment window, and lower efficacy.

[0007] A representative example of third-generation ADCs is enfortumab vedotin, the second ADC to target solid tumors, which is suitable for patients who have not responded to PD-1 / PD-L1 antibody therapy, but who are less sensitive to tubulin inhibitors.

[0008] Currently, there is still a need for the development of drug molecules and their complexes that have rational molecular structure design, improved pharmacodynamic activity, and controllable safety. [Overview of the project]

[0009] To address the technical challenges described above, this disclosure provides ligand-drug conjugates represented by formula (C) below, stereoisomers, racemates, tautomers, isotopologs, isotopic markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof. Tp-LG (C) (wherein Tp is a targeting moiety, L is selected from a chemical bond or a linker, G is a group represented by the following formula (G), [Chemical Formula] wherein A is absent, or is selected from the following groups unsubstituted or optionally substituted with one, two or more R A : an alkylene group, an alkenylene group, an alkynylene group, a cycloalkyl group, an aryl group, a heteroaryl group, a heterocyclyl group, or a combination of two or more of the foregoing groups; said alkylene group, alkenylene group, alkynylene group, cycloalkyl group, aryl group, heteroaryl group, heterocyclyl group, or combination of two or more of the foregoing groups is not interrupted, or may be optionally interrupted, by one, two or more groups selected from -O-, -S-, -NR 5- , -NR 6 C(=O)-, -C(=O)NR 6 -, -C(=O)-, -NR 7 C(=O)NR 8 - or -OC(=O)-, R 1 is selected from the following groups unsubstituted or optionally substituted with one, two or more R B : a cycloalkyl group, a cycloalkylalkyl group, a cycloalkyloxy group, a heterocyclyl group, a heterocyclylalkyl group, and a heterocyclyloxy group, X is selected from O or S, Z is selected from 0 or 1, R 2 is selected from hydrogen, deuterium, halogen, hydroxy, mercapto, amino, cyano, and the following groups unsubstituted or optionally substituted with one, two or more R C : an alkyl group, an alkyloxy group, a cycloalkyl group, a cycloalkylalkyl group, and a cycloalkyloxy group, R 22R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R C The following groups are optionally substituted by: alkyl groups, alkyloxy groups, cycloalkyl groups, cycloalkylalkyl groups, and cycloalkyloxy groups, selected from the above. R 3 R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R C The following groups are optionally substituted by: alkyl groups, alkyloxy groups, cycloalkyl groups, cycloalkylalkyl groups, and cycloalkyloxy groups, selected from the above. R 4 R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R C The following groups are optionally substituted by: alkyl groups, alkyloxy groups, cycloalkyl groups, cycloalkylalkyl groups, and cycloalkyloxy groups, selected from the above. Alternatively, R 2 , R 3 These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. D Forms a ring structure arbitrarily substituted by, Alternatively, R 3 , R 4 These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. D Forms a ring structure arbitrarily substituted by, Alternatively, R 22 , R 4 These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. D Forms a ring structure arbitrarily substituted by, B does not exist, or -O-, -S-, -S(=O)-, -C(=O)-, -NR 5 -, -C=N-NR 9 -, -C=NO-, or -NR 10 -NR 11 - Selected from, R5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 These are the same or different, and each independently consists of hydrogen, deuterium, unsubstituted or one, two or more R atoms. E The following groups are optionally substituted by: alkyl groups, cycloalkyl groups, cycloalkylalkyl groups, aryl groups, arylalkyl groups, heteroaryl groups, heteroarylalkyl groups, heterocyclyl groups, heterocyclylalkyl groups, HC(=O)-, alkyl C(=O)-, cycloalkyl C(=O)NH-, heterocyclyl C(=O)NH-, aryl C(=O)NH-, and heteroaryl C(=O)NH-, selected from these. Each R A , R B , R C , R D , R E These are the same or different, and each independently consists of a deuterated group, halogen, hydroxyl group, cyano group, nitro group, oxo group (=O), unsubstituted or one, two or more R groups. F The following groups are optionally substituted by: alkyl group, alkyloxy group, cycloalkyl group, cycloalkylalkyl group, cycloalkyloxy group, aryl group, arylalkyl group, aryloxy group, heteroaryl group, heteroarylalkyl group, heteroaryloxy group, heterocyclyl group, heterocyclylalkyl group, heterocyclyloxy group, NH2, HC(=O)NH-, alkylC(=O)NH-, cycloalkylC(=O)NH-, heterocyclylC(=O)NH-, arylC(=O)NH-, heteroarylC(=O)NH-, selected from the above. Each R FThey are the same or different, and each is independently selected from deuterated groups, halogens, hydroxyl groups, cyano groups, nitro groups, oxo groups (=O), alkyl groups, alkyloxy groups, cycloalkyl groups, cycloalkylalkyl groups, cycloalkyloxy groups, aryl groups, arylalkyl groups, aryloxy groups, heteroaryl groups, heteroarylalkyl groups, heteroaryloxy groups, heterocyclyl groups, heterocyclylalkyl groups, heterocyclyloxy groups, NH2, HC(=O)NH-, alkylC(=O)NH-, cycloalkylC(=O)NH-, heterocyclylC(=O)NH-, arylC(=O)NH-, heteroarylC(=O)NH-, The wavy line indicates the connection point with L.

[0010] According to embodiments of this disclosure, the base in formula (G) is independently selected from the following definitions: Here, A does not exist, or is unsubstituted, or has one, two or more Rs. A The following base: C, which is arbitrarily substituted by: 1~10 Alkylene group, C 2~10 Alkenylene group, C 2~10 Alkynylene group, C 3~10 Cycloalkyl groups, C 6~12 Selected from an aryl group, a 5-12 membered heteroaryl group, a 5-12 membered heterocyclyl group, or a combination of two or more of these groups, the C 1~10 Alkylene group, C 2~10 Alkenylene group, C 2~10 Alkynylene group, C 3~10 Cycloalkyl groups, C 6~12 Aryl groups, 5-12 membered heteroaryl groups, 5-12 membered heterocyclyl groups, or combinations of two or more of these groups are classified as -O-, -S-, -NR 5- , -NR 6 C(=O)-, -C(=O)NR 6 -, -C(=O)-, -NR 7 C(=O)NR 8-Or -OC(=O)- may or may not be separated by one, two or more groups selected from -OC(=O)-, preferably A is absent, unsubstituted or with one, two or more R A The following base: C, which is arbitrarily substituted by: 1~6 Alkylene group, C 2~6 Alkenylene group, C 2~6 Alkynylene group, C 3~6 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 5-10 membered heteroaryl group, a 5-10 membered heterocyclyl group, or a combination of two or more of these groups, the C 1~6 Alkylene group, C 2~6 Alkenylene group, C 2~6 Alkynylene group, C 3~6 Cycloalkyl groups, C 6~10 Aryl groups, 5-10 membered heteroaryl groups, 5-10 membered heterocyclyl groups, or combinations of two or more of these groups are classified as -O-, -S-, -NR 5- , -NR 6 C(=O)-, -C(=O)NR 6 -, -C(=O)-, -NR 7 C(=O)NR 8 -Or -OC(=O)- may or may not be separated by one, two or more elements selected from OC(=O), R 1 This is either unsubstituted or with one, two, or more Rs. B The following base: C, which is arbitrarily substituted by: 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl C 1~10 Alkyl alkyl group, C 3~10 Cycloalkyloxy group, 3-10 membered heterocyclyl group, 3-10 membered heterocyclyl C 1~10 Selected from alkyl groups and 3-10 membered heterocyclyloxy groups, preferably R 1 This is either unsubstituted or with one, two, or more Rs. B The following base: C, which is arbitrarily substituted by: 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl C1~6 alkyl group, C 3~6 cycloalkyloxy group, 3- to 6-membered heterocyclyl group, 3- to 6-membered heterocyclyl C 1~6 alkyl group, and 3- to 6-membered heterocyclyloxy group, X is selected from O or S, Z is selected from 0 or 1, R 2 is hydrogen, deuterium, halogen, hydroxy group, mercapto group, amino group, cyano group, or the following groups unsubstituted or optionally substituted with one, two or more R C : C 3~10 alkyl group, C 3~10 alkyloxy group, C 3~10 cycloalkyl group, C 3~10 cycloalkyl C 1~10 alkyl group, C 3~10 cycloalkyloxy group, preferably R 2 is hydrogen, deuterium, halogen, hydroxy group, mercapto group, amino group, cyano group, or the following groups unsubstituted or optionally substituted with one, two or more R C : C 1~6 alkyl group, C 1~6 alkyloxy group, C 3~6 cycloalkyl group, C 3~6 cycloalkyl C 1~6 alkyl group, C 3~6 cycloalkyloxy group, R 22 is hydrogen, deuterium, halogen, hydroxy group, mercapto group, amino group, cyano group, or the following groups unsubstituted or optionally substituted with one, two or more R C : C 3~10 alkyl group, C 3~10 alkyloxy group, C 3~10 cycloalkyl group, C 3~10 cycloalkyl C 1~10 alkyl group, C 3~10 cycloalkyloxy group, preferably R 2R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R C The following base: C, which is arbitrarily substituted by: 1~6 Alkyl alkyl group, C 1~6 Alkyloxy group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl C 1~6 Alkyl alkyl group, C 3~6 Selected from cycloalkyloxy groups, R 3 R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R C The following base: C, which is arbitrarily substituted by: 1~10 Alkyl alkyl group, C 1~10 Alkyloxy group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl C 1~10 Alkyl alkyl group, C 3~10 Selected from cycloalkyloxy groups, preferably R 3 R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R C The following base: C, which is arbitrarily substituted by: 1~6 Alkyl alkyl group, C 1~6 Alkyloxy group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl C 1~6 Alkyl alkyl group, C 3~6 Selected from cycloalkyloxy groups, R 4 R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R C The following base: C, which is arbitrarily substituted by: 1~10 Alkyl alkyl group, C 1~10 Alkyloxy group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl C 1~10 Alkyl alkyl group, C 3~10 Selected from cycloalkyloxy groups, preferably R4 R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R C The following base: C, which is arbitrarily substituted by: 1~6 Alkyl alkyl group, C 1~6 Alkyloxy group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl C 1~6 Alkyl alkyl group, C 3~6 Selected from cycloalkyloxy groups, Alternatively, R 2 , R 3 These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. D A 4-10 membered ring structure is formed by which the 4-10 membered ring structure may be selected from, for example, 4, 5, 6, 7, 8, 9, or 10 membered heteromonocyclic hydrocarbon groups, heterodicyclic hydrocarbon groups, monocyclic hydrocarbon groups, and bicyclic hydrocarbon groups, wherein the heteromonocyclic hydrocarbon group and heterodicyclic hydrocarbon group contain one, two or more O, S, N, or carbonyl groups, or any combination thereof. Alternatively, R 3 , R 4 These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. D A 4-10 membered ring structure is formed by which the 4-10 membered ring structure may be selected from, for example, 4, 5, 6, 7, 8, 9, or 10 membered monocyclic hydrocarbon groups, bicyclic hydrocarbon groups, heteromonocyclic hydrocarbon groups, and heterobicyclic hydrocarbon groups, wherein the heteromonocyclic hydrocarbon group and heterobicyclic hydrocarbon group contain one, two or more O, S, N, or carbonyl groups, or any combination thereof. Alternatively, R 22 , R 4 These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. DA 4-10 membered ring structure is formed by which the 4-10 membered ring structure may be selected from, for example, 4, 5, 6, 7, 8, 9, or 10 membered monocyclic hydrocarbon groups, bicyclic hydrocarbon groups, heteromonocyclic hydrocarbon groups, and heterobicyclic hydrocarbon groups, wherein the heteromonocyclic hydrocarbon group and heterobicyclic hydrocarbon group contain one, two or more O, S, N, or carbonyl groups, or any combination thereof. B does not exist, or -O-, -S-, -S(=O)-, -C(=O)-, -NR 5 -, -C=N-NR 9 -, -C=NO-, or -NR 10 -NR 11 - Selected from, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 These are the same or different, and each independently consists of hydrogen, deuterium, unsubstituted or one, two or more R atoms. E The following base: C, which is arbitrarily substituted by: 1~10 Alkyl alkyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl C 1~10 Alkyl alkyl group, C 6~12 Aryl group, C 6~12 Aryl C 1~10 Alkyl group, 5-12 membered heteroaryl group, 5-12 membered heteroaryl C 1~10 Alkyl group, 5-12 membered heterocyclyl group, 5-12 membered heterocyclyl C 1~10 Alkyl alkyl group, HC(=O)-, C 1~10 Alkyl C(=O)-, C 3~10 Cycloalkyl C(=O)NH-, 5-12 member heterocyclyl C(=O)NH-, C 6~12 Selected from aryl C(=O)NH- and 5-12 member heteroaryl C(=O)NH-, preferably R 5 , R 6 , R 7 , R 8 , R 9 , R 10, R 11 These are the same or different, and each independently consists of hydrogen, deuterium, unsubstituted or one, two or more R atoms. E The following base: C, which is arbitrarily substituted by: 1~6 Alkyl alkyl group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl C 1~6 Alkyl alkyl group, C 6~10 Aryl group, C 6~10 Aryl C 1~6 Alkyl group, 5-6 member heteroaryl group, 5-6 member heteroaryl C 1~6 Alkyl group, 5-6 membered heterocyclyl group, 5-6 membered heterocyclyl C 1~6 Alkyl alkyl group, HC(=O)-, C 1~6 Alkyl C(=O)-, C 3~6 Cycloalkyl C(=O)NH-, 5-6 member heterocyclyl C(=O)NH-, C 6~10 Selected from aryl C(=O)NH- and 5-6 member heteroaryl C(=O)NH-, Each R A , R B , R C , R D , R E These are the same or different, and each independently contains a deuterated group, halogen, hydroxyl group, cyano group, nitro group, unsubstituted or one, two or more R groups. F The following base: C, which is arbitrarily substituted by: 1~10 Alkyl alkyl group, C 1~10 Alkyloxy group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl C 1~10 Alkyl alkyl group, C 3~10 Cycloalkyloxy group, C 6~12 Aryl group, C 6~12 Aryl C 1~10 Alkyl alkyl group, C 6~12 Aryloxy group, 5-12 membered heteroaryl group, 5-12 membered heteroaryl C 1~10 Alkyl group, 5-12 member heteroaryloxy group, 5-12 member heterocyclyl group, 5-12 member heterocyclyl C 1~10Alkyl group, 5-12 member heterocyclyloxy group, NH2, HC(=O)NH-, C 1~10 Alkyl C(=O)NH-, C 3~10 Cycloalkyl C(=O)NH-, 5-12 member heterocyclyl C(=O)NH-, C 6~12 Selected from aryl C(=O)NH- and 5- to 12-membered heteroaryl C(=O)NH-, preferably each R A , R B , R C , R D , R E These are the same or different, and each independently contains a deuterated group, halogen, hydroxyl group, cyano group, nitro group, unsubstituted or one, two or more R groups. F The following base: C, which is arbitrarily substituted by: 1~6 Alkyl alkyl group, C 1~6 Alkyloxy group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl C 1~6 Alkyl alkyl group, C 3~6 Cycloalkyloxy group, C 6~10 Aryl group, C 6~10 Aryl C 1~6 Alkyl alkyl group, C 6~10 Aryloxy group, 5-6 member heteroaryl group, 5-6 member heteroaryl C 1~6 Alkyl group, 5-6 member heteroaryloxy group, 5-6 member heterocyclyl group, 5-6 member heterocyclyl C 1~6 Alkyl group, 5-6 member heterocyclyloxy group, NH2, HC(=O)NH-, C 1~6 Alkyl C(=O)NH-, C 3~6 Cycloalkyl C(=O)NH-, 5-6 member heterocyclyl C(=O)NH-, C 6~10 Selected from aryl C(=O)NH- and 5-6 member heteroaryl C(=O)NH-, Each R F These are the same or different, and each is independently a deuterated group, halogen, hydroxyl group, cyano group, nitro group, alkyl group, C 1~10 Alkyloxy group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl C 1~10Alkyl alkyl group, C 3~10 Cycloalkyloxy group, C 6~12 Aryl group, C 6~12 Aryl C 1~10 Alkyl alkyl group, C 6~12 Aryloxy group, 5-12 membered heteroaryl group, 5-12 membered heteroaryl C 1~10 Alkyl group, 5-12 member heteroaryloxy group, 5-12 member heterocyclyl group, 5-12 member heterocyclyl C 1~10 Alkyl group, 5-12 member heterocyclyloxy group, NH2, HC(=O)NH-, C 1~10 Alkyl C(=O)NH-, C 3~10 Cycloalkyl C(=O)NH-, 5-12 member heterocyclyl C(=O)NH-, C 6~12 Selected from aryl C(=O)NH- and 5- to 12-membered heteroaryl C(=O)NH-, preferably each R F These are the same or different, and each is independently a deuterated group, halogen, hydroxyl group, cyano group, nitro group, alkyl group, C 1~6 Alkyloxy group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl C 1~6 Alkyl alkyl group, C 3~6 Cycloalkyloxy group, C 6~10 Aryl group, C 6~10 Aryl C 1~6 Alkyl alkyl group, C 6~10 Aryloxy group, 5-6 member heteroaryl group, 5-6 member heteroaryl C 1~6 Alkyl group, 5-6 member heteroaryloxy group, 5-6 member heterocyclyl group, 5-6 member heterocyclyl C 1~6 Alkyl group, 5-6 member heterocyclyloxy group, NH2, HC(=O)NH-, C 1~6 Alkyl C(=O)NH-, C 3~6 Cycloalkyl C(=O)NH-, 5-6 member heterocyclyl C(=O)NH-, C 6~10 The choice is made from aryl C(=O)NH- or 5- to 6-membered heteroaryl C(=O)NH-.

[0011] According to embodiments of this disclosure, the base of formula (G) may be independently selected from the following definitions:

[0012] A is either absent or one selected from the following substructures, where the substructure is unsubstituted or has one, two or more R A Replaced arbitrarily by, -(CH2) n1 -, -O(CH2) n2 -, -S(CH2) n3 -, -NR 5 (CH2) n4 -, -NR 6 C(=O)(CH2) n5 -, -C(=O)(CH2) n6 -, -NR 7 C(=O)NR 8 (CH2) n7 -, -OC(=O)(CH2) n8 -, -C=C(CH2) n9 -, -C≡C(CH2) n10 -, [ka] Even if that is the case, n1, n2, n3, n4, n5, n6, n7, n8, n9, n10 are each independent integers selected from 0 to 6. R 1 This is either unsubstituted or with one, two, or more Rs. B The following base: C, which is arbitrarily substituted by: 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl C 1~6 Selected from alkyl groups, for example, R 1 This is either unsubstituted or with one, two, or more Rs. B Bases arbitrarily substituted by: [ka] Selected from, R 2 It is selected from hydrogen, R 22 It is selected from hydrogen, R 3 This is either unsubstituted or with one, two, or more Rs. C C arbitrarily substituted by 1~6 Selected from alkyl groups, for example, R 3 The group is selected from a methyl group, an ethyl group, and a propyl group. R 4 It is selected from halogens, B does not exist, or -O-, -S-, NR 5 Selected from, R 5 H, deuterium, C 1~6 Alkyl alkyl group, C 3~6 Selected from cycloalkyl groups.

[0013] According to embodiments of this disclosure, R 3 , R 4 These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. D The following ring structure is formed by substitution. [ka]

[0014] According to embodiments of this disclosure, R 3 , R 4 Together with the benzene rings linked thereto, these form one of the following substructures, where the substructure is unsubstituted or has one, two or more R D It may also be arbitrarily replaced by [this]. [ka] (Here, R D (It has the definitions described above.)

[0015] According to embodiments of this disclosure, the base of formula (G) may be independently selected from the following definitions.

[0016] A is either absent or one selected from the following substructures, where the substructure is either unsubstituted or has one, two or more R A It may also be arbitrarily replaced by [this]. [ka] B does not exist, or -O-, -S-, NR 5 Selected from, R 5 H, deuterium, C 1~6 Alkyl alkyl group, C 3~6 Selected from cycloalkyl groups.

[0017] In some embodiments, A is either unsubstituted or has one, two, or more R A The following structures are selected, which are arbitrarily substituted by [the specified variable]. [ka]

[0018] According to embodiments of this disclosure, in G, [ka] The following bases may be selected. [ka]

[0019] According to embodiments of the present disclosure, G is selected from the groups represented by the following formulas (G-1) or (G-2). [ka] (Here, A, B, R 1 , R 2 , R 22 , R 3 , R 4 (It has the definitions described above, independently.)

[0020] According to embodiments of the present disclosure, G is selected from the groups represented by formulas (G-3), (G-4), (G-5), or (G-6). [ka] (Here, A, B, R 1 (It has the definitions described above, independently.)

[0021] According to embodiments of this disclosure, G is selected from the following bases. [ka] (Here, A, B, R 2 , R 22 , R 3 , R 4 (It has the definitions described above, independently.)

[0022] According to embodiments of this disclosure, G is selected from the following bases. [ka] (Here, A, B, R 2 , R 22 , R 3 , R 4 (It has the definitions described above, independently.)

[0023] According to exemplary embodiments of this disclosure, G is selected from the following bases. [Table 1A(1)] [Table 1A(2)] [Table 1A(3)]

[0024] In the above embodiments of the present disclosure, L is selected from a chemical bond or a linker represented by formula (L) as defined below. #L1 -L 2 -L 3 -L 4 * (L) (Here, L 1 This is the linking portion with the targeting portion Tp, and the reactive group L 1 ' is formed by the targeting portion Tp, and # represents the connection site with the targeting portion Tp. For example, L 1 If ' is a pyrimidinyl group or a maleimide group, L 1 It has the following structure: [ka] L 2 It does not exist, or L 1 and L 3 This is the spacer part, L 3 This is the peptide portion, L 4 It is either absent or is a linking portion between the peptide portion and the biologically active molecule G, and the reactive group L 4 It is produced by reacting ' with biologically active molecule G or an intermediate thereof, and * is the linking site with biologically active molecule G. Optional, Between the above portion of L, preferably L 1 and L 2 Between, or L 2 and L 3 Between, or L 2 Replace with L 2 By inserting it, the following hydrophilic portion is included, Here, the hydrophilic portion is a divalent unit substituted with one, two, or more hydrophilic groups, for example, a phenylene group substituted with one, two, or more hydrophilic groups, or an amino acid residue substituted with one, two, or more hydrophilic groups, preferably, [ka] The hydrophilic portion is a divalent unit formed by the hydrophilic group itself, for example, [ka] or -(CH2CH2O) p - may be, R 12 , R 12 ' is the same or different, hydrophilic group or substituent listed below: hydrogen, halogen, cyano group, amino group, nitro group, unsubstituted or one, two or more R zg C arbitrarily substituted by 1~10 Alkyl alkyl group, C 1~10 Alkyloxy group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl C 1~10 Alkyl alkyl group, C 3~10 Selected from cycloalkyloxy groups, where R 12 , R 12’ At least one of these is selected from hydrophilic groups.

[0025] The hydrophilic group is optionally substituted with a polyethylene glycol group, a polyethylene glycol divalent unit, or 1 to 10 hydroxyl groups. 1~10 Selected from alkyl groups, sugar ring-containing groups, or heterocyclyl divalent units containing a nitrogen atom, such as piperidinyl groups or piperadyl groups, preferably polyethylene glycol groups, and more preferably -(CH2CH2O) p -C 1~10 Alkyl group, -C(=O)-NH-(CH2CH2O) p -C 1~10 Alkyl group, or -NH-(CH2CH2O) p -C 1~10 C is optionally substituted with an alkyl group, or preferably with 1 to 10 hydroxyl groups. 1~10 Alkyl alkyl groups, more preferably [ka] And, Each p is the same or different, and independently selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. Each R zg They are the same or different, and each is independently a halogen, hydroxyl group, amino group, cyano group, nitro group, C 1~10 Alkyl alkyl group, C 1~10 Alkyloxy group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl C 1~10 Alkyl alkyl group, C 3~10 Selected from cycloalkyloxy groups, Preferably, each R zg They are the same or different, and each is independently a halogen, hydroxyl group, amino group, cyano group, nitro group, C 1~6 Alkyl alkyl group, C 1~6 Alkyloxy group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl C 1~6 Alkyl alkyl group, C 3~6 Selected from cycloalkyloxy groups,

[0026] In one embodiment of this disclosure, L does not have the hydrophilic portion defined above.

[0027] In one embodiment of this disclosure, L including the hydrophilic portion is, for example, the following: [Table 1B]

[0028] In further preferred embodiments of this disclosure, L 1 This is any group L that reacts with the targeting moiety Tp. 1 ' is formed by L 1' is preferably a mercapto-reactive group, an amino-reactive group, a carboxy-reactive group, a dithiol crosslinking group, etc., and for antibodies introducing non-natural amino acids, it may be selected from click chemistry-reactive groups, such as ketones, hydrazines or hydrazides, azides, alkynes, cyclopropenes or dienes, and if the Tp portion is an antibody, the linking site comprises any suitable amino acid residue or an N297 glycan complex of the CH2 domain, such as fucose, galactose, N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), and sialic acid (SA) introduced by glycoengineering, and the linking reaction comprises a chemical or enzymatic reaction, for example, transferring an amine-containing drug linker or reactive spacer to a deglycosylated antibody using transglutaminase (MTGase). L 1 ' is preferably a mercapto-reactive group, L 1 ' is preferably a mercapto-reactive group having the following structure, Hal-Het- Hal is a halogen, OMs, OTs, OTf, nitro group, and one, two or more R groups. z8 The following base: C, which is arbitrarily substituted by: 1~10 Alkylthioether group, C 6~12 Arylthioether group, 5-12 member heteroarylthioether group, C 1~10 Alkyl sulfoxide group, C 6~12 Aryl sulfoxide group, 5-12 member heteroaryl sulfoxide group, C 1~10 Alkyl sulfonyl group, C 6~12 Selected from arylsulfonyl groups and 5-12 member heteroarylsulfonyl groups, where R z8 These are independently H (hydrogen), D (deuterium), halogen, CN, nitro group, and C 1~6 Alkyl, halo C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 6~12 Selected from 5-membered aryl groups and 5-12 membered heteroaryl groups, Het has one, two or more R z9Selected from 5-12 member heteroaryl groups optionally substituted by, where R z9 These are independently H (hydrogen), D (deuterium), halogen, CN, nitro group, and C 1~10 Alkyl groups, and halo C 1~10 Selected from alkyl groups, preferably Het has one, two or more R z9 Selected from 5-10 member heteroaryl groups optionally substituted by, where R z9 These are independently H (hydrogen), D (deuterium), halogen, CN, nitro group, and C 1~4 Alkyl groups, and halo C 1~4 Selected from alkyl groups, In a preferred embodiment, Hal is a methanesulfonyl group, and Het is a pyrimidine. In a preferred embodiment, Hal-Het- is as follows: [ka] Corresponding L 1 The structure is as follows: [ka] Furthermore, L 1 '-L 2 Preferably, it has the following structure. [ka]

[0029] q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. R z4 and R z5 H and C are the same or different, and independently of each other. 1~4 Alkyl alkyl group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl group-C 1~4 Selected from alkyl groups, or R z4 or R z5 C 3~6 Forms a cycloalkyl group,

[0030] In further preferred embodiments of this disclosure, L 1 '-L 2 It has the following structure. [ka] Or, L 1 ' is more preferably a maleimide group or a substituted maleimide group, and L 1 -L 2 Preferably, the structure is as follows: A fragment produced from (N-maleimidomethyl)-carboxylate-N-hydroxysuccinimide ester having the following structure, [ka] (q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8) Alternatively, a fragment produced from m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) having the following structure, [ka] A fragment produced from 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate succinimide ester (SMCC) having the following structure, [ka] That is the case.

[0031] Further embodiments of this disclosure include: L 2 C does not exist. 1~10 Alkylene group, C 2~10 Alkenylene group, C 2~10 Alkynylene group, C 3~10 Cycloalkyl groups, C 6~12 Selected from an aryl group, a 5-12 membered heteroaryl group, a 5-12 membered heterocyclyl group, or a combination of two or more of these groups, the C 1~10 Alkylene group, C2~10 Alkenylene group, C 2~10 Alkynylene group, C 3~10 Cycloalkyl groups, C 6~12 The aryl group, the 5-12 membered heteroaryl group, the 5-12 membered heterocyclyl group, or a combination of two or more of these groups may not be separated by a carbonyl group, O, S, or N atom, or may be separated as such. 1~10 Alkylene group, C 2~10 Alkenylene group, C 2~10 Alkynylene group, C 3~10 Cycloalkyl groups, C 6~12 An aryl group, a 5-12 membered heteroaryl group, a 5-12 membered heterocyclyl group, or a combination of two or more of these groups is C 1~6 Alkyl alkyl group, C 3~6 Cycloalkyl groups, halogen atoms, halo C 1~6 It may be optionally substituted with an alkyl group, and optionally, the C 1~6 Alkyl group, or halo C 1~6 Alkyl groups, along with the C atoms linked to them, are C 3~6 A cycloalkyl group may be formed, L 2 L is formed via any functional group or covalent bond. 1 or L 3 The fragments are joined together, Preferably, L 2 is, -(CH2) q -, -C(=O)-NH-(CH2) q -C(=O)-, -(CH2) q -C(=O)-, -(CH2) q -NH-C(=O)-, -(CH2) q -NCH3-C(=O)-, -(C≡C)-(CH2) q -C(R z4 R z5 )-C(=O)- or -Cy-(CH2) q -C(R z4 R z5 )-C(=O)- is selected, where q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. Here, Cy is a 5-12 membered heteroaryl group or heterocyclyl group optionally containing an S, O, or N heteroatom, and also contains H (hydrogen), D (deuterium), halogen, CN, nitro group, and C 1~4 Alkyl groups, and halo C 1~4 It is optionally substituted with an alkyl group, preferably at least three atoms of Cy are N, more preferably three consecutive atoms of Cy are N, and even more preferably Cy is a 1,2,3-triazolyl group. Preferably, R z4 and R z5 H and C are the same or different, and independently of each other. 1~4 Alkyl alkyl group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl group-C 1~4 Selected from alkyl groups, or R z4 or R z5 C 3~6 Forms a cycloalkyl group, Preferably, L 2 The peptide fragment L is transmitted via -NHC(=O)-, -NCH3C(=O)-, or -C(=O)-. 3 It is ligated to the N-terminus of

[0032] Further embodiments of this disclosure include: L 3The peptide group is selected from a divalent peptide group containing 2 to 8 arbitrarily placed natural or non-natural, L-type or D-type amino acid residues, each of which may be the same or different, and each may be independently one of the following amino acid residues: alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Ile). Nin (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolidine (Pyl), homoserine, homocysteine, demethylpyrrolidine, selected from analogs of the above amino acids, or AA 1 Selected from the amino acid residues shown, or their stereoisomers, [ka] Here, R G and R H H is not H at the same time, and each is independent of H, [ka] Selected from, Alternatively, R G and R H These, along with the carbon atoms they jointly link, are either unsubstituted or have one, two, or more R atoms. L C arbitrarily substituted by 3~10 Forming a cycloalkyl group or a 3-10 membered heterocyclyl group, r and r1 are each independent integers selected from 0 to 10. R I , R J , R K Each of these is independently H, unsubstituted, or one, two or more R M C arbitrarily substituted by1~6 Alkyl alkyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl C 1~10 Selected from alkyl groups and ester groups, Alternatively, R I and R J These, along with the nitrogen atom they collectively link, are either unsubstituted or have one, two, or more R atoms. L They form a 4-10 member heterocyclyl group which is optionally substituted by R M , R L They are the same or different, each independently selected from deuterated groups, halogens, hydroxyl groups, cyano groups, nitro groups, alkyl groups, alkyloxy groups, cycloalkyl groups, cycloalkylalkyl groups, cycloalkyloxy groups, aryl groups, arylalkyl groups, aryloxy groups, heteroaryl groups, heteroarylalkyl groups, heteroaryloxy groups, heterocyclyl groups, heterocyclylalkyl groups, heterocyclyloxy groups, NH2, alkylamino groups, dialkylamino acids, HC(=O)NH-, alkylC(=O)NH-, cycloalkylC(=O)NH-, heterocyclylC(=O)NH-, arylC(=O)NH-, heteroarylC(=O)NH-, and optionally, two R groups linked to the same carbon atom. M or R L C 3~6 Forms a cycloalkyl group, More preferably, L 3 These are any substituted natural or unnatural, L-type or D-type amino acid residues, or AA 1A combination of 2, 3, 4, 5, or 6 amino acid residues is selected from a divalent peptide group, where each of the amino acid residues is the same or different, and each is independently one of the following amino acids: alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine Metholone (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolidine (Pyl), homoserine, homocysteine, demethylpyrrolidine, analogs of the above amino acids or AA 1 Selected from, for example, -ValCit-;-ValAA 1 -;-CitVal-;-AlaAla-;-AlaCit-;-CitAla-;-AsnCit-;-CitAsn-;-CitCit-;-ValGlu-;-GluVal-;-SerCit-;-CitSer-;-L ysCit-;-CitLys-;-AspCit-;-CitAsp-;-AlaVal-;-ValAla-;-PheAla-;-AlaPhe-;-PheLys-;-LysPhe-;-ValLys-;-GlyAA 1 -;-LysVal-;-AlaLys-;-LysAla-;-PheCit-;-CitPhe-;-LeuCit-;-CitLeu-;-IleCit-;-CitIle-;-PheArg-;-ArgPhe-;-CitTrp-;-TrpCit-;-AlaAlaAla-;-PhePheLys-;-ValAA 1 Gly-;-AlaAA 1 Gly-;- GlyAA 1Gly-;-LysPhePhe-;-DPhePheLys-;-DLysPhePhe-;-GlyPheLys-;-LysPheGly-;-GlyPheLeuGly-;-GlyLeuPheGly-;-Ala LeuAlaLeu-;-GlyGlyGly-;-GlyGlyGlyGly-;-GlyPheValGly-;-GlyValPheGly-;-GlyGlyPheGly-;-GlyGlyValGly-, AA 1 In the amino acid residues, preferably, r and r1 are each independent integers selected from 0 to 5. R G and R H Of these, one is H, and the other is [ka] Selected from, Alternatively, R G and R H These, along with the carbon atoms they jointly link, are either unsubstituted or have one, two, or more R atoms. L This forms a 5-6 member heterocyclyl group which is optionally substituted by R I , R J , R K Each of these is independently H, unsubstituted, or one, two or more R M Methyl groups, ethyl groups, n-propyl groups, n-butyl groups, C, which are optionally substituted by 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl C 1~6 Selected from alkyl, -COOCH3, COOCH2CH3, -COOCH2CH2CH3, -COOCH(CH3)2, -COOC(CH3)3, and -COOCH2CH2CH2CH3, Alternatively, R I and R J These, along with the nitrogen atom they collectively link, are either unsubstituted or have one, two, or more R atoms. L This forms a 5-6 member heterocyclyl group which is optionally substituted by Most preferably, L 3 -ValAA 1 Selected from Gly-, Here, AA 1 In the amino acid residue, r is 0 and r1 is 4. R G and R H Of these, one is H, and the other is [ka] Selected from, Alternatively, R G and R H These, along with the carbon atoms that are linked together, [ka] This forms, where * is R G and R H This represents carbon atoms that are linked together, R I , R J , R K Each of these is independently H, unsubstituted, or one, two or more R M Methyl groups, ethyl groups, n-propyl groups, n-butyl groups, C are substituted by 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl C 1~4 Selected from alkyl groups, Alternatively, R I and R J These, along with the nitrogen atoms that are linked together, [ka] It forms.

[0033] Further embodiments of this disclosure include: AA 1 The amino acid residue is characterized by being one selected from the following substructures. [ka] [ka]

[0034] Further embodiments of this disclosure include: L 4 It does not exist, or is selected from the following: [ka] More preferably, L 4 teeth, [ka] And, Most preferably, L 4 teeth, [ka] And the corresponding L 4 The reactive group is in the form of acetate, [ka] The reaction between that and the compound of formula (GH) (where B is an oxygen atom) is shown by the following equation. [ka] L 4 If no corresponding L exists, 4 'The reactive group is L 3 It is formed by the active ester of a terminal amino acid, such as glycine.

[0035] Further embodiments of this disclosure include: L 1 This is a structure in which a maleimide group, a substituted maleimide group, or a mercapto-reactive group selected from Hal-Het- is bonded to Tp. L 1 and L 2 Between, or L 2 and L 3 Between, or L 2Replace with L 2 By inserting it, the hydrophilic portion defined above is included.

[0036] Further embodiments of this disclosure include: L 1 This is a structure in which a mercapto-reactive group selected from Hal-Het- is bound to Tp, L 4 teeth, [ka] That is the case.

[0037] Further embodiments of this disclosure include: L 1 -L 2 L has the following structure 1 '-L 2 This is formed when it is coupled to the trump. [ka] q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. R z4 and R z5 H and C are the same or different, and independently of each other. 1~4 Alkyl alkyl group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl group-C 1~4 Selected from alkyl groups, or R z4 or R z5 C 3~6 A cycloalkyl group is formed, where R z4 or R z5 At least one of them is not H, More preferably, R z4 or R z5 C 3~6 Forms a cycloalkyl group, L 1 -L 2 Most preferably, [ka] It is formed when it is joined to the trumpet.

[0038] In the L defined above, each fragment L 1 -L 4 Alternatively, the hydrophilic portion may be linked via any chemical bond, such as a direct bond, an ester bond (-CO-O-), an amide bond (-CO-NH-), an ether bond (-O-), a thioether bond (-S-), a carbamate bond (-N-CO-O-), or a ureido group (-O-CO-O-). Preferably, the H atoms in each peptide bond or amide bond in L may be optionally substituted with methyl groups.

[0039] This disclosure further provides a complex having the following structure. Tp-LD (D) (Here, Tp is the targeting part, D is a biologically active molecular fragment, preferably a molecular fragment having antitumor biological activity. L is selected from the linkers shown in equation (L), #L 1 -L 2 -L 3 -L 4 * (L) Here, L 1 This is the linking portion with the targeting portion Tp, and the reactive group L 1 ' is formed by the targeted portion Tp, and # represents the connection point with the Tp portion, L 1 Preferably, [ka] And, L 2 is -(C≡C)-(CH2) q -C(R z4 R z5 )-C(=O)- or -(CH2) q -C(R z4 R z5 )-C(=O)- is selected, Here, L 1 '-L2 It has the following structure: [ka] q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. R z4 and R z5 H and C are the same or different, and independently of each other. 1~4 Alkyl alkyl group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl group-C 1~4 Selected from alkyl groups, or R z4 or R z5 Together, they form a C3-6 cycloalkyl group, where R z4 or R z5 At least one of them is not H, or L 2 is -(C≡C)-(CH2) q Selected from -C(=O)-, L 2 and L 3 The hydrophilic portion defined below is included between the two. [ka] Furthermore, L 3 -ValAA 1 Gly-, and here AA 1 This is as defined above, L 4 It is either absent or is the linking portion between the peptide portion and the biologically active molecule D, and the reactive group L 4 (This is produced by reacting ' with a biologically active molecule, and * represents the linkage site with biologically active molecule D.)

[0040] This disclosure further provides intermediates for synthesizing complexes having the following structure. L 1 '-L 2 -L 3 -L 4 -G(C') (Here, G, L 1', L 2 , L 3 , L 4 (This is as defined above.)

[0041] This disclosure further provides linker-drug combinations. L 1 '-L 2 -L 3 -L 4 -D (L here) 1 ', L 2 , L 3 , L 4 D is as defined above, however, L 1 ' is a reactive group linked to the targeting moiety Tp, L 1 ' is preferably, [ka] And, L 2 is -(C≡C)-(CH2) q -C(R z4 R z5 )-C(=O)- or -(CH2) q -C(R z4 R z5 )-C(=O)- is selected, Here, L 1 '-L 2 It has the following structure: [ka] q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. R z4 and R z5 H and C are the same or different, and independently of each other. 1~4 Alkyl alkyl group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl group-C 1~4 Selected from alkyl groups, or R z4 or R z5 C3~6 A cycloalkyl group is formed, where R z4 or R z5 At least one of them is not H, or L 2 is -(C≡C)-(CH2) q Selected from -C(=O)-, L 2 and L 3 Between them is the hydrophilic portion defined above, [ka] Furthermore, L 3 -ValAA 1 Gly-, and here AA 1 This is as defined above, L 4 It is either absent or is the linking portion between the peptide portion and the biologically active molecule D, and the reactive group L 4 (This is produced by reacting ' with a biologically active molecule, and * represents the linkage site with biologically active molecule D.)

[0042] Those skilled in the art will understand that the biologically active molecule D is a compound having biological activity or potential biological activity, as described in or disclosed in the Chinese, American, or European pharmacopoeia. As an example, the drug may be selected from cytotoxic agents, cell proliferation inhibitors, or immunosuppressants, such as antitubulin agents, tubulin inhibitors, DNA sulcus binding agents, DNA replication inhibitors, alkylating agents, antibiotics, folate antagonists, antimetabolites, chemotherapy-sensitive agents, topoisomerase inhibitors, and vinca alkaloids. Examples of such cytotoxic agents include auristatin, camptothecin, duocalmycin, etoposide, meitansine and meitansine alkaloids, taxanes, benzodiazepines or benzodiazepine-containing drugs, and vinca alkaloids.

[0043] Tp is the targeting site (e.g., small molecule ligand, protein, polypeptide, or non-protein reagent (e.g., sugar, RNA, or DNA)).

[0044] In further preferred embodiments of this disclosure, the targets of Tp include epidermal growth factor, Trop-2, CD37, HER2, CD70, EGFRvIII, Mesothelin, Folate receptor 1, Mucin 1, CD138, CD20, CD19, CD30, SLTRK6, Nectin 4, Tissue factor, Mucin 16, Endothelin receptor, STEAP1, SLC39A6, Guanylylcyclase C, PSMA, CCD79b, CD22, Sodium phosphate cotransporter 2B, GPNMB, Trophoblast glycoprotein, AGS-16, EGFR, CD33, CD66e, CD74, CD56, PD-L1, TACSTD2, DR5, E16, 0772P, MPF, Napi3b, Sema 5b, and PSCA. hlg, ETBR, MSG783, STEAP2, TrpM4, CRIPTO, CD21, CD79b, FcRH2, NCA, MDP, IL20Rα, Brevican, EphB2R, ASLG659, PSCA, GEDA, BAFF-R, CD79a, CXCR5, HLA-DOB, P2X5, CD72, LY64 , FcRH1, IRTA2, TENB2, integrin α5β6, α4β7, FGF2, FGFR2, Her3, CA6, DLL3, DLL4, P-cadherin, EpCAM, pCAD, CD223, LYPD3, LY6E, EFNA4, ROR1, SLITRK6, 5T4, ENPP3, Claudin18.2, BMPR1B, Tyro7, c-Met, ApoE, CD1 lc, CD40, CD45(PTPRC), CD49D(ITGA4), CD80, CSF1R, CTSD, GZMB, Ly86, MS4A7, PIK3AP1, PIK3CD, CCR5, IFNG, IL10RA1, I L-6, ACTA2, COL7A1, LOX, LRRC15, MCPT8, MMP10, NOG, SERPINEl, STAT1, TGFBR1, CTSS, PGF, VEGFA, C1QA, C1QB, ANGPTL4, Selected from EGLN, EGLN3, BNIP3, AIF1, CCL5, CXCL10, CXCL11, IFI6, PLOD2, KISS1R, STC2, DDIT4, PFKFB3, PGK1, PDK1, AKR1C1, AKR1C2, CADM1, CDH11, COL6A3, CTGF, HMOX1, KRT33A, LUM, WNT5A, IGFBP3, MMP14, CDCP1, PDGFRA, TCF4, TGF, TGFB1, TGFB2, CDl lb, ADGRE1, EMR2, TNFRSF21, UPK1B, TNFSF9, MMP16, MFI2, IGF-1R, RNF43, NaPi2b, and BCMA. In further preferred embodiments of the present disclosure, Tp is a small molecule ligand, such as a folic acid derivative, a glutamate urea derivative, a somatostatin derivative, an aryl sulfonamide derivative (e.g., a carbonic anhydrase IX inhibitor), an ICG dye, a cyanine dye or a derivative thereof. According to embodiments of this disclosure, the ligand is preferably selected from an antibody or its antigen-binding fragment, and the antibody is preferably selected from a chimeric antibody, a humanized antibody or a fully human antibody, and is preferably a monoclonal antibody. According to exemplary embodiments of the present disclosure, the antibody or its antigen-binding fragment is at least one antibody or its antigen-binding fragment selected from anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-MUCl antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, or anti-Mesothelin antibody, wherein the antibody may be a bispecific antibody or a multispecific antibody. For example, the antibody or its antigen-binding fragment is at least one antibody or its antigen-binding fragment selected from Trastuzumab, Pertuzumab, Nimotuzumab, Enoblituzumab, Emibetuzumab, Inotuzumab, Pinatuzumab, Brentuximab, Gemtuzumab, Bivatuzumab, Lorvotuzumab, cBR96, and Glembatumumab.

[0045] According to embodiments of the present disclosure, the complex, its linker, or linker-drug may be one selected from the following, where u is an integer selected from 0 to 10, G has the definitions described above, and LG has the definition of Tp described above. [Table 1C(1)] [Table 1C(2)] [Table 1C(3)] [Table 1C(4)] [Table 1C(5)] [Table 1C(6)] [Table 1C(7)] [Table 1C(8)] [Table 1C(9)] [Table 1C(10)]

[0046] According to embodiments of the present disclosure, the composite may have a structure represented by the following formula. [ka] (Here, R 1 , R 2 , R 22 , R 3 , R 4 , R G , R H A, B, X, Z, L 1 , L 2 Tp has the definitions described above.

[0047] According to embodiments of the present disclosure, the composite may have a structure represented by the following formula. [ka] (Here, A, B, R 3 , R 4 , L 1 , L 2 Tp has the definitions described above.

[0048] According to embodiments of the present disclosure, the composite may have a structure represented by the following formula. [ka] (Here, A, B, L 1 , L 2 Tp has the definitions described above.

[0049] According to embodiments of this disclosure, the ligand-drug conjugate represented by formula (C) is schematically represented by the following formula (C) A ) A structure like this is also acceptable. Tp-(LG)y (C A ) (Here, Tp, L, and G are defined as above, y represents the average number (DAR) of small molecule drugs conjugated to each monoclonal antibody, and may be an integer or decimal, for example, an integer or decimal from 1 to 50, an integer from 1 to 20, or a decimal or an integer or decimal from 1 to 10.

[0050] According to embodiments of the present disclosure, the composite may have a structure represented by the following formula. [ka] (Here, R 1 , R 2 , R 22 , R 3 , R 4 , R G , R H A, B, X, Z, L 1 , L 2 Tp and y have the definitions described above.

[0051] According to embodiments of the present disclosure, the composite may have a structure represented by the following formula. [ka] (Here, A, B, R 3 , R 4 , L 1 , L 2 Tp and y have the definitions described above.

[0052] According to embodiments of the present disclosure, the composite may have a structure represented by the following formula. [ka] (Here, A, B, L 1 , L 2 Tp and y have the definitions described above.

[0053] According to embodiments of the present disclosure, the composite may be one selected from the following: [ka] [ka] [ka] [ka] (Here, R 3 , R 4 It has the definitions described above, u is an integer selected from 0 to 10. r2 may be an integer selected from 0 to 4, such as 0, 1, 2, 3, or 4, and r3 and r4 may each be integers selected from 0 to 3, such as 0, 1, 2, or 3. K is either C or N. R z6 , R z7 They are the same or different, and each is independently selected from hydrogen, an amino group, an alkylamino group, or a dialkylamino group, an alkyl group, an alkyloxy group, a cycloalkyl group, a cycloalkylalkyl group, or a cycloalkyloxy group. Alternatively, R z6 , R z7 These, together with the atoms linked to them, form a ring structure, preferably C 1~4A 5-6 membered heterocyclyl group is optionally substituted with an alkyl group, and the 5-6 membered heterocyclyl group is preferably a piperidinyl group or a piperazyl group. mAb stands for monoclonal antibody, y represents the average number (DAR) of small molecule drugs conjugated to each monoclonal antibody, and may be an integer or decimal, for example, an integer or decimal from 1 to 50, an integer from 1 to 20, or a decimal or an integer or decimal from 1 to 10.

[0054] According to embodiments of this disclosure, the example of the compound of the complex intermediate linker and the drug may be one selected from the following: [Table 1D(1)] [Table 1D(2)] [Table 1D(3)] [Table 1D(4)] [Table 1D(5)] [Table 1D(6)] [Table 1D(7)] [Table 1D(8)] [Table 1D(9)] [Table 1D(10)] [Table 1D(11)] [Table 1D(12)] [Table 1D(13)] [Table 1D(14)] [Table 1D(15)] [Table 1D(16)] [Table 1D(17)] [Table 1D(18)] [Table 1D(19)]

[0055] According to embodiments of the present disclosure, the example of the composite may be one selected from the following, where y represents the average number (DAR) of small molecule drugs conjugated to each monoclonal antibody, and may be an integer or decimal, for example, an integer or decimal from 1 to 50, an integer from 1 to 20, or a decimal or an integer or decimal from 1 to 10. [Table 1E(1)] [Table 1E(2)] [Table 1E(3)] [Table 1E(4)] [Table 1E(5)] [Table 1E(6)] [Table 1E(7)] [Table 1E(8)] [Table 1E(9)] [Table 1E(10)] [Table 1E(11)] [Table 1E(12)] [Table 1E(13)] [Table 1E(14)] [Table 1E(15)] [Table 1E(16)] [Table 1E(17)] [Table 1E(18)]

[0056] This disclosure further provides methods for preparing ligand drug conjugates, their stereoisomers, racemates, tautomers, isotopologs, isotopic markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof, the preparation methods comprising the following steps: Step 1: L 1 '-L 2 -L3 -L 4 Provides a linker indicated by '(L)', Preferably, in the linker described above, L 4 'teeth, [ka] The reaction form is preferably acetate, More preferably, L 4 'teeth, [ka] The reaction form is preferably acetate, and its structure is shown below. [ka] Or, L 4 It does not exist, and in this case, L 4 ' is L 3 Reaction form (for example, L 3 The glycine gly at the C-terminus forms an active ester, L 4 'B forms a direct amide bond with GH of N, Step 2: The linker is reacted with the compound of formula (GH) to form L 1 '-L 2 -L 3 -L 4 -G(C') bonded intermediate is obtained, Here, the structure of equation (GH) is shown below. [ka] (Here, A, B, Z, X, R 1 , R 2 , R 22 , R 3 , R 4 , L 1 ', L 1 , L 2 , L 3 , L 4 , L 4 ' independently has the above definition.'

[0057] In specific embodiments of this disclosure, the following preparation method is also provided: Step 1: L 4 Provides a linker fragment containing ' and the L 4 ' is as defined above, Step 2: L 4 A linker fragment containing ' is combined with the compound of formula (GH), L 4 A linker fragment containing ' is obtained - G intermediate, Step 3: Provide another linker fragment and react it with the above intermediate to form a complete linker L 1 '-L 2 -L 3 -L 4 -G(C') bond intermediate is formed, Preferably, L 4 Linker fragments containing ' are [ka] Therefore, B reacts with -O- GH to form a linkage via an ether bond. Preferably, another linker fragment is [ka] That is the case.

[0058] Preferably, the preparation method further includes a fourth step of binding the binding intermediate of formula (C') to the targeting moiety Tp, Optionally, and if necessary, the functional groups of the reaction substrate can be protected with protecting groups known in the art to ensure the reaction proceeds smoothly, and the protecting groups can be removed after the reaction is complete.

[0059] This disclosure further provides a bonding intermediate having the following structure. [ka] (Here, G N is H or any amino group protecting group, A, R 1 , R 2 , R 22 , R3 , R 4 X and Z independently have the above definitions.

[0060] This disclosure further provides linker fragment compounds having the following structure. L 1 '-L 2 -ValAA 1 '(L'') (Here, (Here, L 1 ' is a reactive group, preferably, [ka] And, L 2 is -(C≡C)-(CH2) q -C(R z4 R z5 )-C(=O)- or -(CH2) q -C(R z4 R z5 )-C(=O) is selected, Here, L 1 '-L 2 It has the following structure: L 1 '-L 2 teeth, [ka] And, q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. R z4 and R z5 H and C are the same or different, and independently of each other. 1~4 Alkyl alkyl group, C 3~6 Cycloalkyl groups, C 3~6 Cycloalkyl group-C 1~4 Selected from alkyl groups, or R z4 or R z5 C 3~6 A cycloalkyl group is formed, where R z4 or R z5 At least one of them is not H, or L 2 is -(C≡C)-(CH2) q Selected from -C(=O)-, L 2 and L 3 Between them is the hydrophilic portion defined above, [ka] AA 1 ' is, AA 1 The substance itself or its reaction form, for example, an active ester, where AA 1 (This is as defined above.)

[0061] This disclosure further provides a linker. L 1 '-L 2 -L 3 -L 4 '(L') (Here, L 1 '-L 2 This is defined above. [ka] And, or L 2 is -(C≡C)-(CH2) q Selected from -C(=O)-, L 2 and L 3 Between them is the hydrophilic portion defined above, [ka] and L 3 -ValAA 1 Gly-, and here AA 1 This is as defined above. L' is preferably the following: [Table 1F(1)] [Table 1F(2)] [Table 1F(3)] [Table 1F(4)]

[0062] This disclosure further provides a compound in which the above-described group G is linked to a hydrogen atom, wherein group B is linked to a hydrogen atom.

[0063] This disclosure further provides compounds represented by the following formula (GH), their stereoisomers, racemates, tautomers, isotopologs, isotopic markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof. [ka] (Here, A, B, X, Z, R 1 , R 2 , R 22 , R 3 , R 4 Each of these has its own independent definition.

[0064] According to embodiments of the present disclosure, in formula (GH) described in the context of the specification, the hydrogen, carbon, or other atoms in the structural formula may be optionally substituted with their isotopes, regardless of whether the group is selected from the above definitions, directly depicted in the structural formula, or defined as a substituent or unsubstituted. For example, the hydrogen atom in any group of formula (GH) is: 1 H, 2 H or 3 H may be selected from. For example, any substituent in an unsubstituted or substituted alkyl, alkylene, alkylidene, phenyl, pyridyl, or lactone group of a compound of formula (GH), or any hydrogen atom in its ring-forming atom (if any), can be independently: 1 H, 2 H or 3 It may also be selected from H.

[0065] According to embodiments of this disclosure, the compound represented by formula (GH) may be selected from the compounds represented by the following formula (GH-1). [ka] (Here, A, B, Z, R 1 , R 2 , R 22 , R 3 , R 4 Each of these has its own independent definition.

[0066] According to embodiments of this disclosure, the compound represented by formula (GH) may be selected from the compounds represented by the following formula (GH-2). [ka] (Here, A, B, Z, R 1 , R 2 , R 22 , R 3 , R 4 Each of these has its own independent definition.

[0067] According to embodiments of this disclosure, the compound represented by formula (GH) may be selected from the following compounds. [ka] [ka]

[0068] This disclosure further provides a method for preparing a compound represented by formula (GH), the method comprising the step of reacting a compound of formula (i) with a compound of formula (ii) to obtain a compound of formula (G'). [ka] (Here, T is, [ka] Alternatively, by reaction methods such as oxidation and reduction [ka] It is a group that can be converted to. Those skilled in the art will know that groups containing active functional groups such as alkenyl groups, aldehyde groups, carbonyl groups, and nitro groups are usually selected as T. [ka] It can be understood that this can be introduced. Specifically, when the active functional group is a carbon-containing structure such as an alkenyl group, aldehyde group, or carbonyl group, the residue obtained by removing the active functional group from T has one less carbon than A, and when the active functional group is a nitro group, the residue obtained by removing the nitro group from T is A, for example the following group form: NO2-C(R 15 R 16 ) m -(CR 17 =CR 18 ) n -C(R 19 R 20 ) o -, (CR 17 =CR 18 ) n -C(R 19 R 20 ) o -, O=CR 21 -C(R 15 R 16 ) m -(CR 17 =CR 18 ) n -C(R 19 R 20 ) o -You may choose from the following options. Here, m, n, and o are each independent integers selected from 0 to 6. Each R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21These are the same or different, and each independently consists of hydrogen, halogen, cyano group, unsubstituted or one, two or more R groups. A The following groups are optionally substituted by: alkyl groups, alkyloxy groups, cycloalkyl groups, cycloalkylalkyl groups, cycloalkyloxy groups, aryl groups, arylalkyl groups, aryloxy groups, heteroaryl groups, heteroarylalkyl groups, heteroaryloxy groups, heterocyclyl groups, heterocyclylalkyl groups, heterocyclyloxy groups, selected from these. Alternatively, R 15 , R 16 These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. A It forms a 3-10 membered ring structure which is arbitrarily substituted by Alternatively, R 19 , R 20 These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. A It forms a 3-10 membered ring structure which is arbitrarily substituted by Here, R 1 , R 2 , R 22 , R 3 , R 4 X and Z independently have the definitions described above.

[0069] This disclosure further provides a method for preparing a compound represented by formula (GH), the method comprising the step of reacting a compound of formula (G') to obtain a compound of formula (GH). [ka] (Here, A, B, R 1 , R 2 , R 22 , R 3 , R 4 X and Z independently have the definitions described above. Here, T is determined by reaction methods such as oxidation and reduction. [ka] a group that can be converted to, for example, a person skilled in the art would generally select a group containing an active functional group such as an alkenyl group, an aldehyde group, a carbonyl group, or a nitro group as T,

Chemical Formula

[0070] The present disclosure further provides a compound represented by formula (i).

Chemical Formula

[0071] This disclosure further provides compounds represented by formula (G'). [ka] (Here, R 1 , R 2 , R 22 , R 3 , R 4 X, Z, and T each have the definitions described above independently.

[0072] This disclosure further provides a pharmaceutical composition comprising at least one selected from the ligand-drug conjugate represented by formula (C), its stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates or pharmaceutically acceptable salts thereof, and the compound represented by formula (GH), its stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates or pharmaceutically acceptable salts thereof. Preferably, the compound represented by formula (GH), its stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates or pharmaceutically acceptable salts thereof, and the ligand drug conjugate represented by formula (C), its stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates or pharmaceutically acceptable salts thereof are present in therapeutically effective amounts.

[0073] According to embodiments of the present disclosure, the pharmaceutical composition comprises at least one therapeutically effective amount selected from the compound represented by formula (GH), its stereoisomers, racemates, tautomers, isotopologs, isotopic markers, nitrogen oxides, prodrugs, solvates or pharmaceutically acceptable salts thereof, and ligand-drug conjugates represented by formula (C), its stereoisomers, its prodrugs or pharmaceutically acceptable salts or solvates.

[0074] This disclosure further provides uses of the compound represented by formula (GH), its stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates or pharmaceutically acceptable salts thereof, or ligand-drug conjugates represented by formula (C), its stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions, used for the prevention and / or treatment of diseases or conditions, and / or the preparation of drugs.

[0075] According to embodiments of this disclosure, the drug is used for the prevention and / or treatment of a disease or condition.

[0076] The present disclosure further provides a method for preventing and / or treating a disease or condition, comprising administering to a patient a therapeutically effective amount of at least one of the following: a compound represented by formula (GH), its stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates or pharmaceutically acceptable salts thereof; or a ligand-drug conjugate represented by formula (C), its stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates or pharmaceutically acceptable salts thereof.

[0077] According to embodiments of the present disclosure, the disease or condition may be selected from tumors, such as solid tumors or hematological cancers.

[0078] Examples of the solid tumors mentioned above include sarcomas, adenocarcinomas, germ cell tumors, and malignant tumors of various organ systems, such as those affecting the liver, lungs, breasts, lymph nodes, bile ducts (e.g., colon), urogenital tract (e.g., kidneys, urothelial cells), prostate, and pharynx. Adenocarcinomas include most colon cancers, rectal cancer, renal cell carcinoma, liver cancer, small cell lung cancer, non-small cell lung cancer, small intestine cancer, and esophageal cancer. In one embodiment, the cancer is melanoma, for example, advanced melanoma. Other treatable cancers include bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, colorectal cancer, anal cancer, peritoneal cancer, stomach cancer, esophageal cancer, salivary gland cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, penile cancer, malignant glioma, neuroblastoma, Hodgkin's disease, non-Hodgkin lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, and chronic or acute leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute leukemia). Examples of cancers include mpablastic leukemia (including chronic lymphocytic leukemia), pediatric solid tumors, lymphocytic lymphomas, bladder cancer, kidney or ureteral cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, neuroendocrine tumors (including carcinoid tumors, gastrinomas, and islet cell carcinomas), mesothelioma, Schwann cell tumors (including acoustic neuromas), meningiomas, epidermoid carcinomas, squamous cell carcinomas, T-cell lymphomas, environmentally induced cancers (including asbestos-induced cancers), and combinations of the aforementioned cancers.

[0079] Examples of the aforementioned blood cancers include leukemia, lymphoma, and malignant lymphoproliferative disorders that can affect the blood, bone marrow, and lymphatic system. Leukemia is divided into acute leukemia and chronic leukemia. Acute leukemia is further divided into acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Chronic leukemia includes chronic myeloid leukemia (CML) and chronic lymphoblastic leukemia (CLL). Other related conditions include myelodysplastic syndromes (MDS, formerly called “preleukemia”), which are a diverse set of hematological disorders that combine the ineffective generation (or developmental abnormalities) of bone marrow blood cells with the risk of conversion to AML. Lymphoma is a blood cell tumor that arises from lymphocytes. Exemplary lymphomas include non-Hodgkin lymphoma and Hodgkin lymphoma.

[0080] According to embodiments of the present disclosure, the pharmaceutical composition may further include pharmaceutically acceptable auxiliary materials, such as carriers or excipients. The pharmaceutically acceptable auxiliary materials are preferably non-reactive or inert to the active ingredient. For example, the pharmaceutically acceptable auxiliary materials include, but are not limited to, at least one selected from fillers, disintegrants, binders, lubricants, surfactants, flavoring agents, wetting agents, and matrices.

[0081] According to embodiments of this disclosure, the administration route of the pharmaceutical composition includes, but is not limited to, gastrointestinal administration or non-gastrointestinal administration. Here, gastrointestinal administration may be oral administration, and non-gastrointestinal administration may be topical administration, transdermal administration, injection, etc.

[0082] In one embodiment, the pharmaceutical composition can be administered via a combination of topical and oral administration.

[0083] According to embodiments of the present disclosure, the dosage form of the pharmaceutical composition may be selected from capsules, tablets, patches, films, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, suppositories, or injections. Definitions and explanations of terms

[0084] Unless otherwise specified, the definitions of terms contained in this specification and claims, including definitions as examples, illustrative definitions, preferred definitions, definitions listed in tables, and definitions of specific compounds in examples, may be arbitrarily combined or linked to one another. Such combinations and links shall be included within the scope of this specification.

[0085] The term "antibody-drug conjugate" (ADC) refers to a configuration in which a target ligand, such as an antibody (e.g., a monoclonal antibody) or antibody fragment, is linked to a small molecule drug with biological activity via a stable chemical linker compound. Those skilled in the art will understand that in such ADCs, the antibody can be linked to a variety of small molecule drugs. The average number of small molecule drugs linked to the antibody is usually expressed as DAR.

[0086] Unless otherwise specified, the numerical ranges described in the present specification and claims are at least equivalent to describing each specific integer value therein. For example, the numerical range "0 to 10" is equivalent to describing each integer value in the numerical range "0 to 10", that is, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. It should be understood that when the expression "one, two or more" is used in describing a substituent in the present specification, "more" refers to an integer of 3 or more, such as 3, 4, 5, 6, 7, 8, 9, or 10. When the expression "one or more" is used in describing a substituent in the present specification, "more" refers to an integer greater than 1, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10. Furthermore, it should be understood that when specific numerical values are defined as "a range", they describe both endpoints of the range, each integer within the range, and each decimal within the range. For example, it should be understood that "0 to 10" not only describes each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least describes combinations of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9. Similarly, it should be understood that the numerical ranges "0 to 5", "0 to 4", "0 to 3", "0 to 6", and "integer or decimal from 1 to 50", "integer or decimal from 1 to 20", "integer or decimal from 1 to 10" describe both endpoints of the above-mentioned numerical ranges, each integer within each range, and decimals within the range.

[0087] The term "isotopologue" includes those in which an atom of a compound or complex of the present disclosure is replaced with another isotope having the same atomic number but different atomic mass or mass number. For example, "hydrogen" in the compound or complex of the present disclosure is protium( 1 H), deuterium( 2 H), and tritium( 3 H), and "carbon" is 12 C, 13 C, and 14C can be selected. Therefore, the compounds or complexes of this disclosure should be understood to include at least various deuterated forms of the compounds or complexes. For example, various available hydrogen atoms (e.g., C) can be bonded to the carbon atom. 1~10 One, two, or more hydrogen atoms of an alkyl group can be independently substituted with deuterium atoms. Those skilled in the art can synthesize the deuterated form of a compound or complex by referring to relevant literature. When preparing the deuterated form of a compound or complex, commercially available deuterated starting materials can be used, or it can be synthesized using deuterating reagents by conventional techniques. Any deuterating reagents include, but are not limited to, borane deuterated, borane trihydrofuran solution, lithium aluminum deuterated hydride, iodoethane deuterated, and iodomethane deuterated.

[0088] The term "isotope marker" is, 111 In, 177 Lu, 212 Bi, 213 Bi, 211 At, 62 Cu, 67 Cu, 90 Y, 125 I, 131 I, 32 P, 33 P, 47 Sc, 111 Ag, 67 Ga, 142 Pr, 153 Sm, 161 Tb, 166 Dy, 166 Ho, 186 Re, 188 Re, 189 Re, 212 Pb, 223 Ra, 225 Ac, 59 Fe, 75 Se, 77 As, 89 Sr, 99 Mo, 105 Rh, 109 Pd, 143 Pr, 149 PM,169 Er, 194 Ir, 198 Au, 199 Au, 227 Th, and 211 This disclosure includes, but is not limited to, compounds or complexes of the present disclosure labeled with at least one element of Pb.

[0089] The term "prodrug" refers to a compound that is converted in vivo to an active compound represented by a general formula. Such conversion is influenced by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compounds disclosed herein may be esters. Examples of esters that can function as prodrugs in the prior invention include phenyl esters and aliphatic (C) esters. 1~24This includes esters, acyloxymethyl esters, carbonate esters, carbamates, and amino acid esters. For example, the compounds in this disclosure contain a hydroxyl group, meaning that a prodrug form of the compound can be obtained by acylation. Other prodrug forms include phosphate esters obtained by phosphorylation of the hydroxyl group of the parent compound. For a detailed discussion of prodrugs, please refer to the following references: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series; Edward B. Roche, ed., Bioreversible Carriersin Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautioetal., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Heckeretal., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0090] The term "nitrogen oxide" refers to the oxidation of one or more nitrogen atoms to form an N-oxide when a compound has multiple amine functional groups. Specific examples of N-oxides include N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be produced using the LWDeady method (Syn.Comm.1977, 7,509-514). In this method, the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0091] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0092] The term "alkyl group" preferably refers to a linear or branched saturated monovalent hydrocarbon group, preferably "C 1~10 It should be understood as an alkyl group. 1~10 "Alkyl group" should preferably be understood to refer to a linear or branched saturated monovalent hydrocarbon group having 1 to 10 carbon atoms. For example, "C 1~6 "Alkyl group" refers to linear and branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. 1~4"Alkyl group" refers to linear and branched alkyl groups having 1, 2, 3, or 4 carbon atoms. Examples of such alkyl groups include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, 2-methylbutyl group, 1-methylbutyl group, 1-ethylpropyl group, 1,2-dimethylpropyl group, neopentyl group, 1,1-dimethylpropyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 2-ethylbutyl group, 1-ethylbutyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 2,3-dimethylbutyl group, 1,3-dimethylbutyl group, or 1,2-dimethylbutyl group, or their isomers.

[0093] The term "cycloalkyl group" refers to a saturated monovalent monocyclic or bicyclic (condensed ring, crosslinked ring, or spiro ring) hydrocarbon group, preferably "C 3~10 It should be understood to refer to "cycloalkyl group". 3~10 The term "cycloalkyl group" should be understood to refer to a saturated monovalent monocyclic or bicyclic (fused, bridging, or spirocyclic) hydrocarbon group having 3 to 10 carbon atoms, for example, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 3~6 The term "cycloalkyl group" refers to a group having 3 to 6 carbon atoms, for example, 3, 4, 5, or 6 carbon atoms. The cycloalkyl group may be a monocyclic hydrocarbon group such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, or cyclodecyl group, or a bicyclic hydrocarbon group such as a decahydronaphthalene ring.

[0094] The term "ring structure" should be understood to refer to a group having a monocyclic, bicyclic (fused ring, bridging ring, or spiro ring) or more ring structures, such as a monocyclic hydrocarbon group, a bicyclic hydrocarbon group, a tricyclic hydrocarbon group, a heteromonocyclic hydrocarbon group, a heterodicyclic hydrocarbon group, a heterotricyclic hydrocarbon group, etc., and the ring structure may be saturated or unsaturated. The term "ring structure" may preferably refer to a 4- to 10-membered ring structure having 4, 5, 6, 7, 8, 9, or 10 ring atoms, or preferably a 3- to 10-membered ring structure having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms. The heteromonocyclic hydrocarbon group, heterodicyclic hydrocarbon group, and heterotricyclic hydrocarbon group may contain 1 to 10, preferably 1 to 5, heteroatoms independently selected from N, O, and S, for example, 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, and S. The bicyclic ring may have the following ring structures, either without heteroatoms or containing one, two, or three heteroatoms independently selected from N, O, and S: one or two independently or fused together, of aryl groups, heteroaryl groups, cycloalkyl groups, and heterocyclyl groups; a spiro[2.5] ring, a spiro[3.3] ring, a spiro[4.2] ring, a spiro[4.3] ring, a spiro[5.2] ring, a spiro[5.4] ring, a bicyclo[2.1.1], a bicyclo[2.2.1], a bicyclo[2.2.2], a bicyclo[3.2.1], a bicyclo[4.1.0], etc. Alternatively, the ring structure may have one, two, three, four, or five double bonds, such as carbon-carbon double bonds or carbon-nitrogen double bonds.

[0095] Linked substituents are described in various places in this disclosure. Where the structure clearly requires a linking group, the Markash variable given for that group should be understood as a linking group. For example, where the structure requires a linking group and the definition of the Markash group for that variable is given as "alkyl group" or "aryl group", then "alkyl group" or "aryl group" should be understood as representing a linked alkylene group or arylene group, respectively.

[0096] The term "alkylene group" should be understood to mean a saturated linear or branched aliphatic hydrocarbon group having two residues, each consisting of the same carbon atom or two different carbon atoms of the parent alkane with two hydrogen atoms removed. This is a linear or branched group containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), and more preferably an alkylene group containing 1 to 6 or 1 to 4 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and 1,5-butylene (-CH2CH2CH2CH2CH2-). The alkylene group may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linkage point, and it is preferable that the substituent is independently substituted with one or more substituents selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0097] The term "alkenylene group" should be understood to mean a linear or branched group having 1 to 20 carbon atoms and containing at least one carbon-carbon double bond, preferably 2 to 10 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms) and containing at least one carbon-carbon double bond, and more preferably 2 to 6 carbon atoms and containing at least one carbon-carbon double bond. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -C(CH3)=CH-, -CH=CHCH2CH2-, -CH=CHCH2-, -CH=CHCH2CH=CH-, -CH=CHCH2CH2CH=CH-, and -CH=CHCH2CH=CHCH2CH=CH-. The alkenylene group may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linkage point, and it is preferable that the substituent is independently substituted by one or more substituents selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0098] The term "alkynylene group" should be understood to mean a linear or branched group having 1 to 20 carbon atoms and containing at least one carbon-carbon triple bond, preferably 1 to 10 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms) and containing at least one carbon-carbon triple bond, more preferably 1 to 6 carbon atoms or 1 to 4 carbon atoms and containing at least one carbon-carbon triple bond. Non-limiting examples of alkynylene groups include, but are not limited to, -CH≡CH-, -C(CH3)≡CH-, -CH≡CHCH2CH2-, -CH≡CHCH2CH≡CH-, -CH≡CHCH2CH2CH≡CH-, and -CH≡CHCH2CH≡CHCH2CH≡CH-. The alkylylene group may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linkage point, and it is preferable that the substituent is independently substituted by one or more substituents selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0099] When the groups of the compounds described in this disclosure form the above-mentioned ring structure, and then form a fused ring, spiro ring, or bicyclic ring with the original ring structure of the compound, and when unsaturated bonds exist in the original ring structure of the compound, the ring structure formed by these groups should preferably be understood to maintain the unsaturated bonds of the original ring structure.

[0100] The term "heterocyclyl group" refers to a saturated monovalent monocyclic or bicyclic (fused ring, bridging ring, or spiro ring) hydrocarbon group containing 1 to 5 heteroatoms independently selected from N, O, and S, and is preferably a "3-20 membered heterocyclyl group." A "3-20 membered heterocyclyl group" refers to a saturated monovalent monocyclic or bicyclic (fused ring, bridging ring, or spiro ring) hydrocarbon group containing 1 to 5 heteroatoms independently selected from N, O, and S, with a total number of ring-forming atoms of 3 to 20 (for example, 3, 4, 5, 6, 7, 8, 9, 10, etc.), and is preferably a "3-10 membered heterocyclyl group." The term "3-10 membered heterocyclyl group" refers to a saturated monovalent monocyclic or bicyclic (fused, bridging, or spirocyclic) hydrocarbon group comprising 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, e.g., 1, 2, or 3 heteroatoms independently selected from N, O, and S. The heterocyclyl group can be linked to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). In particular, the heterocyclyl group includes, but is not limited to, a four-membered ring such as an azetidinyl group or an oxetidinyl group (e.g., azetidin-1-yl); a five-membered ring such as a tetrahydrofuranyl group, a dioxolenyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, or a pyrrolinyl group; or a six-membered ring such as a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, or a trithianyl group; or a seven-membered ring such as a diazepanyl group. Optionally, the heterocyclyl group may be benzo-condensed. The heterocyclyl group may be bicyclic, for example, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic group such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring, but is not limited to these.The nitrogen-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, and may be, for example, a 2,5-dihydro-1H-pyrrolyl group, a 4H-[1,3,4]thiadiazinyl group, a 4,5-dihydroxazolyl group, or a 4H-[1,4]thiadinyl group, but is not limited thereto, and may be benzo-condensed, for example, a dihydroisoquinolinyl group, but is not limited thereto. According to this disclosure, the heterocyclyl group is non-aromatic. When the heterocyclyl group is linked to another group to form a compound of this disclosure, the carbon atoms on the heterocyclyl group may be linked to the other group, or the heterocyclic atoms on the ring of the heterocyclyl group may be linked to the other group. For example, when the heterocyclyl group is selected from piperazinyl groups, the nitrogen atom of the piperazinyl group may be linked to the other group. Alternatively, if the heterocyclyl group is selected from piperidinyl groups, the nitrogen atom of the piperidinyl ring and the carbon atom at its para position may be linked to other groups.

[0101] The term "aryl group" refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring group, preferably "C 6~20 It should be understood as an "aryl group". 6~20 The term "aryl group" preferably refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, and preferably "C 6~14 "aryl group" or "C 6~12 It should be understood as an "aryl group". 6~14 The term "aryl group" preferably refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6~14 "aryl group", in particular a ring having 6 carbon atoms such as a phenyl group or biphenyl group ("C6 aryl group"), or a ring having 9 carbon atoms such as an indanyl group or indenyl group ("C9 aryl group"), or a ring having 10 carbon atoms such as a tetrahydronaphthyl group, dihydronaphthyl group, naphthyl group ("C 10aryl group"), a ring having 13 carbon atoms such as fluorenyl group ("C 13 aryl group"), or a ring having 14 carbon atoms such as anthracenyl group ("C 14 aryl group"). It should be understood that when the aryl group is substituted, it may be either monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution position, and it may be, for example, ortho, para, or meta substitution.

[0102] The term “heteroaryl group” should be understood to mean a monovalent monocyclic, bicyclic, or tricyclic aromatic ring group, preferably a “5-20 membered heteroaryl group,” containing 1 to 5 heteroatoms independently selected from N, O, and S. The term “5-20 membered heteroaryl group” should be understood to include a monovalent monocyclic, bicyclic, or tricyclic aromatic ring group, having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, such as a “5-14 membered heteroaryl group” or a “5-12 membered heteroaryl group.” The term “5-14 membered heteroaryl group” should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring groups having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and comprising 1 to 5, preferably 1, 2, or 3 heteroatoms independently selected from N, O, and S, which may be benzo-condensed in each case. In particular, heteroaryl groups include thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo derivatives, such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, and others; also The group is selected from pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, and the like; or azosinyl, indadinyl, purinyl, and the like, and their benzo derivatives; or sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthylidinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxadiniyl, and the like. When the heteroaryl group is linked to another group to form a compound of the present disclosure, carbon atoms on the heteroaryl ring may be linked to the other group, or heteroatoms on the heteroaryl ring may be linked to the other group.When the heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, a hydrogen atom on a heteroaryl ring linked to a carbon atom can be substituted, or a hydrogen atom on a heteroaryl ring linked to a heteroatom can be substituted.

[0103] Unless otherwise specified, heterocyclyl groups, heteroaryl groups, or heteroarylene groups include all isomers, including positional isomers. Therefore, non-limiting examples for illustrative purposes include forms in which substitution or bonding with other groups occurs at one, two, or more positions such as the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-positions (if present), including pyridine-2-yl, pyridylene-2-yl, pyridine-3-yl, pyridylene-3-yl, pyridine-4-yl, and pyridylene-4-yl; thiophenyl or thienylene groups including thiophene-2-yl, thienylene-2-yl, thiophene-3-yl, and thienylene-3-yl; and pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, and pyrazole-5-yl.

[0104] The term "oxo" refers to an oxy group substitution (=O) formed by oxidation of a carbon, nitrogen, or sulfur atom in a substituent. It should be understood that when a carbon atom is substituted with an oxy group, a carbonyl group -C(=O)- is formed.

[0105] Unless otherwise specified, the definitions of terms herein also apply to groups containing those terms; for example, the definition of alkyl group applies to alkyl groups in alkyloxy groups or cycloalkylalkyl groups, and the definition of cycloalkyl group applies to cycloalkyl groups in cycloalkyloxy groups or cycloalkylalkyl groups, and also, for example, C 1~10 The definition of an alkyl group is C 1~10 Alkyloxy group or C 3~10 Cycloalkyl C 1~10 C in alkyl groups 1~10It also applies to alkyl groups, C 3~10 The definition of a cycloalkyl group is C 3~10 Cycloalkyloxy group or C 3~10 Cycloalkyl C 1~10 C in alkyl groups 3~10 This also applies to cycloalkyl groups.

[0106] The term "mercapto-reactive group" refers to any group that can react with a mercapto group contained in Tp (e.g., an antibody), such as maleimide groups, substituted maleimide groups, halogens, OMs, OTs, OTf, nitro groups, alkylthioether groups, arylthioether groups, heteroarylthioether groups, alkylsulfoxide groups, arylsulfoxide groups, heteroarylsulfoxide groups, alkylsulfonyl groups, arylsulfonyl groups, and heteroarylsulfonyl groups.

[0107] The term "amino-reactive group" refers to groups that can react with amino groups contained in Tp (e.g., antibodies), such as succinimide esters (NHS), nitrophenyl esters (NPC), pentafluorophenyl esters (PFP), aldehyde groups (CHO) such as acetaldehyde and propionaldehyde groups, epoxy groups (EPO), and isothiocyanates (ISC).

[0108] The term "carboxyl-reactive group" refers to any group that can react with a carboxyl group contained in Tp (e.g., an antibody), such as hydroxyl groups, amino groups, mercapto groups, halogens, amidino groups, and guanidino groups.

[0109] The term "dithiol crosslinking group" refers to any bifunctional linker that can react with two free thiol / mercapto groups contained in Tp (e.g., an antibody), such as bismaleimide reagents, to form a crosslink.

[0110] The term "click chemistry reactive group" refers to a group capable of undergoing a "click chemistry" reaction, and includes, for example, ketones, hydrazines or hydrazides, azides, alkynes, cyclopropenes, and dienes. A typical click chemistry reaction is the reaction in which an azide and an alkyne form a five-membered heteroatom ring. Those skilled in the art can introduce click chemistry groups into antibody or other polypeptide target groups Tp using techniques such as codon extension.

[0111] Those skilled in the art will understand that the compounds of this disclosure may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; and if these compounds have both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may form internal salts.

[0112] The compounds of this disclosure may exist in the form of solvates (e.g., hydrates), wherein the compounds of this disclosure include a polar solvent, particularly water, methanol, or ethanol, as lattice structural elements of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0113] The compounds or groups of this disclosure, based on their molecular structure, are chiral or contain chiral carbon atoms, and therefore may exist in various enantiomer forms. Accordingly, these compounds or groups may exist in racemic or optically active forms. For example, group A in general formula (G), (G'), or (GH) may be CR AIf the groups linked to the carbon atom are not identical, the carbon atom is a chiral carbon atom and may have an R or S chiral configuration. The compounds or intermediates of the present disclosure can be isolated into enantiomers by chemical or physical methods known to those skilled in the art, or can be used in synthesis in this form. In the case of racemamines, diastereomers can be obtained from the mixture by reacting with an optically active resolving agent. Examples of suitable resolving agents include tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or optically active acids such as various optically active camphorsulfonic acids. Chromatographic enantiomer resolution can also be advantageously carried out using an optically active resolving agent (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutenate polymers). Suitable eluents for this purpose are water or alcohol-containing solvent mixtures such as hexane / isopropanol / acetonitrile.

[0114] The term "tautomer" refers to a functional isomer resulting from the rapid movement of an atom between two positions within a molecule. Compounds of this disclosure may exhibit tautomerism. Tautomer compounds may exist in two or more interconvertible forms. Proton transfer tautomers arise from the movement of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually yield a mixture whose physicochemical properties match those of the compound mixture. The equilibrium position depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form is dominant, while in phenols, the enol form is dominant. This disclosure encompasses all tautomer forms of compounds.

[0115] The corresponding stable isomers can be separated using known methods such as extraction, filtration, and column chromatography.

[0116] The term “patient” refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans.

[0117] As used herein, the term “therapeutic dose” refers to the amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician is seeking to elicit a biological or medical response in a tissue, system, animal, individual, or human. This includes one or more of the following: (1) prevention of disease: for example, prevention of disease, disorder, or disease in an individual who is susceptible to disease, disorder, or disease but has not yet experienced or developed the pathology or symptoms of the disease; (2) inhibition of disease: for example, inhibition of disease, disorder, or disease in an individual who has experienced or developed the pathology or symptoms of disease, disorder, or disease (i.e., prevention of further progression of the pathology and / or symptoms); (3) relief of disease: for example, relief of disease, disorder, or disease in an individual who has experienced or developed the pathology or symptoms of disease, disorder, or disease (i.e., reversal of the pathology and / or symptoms).

[0118] The term "ligand" refers to a macromolecule that can recognize and bind to an antigen or receptor associated with a target cell. The role of a ligand is to deliver a drug to the target cell population to which it is bound. These ligands include, but are not limited to, protein hormones, lectins, growth factors, antibodies, or other molecules capable of binding to cells. In embodiments of this disclosure, a ligand is denoted as LG, and the ligand can form a linker bond with a linker unit via a heteroatom on the ligand, and is preferably an antibody or its antigen-binding fragment selected from chimeric antibodies, humanized antibodies, fully human antibodies, or mouse-derived antibodies, and is preferably a monoclonal antibody.

[0119] The term “drug” refers to any compound having desired biological activity and reactive functional groups, which can be used to incorporate the drug into the complex of this disclosure. Desired biological activity includes the diagnosis, cure, alleviation, treatment, or prevention of disease in humans or other animals. The reactive functional group is a functional group L 3 or L 4 It forms a bond with the functional group L. In some embodiments, the drug has a functional group L 3 or L 4 It has a nitrogen atom or hydroxyl group that can form a bond with it.

[0120] The term "antibody" refers to immunoglobulins, which include tetrapeptide chains (also called "monoclonal antibodies" or "single epitope antibodies") in which two identical heavy chains and two identical light chains are linked by interchain disulfide bonds, and tetrapeptide chains (also called "bispecific antibodies" or "double epitope antibodies") in which two different heavy chains and two different light chains are 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. Therefore, immunoglobulins are classified into five classes, or isotypes: IgM, IgD, IgG, IgA, and IgE, with corresponding heavy chains being μ, δ, γ, α, and ε chains, respectively. Even within the same Ig class, further subclasses are formed based on differences in the amino acid composition of the 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. Light chains are classified into κ chains and λ chains based on differences in their constant region. Each of the five Ig classes may have either a κ chain or a λ chain. The antibodies described herein are preferably specific antibodies against cell surface antigens on target cells.Non-limiting examples include one or more of the following: anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MUCl antibody, anti-Lewis antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-integrin antibody, anti-PSMA antibody, anti-tenascin C antibody, anti-SLC44A4 antibody, or anti-mesothelin antibody, preferably Examples include trastuzumab (brand name Herceptin), pertuzumab (also known as 2C4, brand name Perjeta), nimotuzumab (brand name Taishinsei), enoblituzumab, emibetuzumab, inotuzumab, pinatuzumab, brentuximab, gemtuzumab, bivatuzumab, lorvotuzumab, cBR96, or glembatumumab.

[0121] The sequence of approximately 110 amino acids near the N-terminus of both the heavy and light chains of an antibody is highly different and is called the variable region (Fv region). The sequence of the remaining amino acids near the C-terminus is relatively stable and is called the constant region. The variable region contains three hypervariable regions (HVRs) and four relatively conserved framework regions (FRs). The three hypervariable regions determine the specificity of the antibody and are also called 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 in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from the amino terminus to the carboxyl terminus. The three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3. The three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.

[0122] The antibodies of this disclosure include mouse-derived antibodies, chimeric antibodies, humanized antibodies, and fully human antibodies, with humanized antibodies and fully human antibodies being preferred.

[0123] In this disclosure, the term “mouse-derived antibody” refers to an antibody prepared using a mouse in accordance with the knowledge and techniques of the art. Preparation involves injecting a specific antigen into a subject, followed by the isolation of a hybridoma expressing an antibody having a desired sequence or functional properties.

[0124] The term "chimeric antibody" refers to an antibody created by fusing the variable region of a mouse-derived antibody with the constant region of a human antibody, and can mitigate the immune response induced by mouse-derived antibodies. To produce a chimeric antibody, first, a hybridoma that secretes mouse-specific monoclonal antibodies is formed. Next, the variable region gene is cloned from the mouse hybridoma cells. Furthermore, if necessary, the constant region gene of a human antibody is cloned, and the mouse variable region gene and the human constant region gene are linked to form a chimeric gene. This is then incorporated into an expression vector, and finally, the chimeric antibody molecule is expressed in a eukaryote or prokaryotic system.

[0125] The term "humanized antibody," also known as a CDR-grafted antibody, refers to an antibody produced by transplanting a mouse CDR sequence into a variable region framework of a human antibody, i.e., a different type of human germline antibody framework sequence. This overcomes heterogeneous reactions induced by chimeric antibodies containing large amounts of mouse protein components. Such framework sequences can be obtained from public DNA databases containing germline antibody gene sequences or from publicly available literature. For example, germline DNA sequences of human heavy and light chain variable region genes are available in the "VBase" human germline sequence database (www.mrccpe.com.ac.uk / vbase) and in Kabat, EA et al., 1991, Sequences of Proteins of Immunological Interest, 5th edition. To avoid a decrease in activity due to reduced immunogenicity, activity can be maintained by introducing minimal reverse or reverse mutations into the human antibody variable region framework sequence. The humanized antibodies in this disclosure also include humanized antibodies that have undergone affinity maturation to CDRs by phage display. Further explanations of humanization methods using mouse antibodies include, for example, the methods by Queen et al., Proc., Natl. Acad. Sci. USA, 88, 2869, 1991 and Winter et al. [Jones et al., Nature, 321, 522 (1986), Riechmann et al., Nature, 332, 323-327 (1988), Verhoeyen et al., Science, 239, 1534 (1988)].

[0126] "Fully humanized antibodies," also known as "fully human monoclonal antibodies," refer to antibodies in which both the variable and constant regions are derived from humans, and which have been freed from immunogenicity, toxicity, and side effects. The development of monoclonal antibodies progresses through four stages: mouse-derived monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies, and fully human monoclonal antibodies. This disclosure relates to fully human monoclonal antibodies. Technologies related to the production of fully human antibodies mainly include human hybridoma technology, EBV-transformed B lymphocyte technology, phage display technology, transgenic mouse antibody production technology, and single B cell antibody production technology.

[0127] The term "antigen-binding fragment" refers to one or more fragments of an antibody that maintain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed using fragments of a full-length antibody. Examples of binding fragments included in "antigen-binding fragments" are: (i) Fab fragments (monovalent fragments consisting of VL, VH, CL, and CH1 domains), (ii) F(ab')2 fragments (bivalent fragments containing two Fab fragments linked by a disulfide bond in the hinge region), (iii) Fd fragments consisting of VH and CH1 domains, (iv) Fv fragments consisting of VH and VL domains of one arm of the antibody, (v) single domain or dAb fragments consisting of a VH domain (Ward et al., (1989) Nature 341:544-546), (vi) isolated complementarity-determining regions (CDRs), or (vii) combinations of two or more isolated CDRs arbitrarily linked by a synthetic linker. Furthermore, although the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be linked by a synthetic linker using recombination, thereby forming a monovalent molecule with the VL and VH regions paired together to produce a single protein chain (called single-chain Fv (scFv); see, for example, Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci USA 85:5879-5883). Such single-chain antibodies are also included in the term "antigen-binding fragment" of an antibody. These antibody fragments are obtained using prior art known to those skilled in the art and are screened for their functionality, similar to complete antibodies. The antigen-binding portion can be generated by recombinant DNA technology or by enzymatic or chemical cleavage of complete immunoglobulins. Antibodies can be various isotype antibodies, such as IgG (e.g., IgG1, IgG2, IgG3, or IgG4 subtypes), IgA1, IgA2, IgD, IgE, or IgM antibodies.

[0128] Fab is an antibody fragment with antigen-binding activity and a molecular weight of approximately 50,000, obtained by treating an IgG antibody molecule with the protease papain (an enzyme that cleaves the amino acid residue at position 224 of the heavy chain). Approximately half of the N-terminal side of the heavy chain and the entire light chain are linked by disulfide bonds.

[0129] F(ab')2 is an antibody fragment with antigen-binding activity and a molecular weight of approximately 100,000, obtained by digesting the portion below the two disulfide bonds in the hinge region of IgG with pepsin enzyme, and containing two Fab regions linked at the hinge position.

[0130] Fab' is an antibody fragment with antigen-binding activity and a molecular weight of approximately 50,000, obtained by cleaving the disulfide bond in the hinge region of the aforementioned F(ab')2.

[0131] Furthermore, Fab' can be generated by inserting the DNA encoding the antibody's Fab' fragment into a prokaryotic or eukaryotic expression vector, and then introducing the vector into a prokaryotic or eukaryotic organism to express Fab'.

[0132] The terms "single-chain antibody," "single-chain Fv," or "scFv" refer to a molecule containing a variable domain (or region, VH) of an antibody heavy chain and a variable domain (or region, VL) of an antibody light chain linked by a linker. Such scFv molecules may have the common structure NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. A suitable prior art linker consists of a repeat or variant of the GGGGS amino acid sequence, for example, 1 to 4 repeat variants (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90:6444-6448). Other linkers available in this disclosure are described in Alfthan et al. (1995), Protein Eng. 8:725-731, Choi et al. (2001), Eur. J. Immuno l. 31:94-106, Hu et al. (1996), Cancer Res. 56:3055-3061, Kipriyanov et al. (1999), J. Mol. Biol. 293:41-56, and Roovers et al. (2001), Cancer Immunol.

[0133] The term "CDR" refers to the region within the antibody's variable domain that primarily promotes antigen binding, among the six highly variable regions. One of the most commonly used definitions of the six CDRs is presented in Kabat EA et al., (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242). As used herein, Kabat's definition of CDR applies only to the CDR1, CDR2, and CDR3 (CDR L1, CDR L2, CDR L3, or L1, L2, L3) of the light chain variable domain, and to the CDR2 and CDR3 (CDR H2, CDR H3, or H2, H3) of the heavy chain variable domain.

[0134] The term "antibody framework" refers to a portion of the variable domain (VL) or VH that functions as a scaffold for the antigen-binding loop (CDR) of that variable domain. Essentially, it is a variable domain that does not have a CDR.

[0135] The term "epitope" or "antigenic determinant" refers to a site on an antigen to which an immunoglobulin or antibody specifically binds. Epitopes typically consist of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive or discontinuous amino acids that occupy a unique spatial structure. See, for example, Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, GEMorris, Ed. (1996).

[0136] The terms "specific binding," "selective binding," "to bind selectively," and "to bind specifically" refer to an antibody binding to an epitope on a given antigen. Typically, antibodies bind to an epitope of about 10 -7 Less than M, for example, about 10 -8 M, 10 -9 M, or 10 -10 It binds with affinity (KD) of M or less.

[0137] The term "nucleic acid molecule" refers to both DNA and RNA molecules. Nucleic acid molecules can be single-stranded or double-stranded, but double-stranded DNA is preferred. A nucleic acid is described as "effectively ligated" when it has a functional relationship with another nucleic acid sequence. For example, if a promoter or enhancer affects the transcription of a coding sequence, that promoter or enhancer is effectively ligated to that coding sequence.

[0138] The term “vector” refers to a nucleic acid molecule capable of delivering another nucleic acid to which it is ligated. In one embodiment, the vector is a “plasmid,” which refers to a circular double-stranded DNA loop to which additional DNA fragments can be ligated. In another embodiment, the vector is a viral vector, to which additional DNA fragments can be ligated to a viral genome. The vectors disclosed herein can autonomously replicate within the host cell into which they are introduced (e.g., bacterial vectors with bacterial origins of replication and episodic mammalian vectors), or, after being introduced into a host cell, can be integrated into the host cell's genome and replicate together with the host genome (e.g., non-episodic mammalian vectors).

[0139] Conventional methods for the preparation and purification of antibodies and antigen-binding fragments are well known in the prior art, such as those described in Chapters 5-8 and 15 of Cold Spring Harbor's "Guide to Antibody Laboratory Techniques." Antigen-binding fragments can also be prepared using conventional methods. The antibodies or antigen-binding fragments described herein are prepared by adding one or more human FR regions to a non-human CDR region using genetic engineering techniques. Human FR germline sequences can be obtained from the ImMunoGeneTics (IMGT) website (http: / / imgt.cines.fr) or from the journal Immunoglobulin (2001 ISBN 012441351) by alignment with the IMGT Human Antibody Variable Region Germline Gene Database and MOE software.

[0140] The term "host cell" refers to a cell into which an expression vector has been introduced. Host cells can include bacteria, microorganisms, plant cells, and animal cells. Easily transformable bacteria include Enterobacteriaceae such as Escherichia coli and Salmonella, Bacillaceae such as Bacillus subtilis, Pneumococcus, Streptococcus, and Haemophilus influenzae. Suitable microorganisms include Saccharomyces cerevisiae and Pichia pastoris. Suitable animal host cell lines include CHO (Chinese hamster ovary cell line) and NSO cells.

[0141] The engineered antibodies or antigen-binding fragments of this disclosure can be prepared and purified using conventional methods. For example, cDNA sequences encoding heavy and light chains can be cloned and recombinant into a GS expression vector. The recombinant immunoglobulin expression vector can be stably transfected into CHO cells. A more preferred prior art is the mammalian expression system, which results in antibody glycosylation, particularly at the highly conserved N-terminal region of the Fc area. Positive clones are cultured in serum-free medium in a bioreactor to produce antibodies. The antibody-secreting culture can be purified using a standard method with an A or G Sepharose FF column containing a prepared buffer. Nonspecifically bound components are washed away. Bound antibodies are eluted using a pH gradient, and antibody fragments are detected and recovered by SDS-PAGE. The antibodies can be filtered and concentrated using conventional methods. Soluble mixtures and polymers can also be removed using conventional methods such as molecular sieving or ion exchange. The resulting product must be immediately frozen at -70°C or lyophilized.

[0142] The term "peptide" refers to a compound fragment that lies between amino acids and proteins. It is a link between two or more amino acid molecules via peptide bonds, and is a structural and functional fragment of a protein. Hormones and enzymes are essentially peptides.

[0143] The term "sugar" refers to biological macromolecules composed of three elements: C, H, and O, and is classified into monosaccharides, disaccharides, polysaccharides, etc.

[0144] The term "amino acid analog" (e.g., "arginine analog," "lysine analog," or "histidine analog") refers to an amino acid variant that maintains at least one function of the amino acid in question, such as side-chain polarity or electrostatic interaction. Such variants may have extended or shorter side chains and maintain side-chain polarity or electrostatic interaction, for example, via one or more -CH2- groups. For example, an arginine analog may contain an additional methylene or ethylene group between the main chain and the guanidine / guanidinium group. [Effects of the Invention]

[0145] Beneficial effects The compounds and conjugates of this disclosure possess excellent tumor cell inhibitory activity, stability, and in vivo therapeutic efficacy in animals, and may function as effective drugs for inhibiting tumor cells and preventing and / or treating cancer. [Brief explanation of the drawing]

[0146] [Figure 1] The results of bystander killing studies of the antibody-drug conjugates of this disclosure against HER2-targeted tumor cells are shown. [Figure 2] The results of bystander killing studies of the antibody-drug conjugates of this disclosure against EGFR-targeted tumor cells are shown. [Modes for carrying out the invention]

[0147] The technical solutions of this disclosure are described in further detail below with reference to specific examples. It should be understood that the following examples are illustrative and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above-mentioned content of this disclosure are included within the scope of protection intended by this disclosure.

[0148] Unless otherwise specified, the raw materials and reagents used in the following examples are either commercially available or can be prepared by known methods. I. Examples of Antibodies

[0149] The following antibodies were prepared using standard antibody preparation methods, such as transfecting eukaryotic cells (HEK293 cells, Life Technologies Cat. No. 11625019) after constructing a vector.

[0150] An example antibody sequence is as follows:

[0151] The following is the sequence of Trastuzumab. Light chain DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:1 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:2 The following is the sequence of Pertuzumab. Light chain DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO.3 Heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO.4 The following is the sequence of Nimotuzumab. Light chain DIQMTQSPSSLSASVGDRVTITCRSSQNIVHSNGNTYLDWYQQTPGKAPKLLIYKVSNRFSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCFQYSHVPWTFGQGTKL QITREVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:5 Heavy chain QVQLQQSGAEVKKPGSSVKVSCKASGYTFTNYYIYWVRQAPGQGLEWIGGINPTSGGSNFNEKFKTRVTITVDESTNTAYMELSSLRSEDTAFYFCARQGLWFDSDGRGFDFW GQGSTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:6 II. Examples of Compounds

[0152] The structure of a compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The chemical shift δ is 10 -6 The values ​​are expressed in ppm. NMR measurements are performed using a Bruker NMR spectrometer, and the solvents used are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0153] For LCMS measurements, the Agilent 1260 Infinity II (ESI) mass spectrometer, Waters UPLC H Class plus (ESI), or Shimadzu LCMS-2020 (ESI) are used.

[0154] For high-performance liquid chromatography (HPLC) analysis, either the Agilent 1260 or the Shimadzu LC-20AD is used.

[0155] For pre-HPLC (preparative high-performance liquid chromatography), a GILSON GX-281 or Agilent 1260 Infinity II preparative high-performance liquid chromatography system is used.

[0156] For chiral preparative chromatography, supercritical fluid chromatography (SFC) is used, with either the Shimadzu LC-30Adsf or Shimadzu LC-20AD being the instruments used.

[0157] For thin-layer chromatography, GF254 acrylic adhesive silica gel plates manufactured by Anhui Liangchen Silica Source Materials Co., Ltd. are used. For silica gel plates used in thin-layer chromatography (TLC), 0.2 mm standard silica gel plates are used, and for product separation and purification by thin-layer chromatography, 0.5 mm standard silica gel plates are used.

[0158] In column chromatography, silica gel with a mesh size of 200-300, manufactured by Anhui Liangchen Silica Source Materials Co., Ltd., is generally used as the support material.

[0159] Mean kinase inhibition rate and IC 50 The values ​​are measured using a SpectraMax i3X microplate reader (MD Instruments, USA).

[0160] The known starting materials of this disclosure can be synthesized using methods known in the art, or purchased from companies such as Bide Pharmaceutical Co., Ltd., Legian Co., Ltd., Shaoyuan Chemical Technology Co., Ltd., and Energy Chemical Co., Ltd.

[0161] Unless otherwise specified, the reactions in the following examples are carried out under an argon or nitrogen atmosphere.

[0162] "Argon atmosphere" or "nitrogen atmosphere" refers to a reaction flask connected to an argon balloon or nitrogen balloon with a capacity of approximately 1 L.

[0163] "Hydrogen atmosphere" refers to a reaction flask connected to a hydrogen balloon with a capacity of approximately 1 liter.

[0164] The hydrogenation reaction typically involves creating a vacuum, filling it with hydrogen, and repeating this process three times.

[0165] "Under an oxygen atmosphere" refers to a reaction flask connected to an oxygen balloon with a capacity of approximately 1 liter.

[0166] In the following examples, unless otherwise specified, "solution" refers to an aqueous solution, and the reaction temperature is room temperature, i.e., 20°C to 30°C.

[0167] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used in column chromatography for purifying the compound, and the developing solvent system for thin-layer chromatography included A: dichloromethane / methanol system and B: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compound and could also be adjusted by adding small amounts of basic or acidic reagents such as triethylamine or acetic acid. Example 2-1: Preparation of Compound 1

[0168] [ka] Step 1 2-(6-cyano-5-oxo-2,3-dihydro-5H-spiro[indolidine-1,2'-[1,3]dioxolan]-7-yl)-3-cyclopropylpropionate ethyl 1b 1a (1.01 g, 3.31 mmol, prepared according to the method disclosed in Example 30 on page 28 of patent application "WO2019238046") was dissolved in 15 mL of acetonitrile, and bromomethylcyclopropane (894.93 mg, 6.63 mmol) and potassium carbonate (916.16 mg, 6.63 mmol) were added, and the mixture was stirred at 80°C for 13 hours. 10 mL of water was added, and the diluted reaction solution was extracted with ethyl acetate (15 mL x 2). The organic phase was washed with saturated sodium chloride solution (10 mL x 2), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated by vacuum distillation, and the resulting residue was purified by silica gel column chromatography using eluent A to obtain the title product 1b (1.12 g, yield: 92%) in the form of a yellow solid. MS m / z (ESI): 359.1 [M+1]. Step 2 3-Cyclopropyl-2-(6-Formyl-5-oxo-2,3-dihydro-5H-spiro[indolidine-1,2'-[1,3]dioxolane]-7-yl]propionate ethyl 1c Dissolve 1b (1.12 g, 3.05 mmol) in a mixed solvent of 5 mL of water, 5 mL of acetonitrile, and 5 mL of formic acid. Under nitrogen gas protection, add ranney nickel (261.72 mg), perform three hydrogen gas purgings, and stir the reaction mixture with hydrogen gas (15 Psi) at 60°C for 4 hours. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with dichloromethane (50 mL x 3), the filtrate was washed with hydrochloric acid aqueous solution (4 M, 20 mL), then with sodium carbonate aqueous solution (12 M, 50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by vacuum distillation, and the resulting residue was purified by reversed-phase liquid chromatography (separation conditions: chromatography column: 120 g Flash Coulmn Welch Ultimate XB_C18 20~40 μm; mobile phase: A-water: B-acetonitrile, isocratic elution, flow rate: 85 mL / min, instrument: ISCO) to obtain the title product 1c (680 mg, yield: 60%) in the form of a yellow solid. MS m / z (ESI): 362.1 [M+1]. Step 3 4-(cyclopropylmethyl)-1,4,7,8-tetrahydro-3H,10H-spiro[pyrano[3,4-f]indolidine-6,2'-[1,3]dioxolane]-3,10-dione1d Dissolve 1c (680 mg, 1.85 mmol) in 10 mL of dichloromethane, and under nitrogen gas protection, lower the temperature to 0°C in an ice bath. Sodium borohydride (108.02 mg, 2.86 mmol) is added in batches, and the reaction mixture is stirred at 0°C for 30 minutes. At 25°C, acetic acid (133.15 mg, 2.22 mmol) is added dropwise to generate gas, and stirring is continued for 2 hours. At 15°C, 30 mL of water is added dropwise to generate gas, and stirring is continued at 15°C for 1.5 hours. Wash the reaction mixture with water (50 mL), and at 15°C, p-toluenesulfonic acid monohydrate (35.15 mg, 184.78 μmol) is added to the washed organic phase, and stirring is continued at 15°C for 12 hours. 50 mL of water was added, and the reaction mixture was extracted with dichloromethane (45 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The resulting residue was purified using silica gel column chromatography in the developing system B to obtain the title product 1d (200 mg, yield: 32%) in the form of a yellow oil. MS m / z (ESI): 318.1 [M+1]. Step 4 4-(cyclopropylmethyl)-4-hydroxy-1,4,7,8-tetrahydro-3H,10H-spiro[pyrano[3,4-f]indolidine-6,2'-[1,3]dioxolane]-3,10-dione1e 1d (202.13 mg, 598.74 μmol) was dissolved in 0.5 mL of methanol, the temperature was lowered to 0°C in an ice bath, potassium carbonate (82.75 mg, 598.74 μmol) was added in batches, and the mixture was stirred at 0°C for 5 hours while oxygen bubbling (15 psi). The reaction mixture was poured into 10 mL of saturated ammonium chloride aqueous solution, concentrated by vacuum distillation to remove methanol, and the reaction mixture (20 mL x 3) was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation to obtain the crude product 1e (140 mg) in the form of a yellow oily substance. The product was used in the next step without purification. MS m / z (ESI): 334.1 [M+1]. Step 5 (S)-4-(cyclopropylmethyl)-4-hydroxy-1,4,7,8-tetrahydro-3H,10H-spiro[3,4-f]indolidine-6,2'-[1,3]dioxolane]-3,10-dione1e-1 (R)-4-(cyclopropylmethyl)-4-hydroxy-1,4,7,8-tetrahydro-3H,10H-spiro[3,4-f]indolidine-6,2'-[1,3]dioxolane]-3,10-dione1e-2 1e (1.30 g, 3.88 mmol) was separated by SFC (separation conditions: chromatography column: DAIEL CHIRALPAK AS 250 mm × 50 mm, 10 μm; mobile phase: A - carbon dioxide: B - methanol (0.1% NH3·H2O), isocratic elution: B: 20%, flow rate: 120 mL / min, instrument: Shimadzu LC-30ADsf) to obtain the title product 1e-1 (301 mg, yield: 22.1%) in the form of a yellow solid, and the title product 1e-2 (285 mg, yield: 19.4%) in the form of a yellow solid. Single-configuration compound 1e-1 SFC analysis: Maintenance time 1.392 minutes. (Chromatography column: Chiralpak AS-350 × 4.6 mm I.D., 3 μm, mobile phase: A-carbon dioxide, B-methanol (0.05% diethylamine), isocratic elution: B%: 5%~40%, flow rate: 3 mL / min, instrument: Shimadzu LC-30ADsf). MS m / z (ESI): 334.0 [M+1]. Single-configuration compound 1e-2 SFC analysis: Maintenance time 1.762 minutes. (Chromatography column: Chiralpak AS-350 × 4.6 mm I.D., 3 μm, mobile phase: A-carbon dioxide, B-methanol (0.05% diethylamine), isocratic elution: B%: 5%~40%, flow rate: 3 mL / min, instrument: Shimadzu LC-30ADsf). MS m / z (ESI): 333.9 [M+1]. Step 6 (S)-4-(cyclopropylmethyl)-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indridine-3,6,10(4H)-trione 1f-1 1e-1 (301 mg, 857 μmol) was dissolved in a mixed solution of 2 mL of trifluoroacetic acid and 0.5 mL of water, and the mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated by vacuum distillation, and the resulting residue was not purified to obtain the crude product 1f-1 (209 mg) in the form of a yellow solid. This product was used in the next step without purification. MS m / z (ESI): 290.1 ​​[M+1]. Step 7 Dissolve 1 g (800 mg, 5.83 mmol) in 20 mL of 1,2-dichloroethane, and under nitrogen gas protection, lower the temperature to 0°C in an ice bath. Add dropwise boron trichloride in dichloromethane solution (1 M, 4.08 mL) and 4-pentennitrile (709 mg, 8.75 mmol), and stir at 80°C for 2 hours under nitrogen gas protection. Cool to room temperature, add hydrochloric acid aqueous solution (2 M, 50 mL), and stir at 80°C for 0.5 hours. Extract with dichloromethane (30 mL x 3), dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue by silica gel column chromatography using developing system B to obtain the title product 1h (220 mg, yield: 17%) in the form of a yellow oil. MS m / z (ESI): 220.2 [M+1]. Step 8 1f-1 (288 mg, 991 μmol) and 1h (220 mg, 991 μmol) were dissolved in 10 mL of toluene, and pyridine 4-methylbenzenesulfonate (124 mg, 495 μmol) and o-cresol (214 mg, 1.98 mmol) were added. The mixture was stirred at 120°C for 2 hours under nitrogen gas protection. 50 mL of water was added to the reaction mixture, and it was extracted with dichloromethane (45 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using cell A to obtain the title product 1i (202 mg, yield: 41%) in the form of a yellow solid. MS m / z (ESI): 473.0 [M+1]. Step 9 1i (200 mg, 406 μmol) was dissolved in 10 mL of dichloromethane, the temperature was lowered to -78°C, and ozone bubbling was performed for 0.5 hours (15 Psi). Excess ozone was removed using nitrogen, and triphenylphosphine (213 mg, 812 μmol) was added at -78°C, and the mixture was stirred at -78°C for 0.5 hours. 50 mL of water was added to the reaction mixture, and it was extracted with dichloromethane (45 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a dichloromethane / tetrahydrofuran system to obtain the title product 1j (70 mg, yield: 36%) in the form of a yellow solid. MS m / z (ESI): 475.3 [M+1]. Step 10 1 joule (70.0 mg, 147 μmol) was dissolved in 5 mL of tetrahydrofuran, and under nitrogen gas protection, sodium borohydride (2.79 mg, 73.7 μmol) was added and the mixture was stirred at -78°C for 1 hour. 10 mL of ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate (8 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography (separation conditions: chromatography column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: A-water (0.225% formic acid): B-acetonitrile, isocratic elution: B%: 22%~42%) to obtain the title product 1 (8.95 mg, yield: 21%) in the form of a yellow solid. MS m / z (ESI): 477.0 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.64 - 7.61 (m, 1H), 7.55 - 7.51 (m, 1H), 7.41 - 7.37 (m, 1H), 6.24 - 6.19 (m, 2H), 5.62 - 5.55 (m, 1H), 5.40 - 5.34 (m, 1H), 5.26 - 5.21 (m, 2H), 3.72 - 3.64 (m, 2H), 3.25 - 3.19 (m, 2H), 1.99 - 1.90 (m, 3H), 1.89 - 1.81 (m, 1H), 0.97 - 0.88 (m, 1H), 0.52 - 0.38 (m, 2H), 0.15 - 0.09 (m, 1H), 0.07 - 0.00 (m, 1H). Example 2-2: Preparation of Compound 2

[0169] [ka] Step 1 2a (1.00 g, 7.99 mmol) was dissolved in 20 mL of 1,2-dichloroethane, and under nitrogen gas protection, the temperature was lowered to 0°C in an ice bath. Dichloromethane solution of boron trichloride (1 M, 10.4 mL) and 4-pentennitrile (777 mg, 9.59 mmol) were added dropwise, and the mixture was stirred at 80°C for 5 hours under nitrogen gas protection. After cooling to room temperature, aqueous hydrochloric acid (2 M, 9 mL) was added, and the mixture was stirred at 80°C for 0.5 hours. Extraction was performed with dichloromethane (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using developing system B to obtain the title product 2b (315 mg, yield: 19%) in the form of a yellow solid. MS m / z (ESI): 208.1 [M+1]. Step 2 1f-1 (400 mg, 1.37 mmol) and 2b (313 mg, 1.51 mmol) were dissolved in 50 mL of toluene, and pyridine 4-methylbenzenesulfonate (207 mg, 823 μmol) and o-cresol (1.19 g, 11.0 mmol) were added. The mixture was stirred at 135°C for 3 hours. The reaction mixture was concentrated by vacuum distillation, and the resulting residue was purified by silica gel column chromatography using cell A to obtain the title product 2c (420 mg, yield: 60%) in the form of a yellow solid. MS m / z (ESI): 461.3 [M+1]. Step 3 2c (100 mg, 197 μmol) was dissolved in 2 mL of dichloromethane, the temperature was lowered to -78°C, and ozone bubbling was performed for 0.5 hours (15 Psi). Excess ozone was removed using nitrogen, and triphenylphosphine (51.7 mg, 197 μmol) was added at -78°C, and the mixture was stirred at -78°C for 0.5 hours. The reaction mixture was concentrated by vacuum distillation, and the resulting residue was purified by silica gel column chromatography using developing system A to obtain the title product 2d (53.0 mg, yield: 54%) in the form of a yellow solid. MS m / z (ESI): 463.2 [M+1]. Step 4 Dissolve 2d (40.0 mg, 80.1 μmol) in a mixed solvent of 2 mL of tetrahydrofuran and 0.1 mL of N,N-dimethylacetamide. Under nitrogen gas protection, add sodium borohydride (1.52 mg, 40.1 μmol), stir at -78°C for 1 hour, add 1 mL of ammonium chloride solution to the reaction mixture, extract with ethyl acetate (2 mL × 3), dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue by preparative high-performance liquid chromatography (separation conditions: chromatography column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: A-water (0.225% formic acid): B-acetonitrile, isocratic elution: B%: 27%~57%). Next, purify by supercritical fluid chromatography (chromatography column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm) The product was purified using a mobile phase of A-carbon dioxide, B-methanol and acetonitrile, and isocratic elution (B%: 55%) to obtain the title product 2 (8.66 mg, yield: 45%) in the form of a pale yellow solid. MS m / z (ESI): 464.9 [M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.24 - 8.17 (m, 1H), 7.80 - 7.73 (m, 1H), 7.73 - 7.67 (m, 1H), 5.64 - 5.57 (m, 1H), 5.44 - 5.33 (m, 3H), 3.75 - 3.66 (m, 2H), 3.40 - 3.34 (m, 2H), 2.60 - 2.52 (m, 3H), 2.04 - 1.96 (m, 2H), 1.94 - 1.82 (m, 2H), 0.93 - 0.89 (m, 1H), 0.52 - 0.38 (m, 2H), 0.17 - 0.08 (m, 1H), 0.07 - -0.04 (m, 1H). Examples 2-3: Preparation of Compound 3

[0170] [ka] Step 1 Dissolve 1 g (1.5 g, 10.94 mmol) in 20 mL of 1,2-dichloroethane, and under nitrogen gas protection, lower the temperature to 0°C in an ice bath. Add dropwise boron trichloride in dichloromethane solution (1 M, 8.75 mL) and 5-hexennitrile (1.56 g, 16.4 mmol), and stir at 80°C for 2 hours under nitrogen gas protection. Cool to room temperature, add hydrochloric acid aqueous solution (2 M, 50 mL), and stir at 80°C for 0.5 hours. Extract with dichloromethane (50 mL × 3), dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue using silica gel column chromatography in developing system B to obtain the title product 3a (502 mg, yield: 19%) in the form of a yellow oil. MS m / z (ESI): 234.0 [M+1]. Step 2 1f-1 (249 mg, 857 μmol) and 3a (200 mg, 780 μmol) were dissolved in 5 mL of toluene, and pyridine 4-methylbenzenesulfonate (150 mg, 600 μmol) and o-cresol (185 mg, 1.71 mmol) were added. The mixture was stirred at 120°C for 2 hours under nitrogen gas protection. 50 mL of water was added to the reaction mixture, and it was extracted with dichloromethane (45 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using cell A to obtain the title product 3b (310 mg, yield: 53%) in the form of a yellow solid. MS m / z (ESI): 487.3 [M+1]. Step 3 3b (250 mg, 513 μmol) was dissolved in 5 mL of dichloromethane, the temperature was lowered to -78°C, and ozone bubbling was performed for 0.5 hours (15 Psi). Excess ozone was removed using nitrogen, and triphenylphosphine (674 mg, 2.57 mmol) was added at -78°C, and the mixture was stirred at -78°C for 0.5 hours. The reaction mixture was concentrated by vacuum distillation, and the resulting residue was purified by silica gel column chromatography using a dichloromethane / tetrahydrofuran eluent to obtain the title product 3c (65.0 mg, yield: 26%) in the form of a yellow solid. MS m / z (ESI): 489.2 [M+1]. Step 4 3c (65.0 mg, 133 μmol) was dissolved in 15 mL of tetrahydrofuran, and under nitrogen gas protection, sodium borohydride (2.5 mg, 66 μmol) was added and the mixture was stirred at -78°C for 1 hour. 20 mL of ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography (separation conditions: chromatography column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: A-water (0.225% formic acid): B-acetonitrile, isocratic elution: B%: 25%~45%) to obtain the title product 3 (5.69 mg, yield: 9%) in the form of a yellow solid. MS m / z (ESI): 491.0 [M+1]. 1 H NMR (400 MHz, CD3OD) δ 7.62 - 7.58 (m, 1H), 7.50 - 7.46 (m, 1H), 7.37 - 7.34 (m, 1H), 6.24 - 6.18 (m, 2H), 5.62 - 5.54 (m, 1H), 5.42 - 5.32 (m, 1H), 5.21 - 5.16 (m, 2H), 3.69 - 3.62 (m, 2H), 3.17 - 3.10 (m, 2H), 1.98 - 1.90 (m, 1H), 1.88 - 1.79 (m, 3H), 1.78 - 1.70 (m, 2H), 0.96 - 0.85 (m, 1H), 0.52 - 0.40 (m, 2H), 0.18 - 0.08 (m, 1H), 0.07 - -0.00 (m, 1H). Examples 2-4: Preparation of Compound 4

[0171] [ka] Examples 2-5: Preparation of Compound 5

[0172] [ka] Examples 2-6: Preparation of Compound 6

[0173] [ka] Examples 2-7: Preparation of Compound 7

[0174] [ka] Examples 2-8: Preparation of Compound 8

[0175] [ka] Examples 2-9: Preparation of Compound 9

[0176] [ka] Examples 2-10: Preparation of Compound 10

[0177] [ka] Example 2-11: Preparation of Compound 11

[0178] [ka] Example 2-12: Preparation of Compound 12

[0179] [ka] Example 2-13: Preparation of Compound 13

[0180] [ka] Example 2-14: Preparation of Compound 14

[0181] [ka] Example 2-15: Preparation of Compound 15

[0182] [ka] Example 2-16: Preparation of Compound 16

[0183] [ka] Example 2-17: Preparation of Compound 17

[0184] [ka] Example 2-18: Preparation of Compound 18

[0185] [ka] Example 2-19: Preparation of Compound 19

[0186] [ka] Example 2-20: Preparation of Compound 20

[0187] [ka] Example 2-21: Preparation of Compound 21

[0188] [ka] Example 2-22: Preparation of Compound 22

[0189] [ka] Example 2-23: Preparation of Compound 23

[0190] [ka] Examples 2-24: Preparation of Compound 24

[0191] [ka] Examples 2-25: Preparation of Compound 25

[0192] [ka] Example 2-26: Preparation of Reference Material 1

[0193] [ka] It was prepared using the method disclosed in Example A1.9 on page 207 of the patent application "WO2022170971 Al". III. Examples of preparation of complex intermediate linker-drug

[0194] Example 3-1 LD-1 [ka] Step 1 LD-1a (2.20 g, 12.1 mmol, prepared using the method disclosed in Example 4 on page 62 of patent application "WO2020077038 A1"), silver nitrite (111 mg, 724 μmol), bis(benzonitrile)palladium(II) dichloride (555 mg, 1.45 mmol), nitromethane (4.90 g, 80.3 mmol), and copper(II) chloride dihydrate (247 mg, 1.45 mmol) were dissolved in 44 mL of tert-butanol, and the mixture was stirred at 25°C for 12 hours in the presence of oxygen after three oxygen gas exchanges. At 25°C, 150 mL of water was added to the reaction mixture and extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The resulting residue was purified using silica gel column chromatography in developing system B to obtain the title product LD-1b (800 mg, yield: 33%) in the form of a white solid. Step 2 LD-1b (800 mg, 4.04 mmol) was dissolved in 24 mL of methanol, then potassium carbonate (1.12 g, 8.07 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (930 mg, 4.84 mmol) were added, and the mixture was stirred at 25°C for 12 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The resulting residue was purified by silica gel column chromatography using cell B to obtain the title product LD-1c (650 mg, yield: 83%) in the form of a white solid. Step 3 LD-1c (650 mg, 3.35 mmol), 5-bromo-2-methylthiopyrimidine (686 mg, 3.35 mmol), triethylamine (3.39 g, 33.4 mmol), cuprous iodide (63.7 mg, 334 μmol), and bis(triphenylphosphine)palladium dichloride (244 mg, 349 μmol) were dissolved in 10 mL of tetrahydrofuran, and the mixture was stirred at 60°C for 2 hours under nitrogen gas protection after three nitrogen purging cycles. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using cell B to obtain the title product LD-1d (770 mg, yield: 68%) in the form of a white solid. MS m / z (ESI): 319.6 [M+1]. Step 4 LD-1d (1.80 g, 5.65 mmol) was dissolved in 20 mL of dichloromethane, and then m-chloroperoxybenzoic acid (2.87 g, 14.1 mmol, purity 85.0%) was added and the mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using the developing system B to obtain the title product LD-1e (1.70 g, yield: 85%) in the form of a white solid. MS m / z (ESI): 351.1 [M+1]. Step 5 LD-1e (500 mg, 1.43 mmol) was dissolved in 6 mL of dichloromethane, and then trifluoroacetic acid (2.30 g, 20.2 mmol) was added and the mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title product crude LD-1f (418 mg) in the form of a white solid. The product was used in the next step without purification. MS m / z (ESI): 295.2 [M+1]. Step 6 LD-1f (10 mg, 34.0 μmol) was dissolved in 1 mL of N,N-dimethylformamide, and then 2-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (13 mg, 34.0 μmol) and N,N-diisopropylethylamine (13 mg, 100.9 μmol) were added in sequence, and the mixture was stirred at 25°C for 0.5 hours. Next, LD-1 g (14.5 mg, 44.0 μmol, prepared using the method disclosed in Example C1.22 on page 241 of patent application "WO2022170971 A1") was added, and the mixture was stirred at 25°C for 3 hours. The reaction mixture was purified without further treatment by pre-HPLC (chromatographic column: InfinityLab Poroshell 120 SB-C18 21.2×150 mm, 4 μm; mobile phase: A-water (0.1% formic acid), B-acetonitrile; isocratic elution: B%: 10%~70%) to obtain the title product LD-1h (8.10 mg, yield: 39%) in the form of a white solid. MS m / z (ESI): 606.5 [M+1]. Step 7 LD-1i (325 mg, 882 μmol) and LD-1 (42 mg, 88.1 μmol) were dissolved in 4 mL of N,N-dimethylformamide, and then ethyl acetate hydrochloride solution (4 mol / L, 100 μL) was added, and the mixture was stirred at 25°C for 15 hours. The reaction mixture was purified without further treatment by reversed-phase liquid chromatography (mobile phase: A-water (0.1% formic acid), B-acetonitrile; isocratic elution: B%: 20%~80%) to obtain the title product LD-1j (34 mg, yield: 48%) in the form of a yellow solid. MS m / z (ESI): 785.6 [M+1]. Step 8 LD-1j (38 mg, 48.4 μmol) was dissolved in 1 mL of N,N-dimethylformamide, and then diethylamine (142 mg, 1.93 mmol) was added and the mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by pre-HPLC (chromatography column: InfinityLab Poroshell 120 SB-C18 21.2 × 250 mm, 4 μm; mobile phase: A-water (0.1% formic acid), B-acetonitrile; isocratic elution: B%: 5%~50%) to obtain the title product LD-1k (11 mg, yield: 40%) in the form of a yellow solid. MS m / z (ESI): 282.2 [1 / 2(M+2)]. Step 9 LD-1k (11 mg, 19.6 μmol), LD-1h (12 mg, 19.8 μmol), and 2-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (9 mg, 23.6 μmol) were dissolved in 1 mL of N,N-dimethylformamide, and then N,N-diisopropylethylamine (8 mg, 61.9 μmol) was added and the mixture was stirred at 25°C for 1 hour. The reaction mixture was purified without further treatment by pre-HPLC (chromatographic column: InfinityLab Poroshell 120 SB-C18 21.2 × 150 mm, 4 μm; mobile phase: A-water (0.1% formic acid), B-acetonitrile; isocratic elution: B%: 20%~55%) to obtain the title product LD-1 (4.3 mg, yield: 19%) in the form of a grayish-white solid. MS m / z (ESI): 576.2 [1 / 2(M+2)]. 1H NMR (400 MHz, DMSO-d6) δ 9.10 - 9.00 (m, 2H), 8.69 - 8.58 (m, 1H), 8.29 - 8.20 (m, 1H), 8.02 - 7.93 (m, 1H), 7.63 - 7.55 (m, 1H), 7.53 - 7.47 (m, 1H), 7.36 - 7.24 (m, 2H), 6.59 - 6.52 (m, 1H), 6.31 - 6.21 (m, 2H), 5.49 - 5.35 (m, 2H), 5.31 - 5.20 (m, 2H), 4.66 - 4.53 (m, 2H), 4.48 - 4.36 (m, 4H), 4.27 - 4.18 (m, 1H), 4.11 - 4.03 (m, 1H), 3.79 - 3.67 (m, 2H), 3.54 - 3.47 (m, 2H), 3.41 - 3.39 (m, 3H), 3.14 - 3.05 (m, 2H), 2.64 - 2.56 (m, 2H), 2.35 - 2.31 (m, 1H), 2.05 - 1.82 (m, 7H), 1.76 - 1.48 (m, 4H), 1.44 - 1.36 (m, 5H), 1.30 - 1.20 (m, 2H), 1.03 - 0.93 (m, 2H), 0.87 - 0.76 (m, 13H), 0.75 - 0.68 (m, 2H), 0.39 - 0.28 (m, 2H), 0.11 - 0.03 (m, 1H), -0.03 - -0.10 (m, 1H). Example 3-2 LD-2

[0195]

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[0196]

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[0197]

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[0198] [ka] Example 3-6 LD-6

[0199] [ka] Example 3-7 LD-7

[0200] [ka] Example 3-8 LD-8

[0201] [ka] Example 3-9 LD-9

[0202] [ka] Examples 3-10 LD-10

[0203] [ka] Step 1 LD-1i (333 mg, 904 μmol) and LD-2 (42 mg, 90.4 μmol) were dissolved in 4 mL of N,N-dimethylformamide, and then ethyl acetate hydrochloride solution (4 mol / L, 100 μL) was added, and the mixture was stirred at 25°C for 15 hours. The reaction mixture was purified without further treatment by pre-HPLC (chromatographic column: InfinityLab Poroshell 120 SB-C18 21.2 × 150 mm, 4 μm; mobile phase: A-water (0.1% formic acid), B-acetonitrile; isocratic elution: B%: 20%~90%) to obtain the title product LD-10a (35 mg, yield: 49%) in the form of a yellow solid. MS m / z (ESI): 773.6 [M+1]. Step 2 LD-10a (35 mg, 44.6 μmol) was dissolved in 1 mL of N,N-dimethylformamide, and then diethylamine (142 mg, 1.94 mmol) was added and the mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by pre-HPLC (chromatography column: InfinityLab Poroshell 120 SB-C18 21.2 × 250 mm, 4 μm; mobile phase: A-water (0.1% formic acid), B-acetonitrile; isocratic elution: B%: 5%~70%) to obtain the title product LD-10b (17 mg, yield: 66%) in the form of a yellow solid. MS m / z (ESI): 551.4 [M+1]. Step 3 LD-10b (17 mg, 30.0 μmol), LD-1h (19 mg, 30.5 μmol), and 2-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (13 mg, 30.5 μmol) were dissolved in 1 mL of N,N-dimethylformamide, and then N,N-diisopropylethylamine (12 mg, 92.8 μmol) was added and the mixture was stirred at 25°C for 1 hour. The reaction mixture was purified without further treatment by pre-HPLC (chromatographic column: InfinityLab Poroshell 120 SB-C18 21.2 × 150 mm, 4 μm; mobile phase: A-water (0.1% formic acid), B-acetonitrile; isocratic elution: B%: 20%~60%) to obtain the title product LD-10 (7.2 mg, yield: 20%) in the form of a white solid. MS m / z (ESI): 570.3 [1 / 2(M+2)]. 1H NMR (400 MHz, DMSO-d6) δ 9.10 - 9.02 (m, 2H), 8.67 - 8.61 (m, 1H), 8.26 - 8.18 (m, 2H), 8.02 - 7.96 (m, 1H), 7.91 - 7.85 (m, 1H), 7.40 - 7.35 (m, 1H), 7.33 - 7.26 (m, 1H), 6.62 - 6.57 (m, 1H), 5.48 - 5.38 (m, 2H), 5.34 - 5.26 (m, 2H), 4.64 - 4.55 (m, 2H), 4.26 - 4.19 (m, 1H), 4.09 - 4.04 (m, 1H), 3.75 - 3.70 (m, 2H), 3.54 - 3.46 (m, 2H), 3.42 - 3.37 (m, 3H), 3.23 - 3.17 (m, 2H), 2.69 - 2.65 (m, 1H), 2.63 - 2.57 (m, 2H), 2.54 - 2.51 (m, 3H), 2.34 - 2.31 (m, 1H), 2.03 - 1.83 (m, 8H), 1.77 - 1.64 (m, 3H), 1.57 - 1.49 (m, 2H), 1.46 - 1.37 (m, 5H), 1.31 - 1.19 (m, 3H), 1.01 - 0.95 (m, 2H), 0.87 - 0.75 (m, 13H), 0.73 - 0.68 (m, 2H), 0.38 - 0.30 (m, 2H), 0.11 - 0.05 (m, 1H), -0.04 - -0.09 (m, 1H). Example 3-11 LD-11

[0204]

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[0205]

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[0206]

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[0207] [ka] Example 3-15 LD-15

[0208] [ka] Example 3-16 LD-16

[0209] [ka] Example 3-17 LD-17

[0210] [ka] Example 3-18 LD-18

[0211] [ka] Example 3-19 LD-19

[0212] [ka] Example 3-20 LD-20

[0213] [ka] Example 3-21 LD-21

[0214] [ka] Example 3-22 LD-22

[0215] [ka] Example 3-23 LD-23

[0216] [ka] Example 3-24 LD-24

[0217] [ka] Example 3-25 LD-25

[0218] [ka] Example 3-26 LD-26

[0219] [ka] Example 3-27 LD-27

[0220] [ka] Example 3-28 LD-28

[0221] [ka] Example 3-29 LD-29

[0222] [ka] Example 3-30 LD-30

[0223] [ka] Example 3-31 LD-31

[0224] [ka] Example 3-32 LD-32

[0225] [ka] Example 3-33 LD-33

[0226] [ka] Example 3-34 LD-34

[0227] [ka] Example 3-35 LD-35

[0228] [ka] Example 3-36 LD-36

[0229] [ka] Example 3-37 LD-37

[0230] [ka] Example 3-38 LD-38

[0231] [ka] Example 3-39 LD-39

[0232] [ka] Example 3-40 LD-40

[0233] [ka] Example 3-41 LD-41

[0234] [ka] Example 3-42 LD-42

[0235] [ka] Example 3-43 LD-43

[0236] [ka] Example 3-44 LD-44

[0237] [ka] Example 3-45 LD-45

[0238] [ka] Example 3-46 LD-46

[0239] [ka] Example 3-47 LD-47

[0240] [ka] Example 3-48 LD-48

[0241] [ka] Example 3-49 LD-49

[0242] [ka] Example 3-50 LD-50

[0243] [ka] Example 3-51 LD-51

[0244] [ka] Example 3-52 LD-52

[0245] [ka] Example 3-53 LD-53

[0246] [ka] Example 3-54 LD-54

[0247] [ka] Example 3-55 LD-55

[0248] [ka] Example 3-56 LD-56

[0249] [ka] Example 3-57 LD-57

[0250] [ka] Example 3-58 LD-58

[0251] [ka] Example 3-59 LD-59

[0252] [ka] Example 3-60 LD-60

[0253] [ka] Example 3-61 LD-61

[0254] [ka] Example 3-62 LD-62

[0255] [ka] Example 3-63 LD-63

[0256] [ka] Example 3-64 LD-64

[0257] [ka] Example 3-65 LD-65

[0258] [ka] Example 3-66 LD-66

[0259] [ka] Example 3-67 LD-67

[0260] [ka] Example 3-68 LD-68

[0261] [ka] Example 3-69 LD-69

[0262] [ka] Example 3-70 LD-70

[0263] [ka] Example 3-71 LD-71

[0264] [ka] IV. Examples of ADC composites antibody complex preparation steps

[0265] A: The antibody was replaced with 50 mM PBS / 1.0 mM EDTA buffer (adjusted to pH 7.4 with sodium hydroxide solution) in an ultrafiltration tube with a molecular weight cutoff of 50 kD, and 5 to 10 equivalents of 10 mM TCEP aqueous solution were added. The mixture was then shaken at 25°C for 3 hours. The linker-drug complex was dissolved in DMSO, and 10-20 equivalents of the linker-drug complex were taken and added to the reduced antibody solution. The mixture was homogeneously mixed by vortex shaking and allowed to stand at 25°C for 2 hours to complete the reaction. 40 equivalents of 100 mM NAC aqueous solution were added, and the Ringer reaction was terminated by shaking at 25°C for 20 minutes. Excess small molecules were removed using an ultrafiltration centrifuge tube with a molecular weight cutoff of 50 kD or a Sephadex G-25 desalting column. The antibody-drug complex was replaced with 50 mM PBS buffer (pH 6.0), and the sample was filtered through a 0.22 μm filtration membrane to obtain the antibody-drug complex, which was stored in a refrigerator at 4°C. The DAR value of the complex was measured by reverse-phase high-performance liquid chromatography or mass spectrometry. B: The antibody was replaced with 50 mM PBS / 1.0 mM EDTA buffer (pH 6.5 with sodium hydroxide solution) in an ultrafiltration tube with a molecular weight cutoff of 50 kD, and 5-10 equivalents of 10 mM TCEP aqueous solution were added. The mixture was then shaken at 25°C for 3 hours. The linker-drug complex was dissolved in DMSO, and then 10-20 equivalents of the linker-drug complex were taken and added dropwise to the reduced antibody solution. The mixture was homogeneously mixed by vortex shaking and allowed to stand at 25°C for 2 hours to complete the reaction. 40 equivalents of 100 mM NAC aqueous solution were added, and the Ringer reaction was terminated by shaking at 25°C for 20 minutes. Excess small molecules were removed using an ultrafiltration tube with a molecular weight cutoff of 50 kD or a Sephadex G-25 desalting column. The antibody-drug complex was replaced with 50 mM PBS buffer (pH 6.0), purified by ultrafiltration, and the sample was filtered through a 0.22 μm filtration membrane to obtain the antibody-drug complex, which was stored in a refrigerator at 4°C. The DAR value of the complex was measured by reverse-phase high-performance liquid chromatography or mass spectrometry. Example 4-1 ADC-1

[0266] [ka] The antibody Trastuzumab and LD-1 were used as raw materials and prepared according to the method of Step A. A PBS buffer of ADC-1, an exemplary product of the mixture FADC-1, was obtained, stored at 4°C, and designated as Example 4-1. The average drug load was calculated using mass spectrometry, resulting in y = 8.00. Example 4-2 ADC-2

[0267] [ka] The antibody Trastuzumab and LD-2 were used as raw materials and prepared according to the method of Step A. A PBS buffer of ADC-2, an exemplary product of the conjugated mixture FADC-2, was obtained and stored at 4°C, and this was designated as Example 4-2. Example 4-3 ADC-3

[0268] [ka] The antibody Trastuzumab and LD-3 were used as raw materials and prepared according to the method of Step A. A PBS buffer of ADC-3, an exemplary product of the conjugated mixture FADC-3, was obtained and stored at 4°C, and this was designated as Example 4-3. Example 4-4 ADC-4

[0269] [ka] The antibody trastuzumab and LD-4 were used as raw materials and prepared according to the method of step A. A PBS buffer of the exemplary product ADC-4 of the conjugated mixture FADC-4 was obtained, stored at 4°C, and designated as Example 4-4. Example 4-5 ADC-5

[0270] [ka] The antibody trastuzumab and LD-5 were used as raw materials and prepared according to the method of step A. An exemplary product of the conjugated mixture FADC-5, ADC-5, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-5. Example 4-6 ADC-6

[0271] [ka] The antibody trastuzumab and LD-6 were used as raw materials and prepared according to the method of step A. An exemplary product of the conjugated mixture FADC-6, ADC-6, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-6. Example 4-7 ADC-7

[0272] [ka] The antibody trastuzumab and LD-7 were used as starting materials and prepared according to the method of step B. An exemplary product of the conjugation mixture (FADC-7A and / or FADC-7B and / or FADC-7C mixture) ADC-7 in PBS buffer was obtained and stored at 4°C. Example 4-8 ADC-8

[0273] [ka] The antibody trastuzumab and LD-8 were used as raw materials and prepared according to the method of step A. A PBS buffer of the exemplary product ADC-8 of the conjugated mixture FADC-8 was obtained, stored at 4°C, and designated as Examples 4-8. Example 4-9 ADC-9

[0274] [ka] The antibody trastuzumab and LD-9 were used as raw materials and prepared according to the method of step A. An exemplary product of the conjugated mixture FADC-9, ADC-9, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-9. Example 4-10 ADC-10

[0275] [ka] The antibody Trastuzumab and LD-10 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-10, ADC-10, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-10. The average drug load calculated by mass spectrometry is y = 8.00. Example 4-11 ADC-11

[0276] [ka] The antibody trastuzumab and LD-11 were used as raw materials and prepared according to the method of step A. An exemplary product of the conjugated mixture FADC-11, ADC-11, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-11. Example 4-12 ADC-12

[0277] [ka] The antibody Trastuzumab and LD-12 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-12, ADC-12, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-12. Example 4-13 ADC-13

[0278] [ka] The antibody Trastuzumab and LD-13 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-13, ADC-13, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-13. Example 4-14 ADC-14

[0279] [ka] The antibody trastuzumab and LD-14 were used as starting materials and prepared according to the method of step B. An exemplary product of the conjugation mixture (FADC-14A and / or FADC-14B and / or FADC-14C mixture) ADC-14 in PBS buffer was obtained and stored at 4°C. Example 4-15 ADC-15

[0280] [ka] The antibody Trastuzumab and LD-15 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-15, ADC-15, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-15. Example 4-16 ADC-16

[0281] [ka] The antibody Trastuzumab and LD-16 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-16, ADC-16, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-16. Example 4-17 ADC-17

[0282] [ka] The antibody Trastuzumab and LD-17 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-17, ADC-17, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-17. Example 4-18 ADC-18

[0283] [ka] The antibody Trastuzumab and LD-18 were used as raw materials and prepared according to the method of Step A. A PBS buffer of the exemplary product ADC-18 of the conjugated mixture FADC-18 was obtained, stored at 4°C, and designated as Example 4-18. Example 4-19 ADC-19

[0284] [ka] The antibody Trastuzumab and LD-19 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-19, ADC-19, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-19. Example 4-20 ADC-20

[0285] [ka] The antibody Trastuzumab and LD-20 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-20, ADC-20, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-20. Example 4-21 ADC-21

[0286] [ka] The antibody Trastuzumab and LD-21 were used as starting materials and prepared according to the method of step B. An exemplary product of the conjugation mixture (FADC-21A and / or FADC-21B and / or FADC-21C mixture) ADC-21 in PBS buffer was obtained and stored at 4°C. Example 4-22 ADC-22

[0287] [ka] The antibody Trastuzumab and LD-22 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-22, ADC-22, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-22. Example 4-23 ADC-23

[0288] [ka] The antibody Trastuzumab and LD-23 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-23, ADC-23, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-23. Example 4-24 ADC-24

[0289] [ka] The antibody Trastuzumab and LD-24 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-24, ADC-24, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-24. Example 4-25 ADC-25

[0290] [ka] The antibody Trastuzumab and LD-25 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-25, ADC-25, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-25. Example 4-26 ADC-26

[0291] [ka] The antibody Trastuzumab and LD-26 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-26, ADC-26, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-26. Example 4-27 ADC-27

[0292] [ka] The antibody Trastuzumab and LD-27 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-27, ADC-27, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-27. Example 4-28 ADC-28

[0293] [ka] The antibody Trastuzumab and LD-28 were used as starting materials and prepared according to the method of step B. An exemplary product of the conjugation mixture (FADC-28A and / or FADC-28B and / or FADC-28C mixture) ADC-28 in PBS buffer was obtained and stored at 4°C. Example 4-29 ADC-29

[0294] [ka] The antibody Trastuzumab and LD-29 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-29, ADC-29, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-29. Example 4-30 ADC-30

[0295] [ka] The antibody Trastuzumab and LD-30 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-30, ADC-30, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-30. Example 4-31 ADC-31

[0296] [ka] The antibody Trastuzumab and LD-31 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-31, ADC-31, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-31. Example 4-32 ADC-32

[0297] [ka] The antibody Trastuzumab and LD-32 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-32, ADC-32, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-32. Example 4-33 ADC-33

[0298] [ka] The antibody Trastuzumab and LD-33 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-33, ADC-33, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-33. Example 4-34 ADC-34

[0299] [ka] The antibody Trastuzumab and LD-34 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-34, ADC-34, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-34. Example 4-35 ADC-35

[0300] [ka] The antibody Trastuzumab and LD-35 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-35, ADC-35, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-35. Example 4-36 ADC-36

[0301] [ka] The antibody Trastuzumab and LD-36 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-36, ADC-36, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-36. Example 4-37 ADC-37

[0302] [ka] The antibody Trastuzumab and LD-37 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-37, ADC-37, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-37. Example 4-38 ADC-38

[0303] [ka] The antibody Trastuzumab and LD-38 were used as raw materials and prepared according to the method of Step A. A PBS buffer of the exemplary product ADC-38 of the conjugated mixture FADC-38 was obtained, stored at 4°C, and designated as Example 4-38. Example 4-39 ADC-39

[0304] [ka] The antibody Trastuzumab and LD-39 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-39, ADC-39, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-39. Example 4-40 ADC-40

[0305] [ka] The antibody Trastuzumab and LD-40 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-40, ADC-40, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-40. Example 4-41 ADC-41

[0306] [ka] The antibody Trastuzumab and LD-41 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-41, ADC-41, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-41. Example 4-42 ADC-42

[0307] [ka] The antibody Trastuzumab and LD-42 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-42, ADC-42, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-42. Example 4-43 ADC-43

[0308] [ka] The antibody Trastuzumab and LD-43 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-43, ADC-43, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-43. Example 4-44 ADC-44

[0309] [ka] The antibody Trastuzumab and LD-44 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-44, ADC-44, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-44. Example 4-45 ADC-45

[0310] [ka] The antibody Trastuzumab and LD-45 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-45, ADC-45, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-45. Example 4-46 ADC-46

[0311] [ka] The antibody Trastuzumab and LD-46 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-46, ADC-46, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-46. Example 4-47 ADC-47

[0312] [ka] The antibody trastuzumab and LD-47 were used as raw materials and prepared according to the method of step A. An exemplary product of the conjugated mixture FADC-47, ADC-47, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-47. Example 4-48 ADC-48

[0313] [ka] The antibody Trastuzumab and LD-48 were used as raw materials and prepared according to the method of Step A. A PBS buffer of the exemplary product ADC-48 of the conjugated mixture FADC-48 was obtained, stored at 4°C, and designated as Examples 4-48. Example 4-49 ADC-49

[0314] [ka] The antibody Trastuzumab and LD-49 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-49, ADC-49, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-49. Example 4-50 ADC-50

[0315] [ka] The antibody Trastuzumab and LD-50 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-50, ADC-50, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-50. Example 4-51 ADC-51

[0316] [ka] The antibody Trastuzumab and LD-51 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-51, ADC-51, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-51. Example 4-52 ADC-52

[0317] [ka] The antibody Trastuzumab and LD-52 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-52, ADC-52, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-52. Example 4-53 ADC-53

[0318] [ka] The antibody Trastuzumab and LD-53 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-53, ADC-53, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-53. Example 4-54 ADC-54

[0319] [ka] The antibody Trastuzumab and LD-54 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-54, ADC-54, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-54. Example 4-55 ADC-55

[0320] [ka] The antibody Trastuzumab and LD-55 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-55, ADC-55, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-55. Example 4-56 ADC-56

[0321] [ka] The antibody Trastuzumab and LD-56 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-56, ADC-56, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-56. Example 4-57 ADC-57

[0322] [ka] The antibody Trastuzumab and LD-57 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-57, ADC-57, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-57. Example 4-58 ADC-58

[0323] [ka] The antibody Trastuzumab and LD-58 were used as raw materials and prepared according to the method of Step A. A PBS buffer of the exemplary product ADC-58 of the conjugated mixture FADC-58 was obtained, stored at 4°C, and designated as Examples 4-58. Example 4-59 ADC-59

[0324] [ka] The antibody Trastuzumab and LD-59 were used as raw materials and prepared according to the method of Step A. A PBS buffer of the exemplary product ADC-59 of the conjugated mixture FADC-59 was obtained, stored at 4°C, and designated as Examples 4-59. Example 4-60 ADC-60

[0325] [ka] The antibody Trastuzumab and LD-60 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-60, ADC-60, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-60. Example 4-61 ADC-61

[0326] [ka] The antibody Trastuzumab and LD-61 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-61, ADC-61, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-61. Example 4-62 ADC-62

[0327] [ka] The antibody Trastuzumab and LD-62 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-62, ADC-62, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-62. Example 4-63 ADC-63

[0328] [ka] The antibody Trastuzumab and LD-63 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-63, ADC-63, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-63. Example 4-64 ADC-64

[0329] [ka] The antibody trastuzumab and LD-64 were used as raw materials and prepared according to the method of step A. An exemplary product of the conjugated mixture FADC-64, ADC-64, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-64. Example 4-65 ADC-65

[0330] [ka] The antibody Trastuzumab and LD-65 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-65, ADC-65, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-65. Example 4-66 ADC-66

[0331] [ka] The antibody Trastuzumab and LD-66 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-66, ADC-66, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-66. Example 4-67 ADC-67

[0332] [ka] The antibody Trastuzumab and LD-67 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-67, ADC-67, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-67. Example 4-68 ADC-68

[0333] [ka] The antibody Trastuzumab and LD-68 were used as raw materials and prepared according to the method of Step A. A PBS buffer of the exemplary product ADC-68 of the conjugated mixture FADC-68 was obtained, stored at 4°C, and designated as Example 4-68. Example 4-69 ADC-69

[0334] [ka] The antibody Trastuzumab and LD-69 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-69, ADC-69, was obtained in PBS buffer, stored at 4°C, and designated as Examples 4-69. Example 4-70 ADC-70

[0335] [ka] The antibody Trastuzumab and LD-70 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-70, ADC-70, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-70. Example 4-71 ADC-71

[0336] [ka] The antibody Trastuzumab and LD-71 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-71, ADC-71, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-71. Example 4-72 ADC-72

[0337] [ka] The antibody Nimotuzumab and LD-1 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-72, ADC-72, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-72. The average drug load calculated by mass spectrometry is y = 8.00. Example 4-73 ADC-73

[0338] [ka] The antibody Nimotuzumab and LD-10 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-73, ADC-73, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-73. The average drug load calculated by mass spectrometry is y = 8.00. Example 4-74 ADC-74

[0339] [ka] The antibody Pertuzumab and LD-1 were used as raw materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-74, ADC-74, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-74. The average drug load calculated by mass spectrometry is y = 8.00. Example 4-75 ADC-75

[0340] [ka] The antibody Pertuzumab and LD-10 were used as starting materials and prepared according to the method of Step A. An exemplary product of the conjugated mixture FADC-75, ADC-75, was obtained in PBS buffer, stored at 4°C, and designated as Example 4-75. The average drug load calculated by mass spectrometry was y = 8.00. Example 4-76 Reference Material 2

[0341] [ka] The antibody Trastuzumab and N-((11S,14S)-11-(4-di-n-propylamino)butyl)-1-((S)-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indragino[1,2-b]quinoline-14-yl)-15-methyl-7,10,13-trioxo-4-oxa-6,9,12-triazahexadecane-14-yl)-6-(2-(methanesulfonyl)pyrimidine-5-yl)hexa-5-inamide (prepared using the method disclosed in Example 2.37 on page 273 of patent application "WO2022170971 Al") were used as raw materials and prepared by the method of step A. A PBS buffer of Reference 2, which is an exemplary product of the conjugated mixture FADC-Reference 2, was obtained, stored at 4°C, and designated as Example 4-76. The average drug load was calculated using mass spectrometry, and the result was y = 8.00. Example 4-77 Reference Material 3

[0342] [ka] The antibody Nimotuzumab and N-((11S,14S)-11-(4-di-n-propylamino)butyl)-1-((S)-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indragino[1,2-b]quinoline-14-yl)-15-methyl-7,10,13-trioxo-4-oxa-6,9,12-triazahexadecane-14-yl)-6-(2-(methanesulfonyl)pyrimidine-5-yl)hexa-5-inamide (prepared using the method disclosed in Example 2.37 on page 273 of Patent Application "WO2022170971 Al") were used as raw materials and prepared by the method of Step A. An exemplary product of the conjugated mixture FADC-reference material 3, a PBS buffer of reference material 3, was obtained, stored at 4°C, and designated as Example 4-77. The average drug load was calculated using mass spectrometry, resulting in y = 8.00. Example 4-78 Reference Material 4

[0343] [ka] The antibody Pertuzumab and N-((11S,14S)-11-(4-di-n-propylamino)butyl)-1-((S)-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indragino[1,2-b]quinoline-14-yl)-15-methyl-7,10,13-trioxo-4-oxa-6,9,12-triazahexadecane-14-yl)-6-(2-(methanesulfonyl)pyrimidine-5-yl)hexa-5-inamide (prepared using the method disclosed in Example 2.37 on page 273 of patent application "WO2022170971 Al") were used as raw materials and prepared by the method of step A. A PBS buffer of Reference 4, which is an exemplary product of the conjugated mixture FADC-Reference 4, was obtained, stored at 4°C, and designated as Example 4-78. The average drug load calculated by mass spectrometry was found to be y = 7.60. Analysis of drug-loaded content in ADC stock solution

[0344] Objectives and principles of the experiment ADC stock solution is an antibody-crosslinked drug, and its mechanism of treatment involves the delivery of toxic molecules to cells through antibody targeting, thereby killing the cells. The amount of drug loaded plays a crucial role in the drug's efficacy. The drug load in ADC stock solution was measured using mass spectrometry and reversed-phase high-performance liquid chromatography (RP-HPLC).

[0345] Method 1: Reverse-phase high-performance liquid chromatography (RP-HPLC) (1) Experimental method: The test sample was diluted to 0.5 mg / mL with ultrapure water, reduced with 25 mM dithiothreitol at 37°C for 30 minutes, and then directly injected at a volume of 5 μL. A reversed-phase chromatography column (Agilent PLRP-S 1000 Å (5 μm) 50 × 2.1 mm) was used, and isocratic elution was performed with mobile phases A and B (A: 0.1% formic acid - 0.025% trifluoroacetic acid - water, B: 0.1% formic acid - 0.025% trifluoroacetic acid - acetonitrile). The flow rate was 0.25 mL / min, the detection wavelength was 280 nm, and the column temperature was 70°C. (2) Data analysis: The light and heavy chain positions were distinguished by comparing the sample spectrum with the spectrum of the bare antibody. Next, the DAR value was calculated by integrating the spectrum of the detected sample. The calculation formula is as follows. LC: 0 (number of bound drugs), LC+1: 2 (number of bound drugs), HC: 0 (number of bound drugs), HC+1: 2 (number of bound drugs), HC+2: 4 (number of bound drugs), HC+3: 6 (number of bound drugs). Total LC peak area = LC peak area + LC+1 peak area; Total HC peak area = HC peak area + HC+1 peak area + HC+2 peak area + HC+3 peak area; LC DAR = Σ (number of bound drugs × percentage of peak area) / Total LC peak area; HC DAR = Σ (number of bound drugs × percentage of peak area) / Total HC peak area; DAR = LC DAR + HC DAR

[0346] Method 2: Mass Spectrometry: (1) Experimental Method: 10 μL of the test sample at a concentration of 1 mg / mL was placed in a 1.5 mL centrifuge tube, 0.5 μL of rapid digestive enzyme (Rapid PNGase F, Adamas) was added, and the mixture was homogeneously vortexed and incubated at 37°C for 60 minutes. After cleaving the N sugar, 6 μL of ultrapure water and 4 μL of 0.5 M dithiothreitol aqueous solution were added to the centrifuge tube, and the mixture was homogeneously vortexed and incubated at 37°C for 30 minutes. After the reaction was complete, the mixture was centrifuged, and 2 μL of the supernatant was injected into a syringe. A reversed-phase chromatography column (Agilent PLRP-S 1000 Å (5 μm) 50 × 2.1 mm) was used, and isocratic elution was performed using mobile phases A and B (A: 0.1% formic acid-water, B: 0.1% formic acid-acetonitrile). The flow rate was 0.5 mL / min, the column temperature was 60°C, and the detection wavelength was 280 nm. ESI-Tof (LC-MS) collected m / z values, the collection mode in mass spectrometry was positive ion mode, and the m / z collection range was 200-3200. Subsequently, the original mass spectrum was deconvolved using software. (2) Data analysis: DAR values ​​were calculated based on the peak height values ​​using a method similar to the reversed-phase high-performance liquid chromatography method described above. III. Examples of Exams Biological evaluation

[0347] Test Example 1: Measurement of in vitro growth inhibitory activity of the general formula (GH) compounds A549, SK-BR-3, and NCI-N87 against tumor cells. 1. Purpose of the examination

[0348] The objective of this experiment was to detect the in vitro killing activity of the compound of formula (GH) disclosed herein against A549 tumor cells (human lung cancer cells, Beijing Tongren Hospital), SK-BR-3 tumor cells (human breast cancer cells, Wuhan Procell, catalog number: CL-0211), and NCI-N87 tumor cells (human gastric cancer cells, Cell Resources Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, catalog number: 3111C0001CCC000481). Cells were treated in vitro with different concentrations of the compound and cultured for 6 days, after which the number of viable cells was detected using the CCK8 (Cell Counting Kit-8, catalog number: TS547) reagent. The in vitro activity of the test compound was determined by IC50. 50 The evaluation was based on the values. 2. Experimental Method

[0349] The following tests were conducted using the in vitro killing activity testing method against A549 cells, SK-BR-3 cells, and NCI-N87 cells as an example. This method is applicable to, but is not limited to, in vitro growth inhibitory activity testing against other tumor cells (such as HCC1569, JIMT-1, and DIFI). (1) Cell culture: SK-BR-3 cells and NCI-N87 cells were cultured in RPMI 1640 medium containing 10% FBS (Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: G211018). A549 cells were cultured in DMEM / F12 medium containing 10% FBS (Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: L310KJ). (2) Cell preparation: Logarithmic growth phase A549 cells, SK-BR-3 cells, and NCI-N87 cells were each taken and washed once with PBS (phosphate buffer, Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: E211004). Next, 2-3 mL of trypsin (0.25% trypsin-EDTA (1x), Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: A121002) was added and digested for 2-3 minutes. After the cells were completely digested, 10 mL of cell culture medium containing 10% FBS was added to elute the digested cells, and the cells were centrifuged at 300 g for 5 minutes, and the supernatant was discarded. Next, 10-20 mL of cell culture medium containing 2% FBS was added to each cell to resuspend them and prepare single-cell suspensions. (3) Cell plating: Mix each single-cell suspension uniformly and adjust the viable cell density with a cell culture medium containing 2% FBS (SK-BR-3 plating density: 3 × 10⁻⁶). 4 Cells / mL, A549 plating density: 2 × 10 4 Cells / mL, NCI-N87 plating density: 4 × 10 4 A cell suspension with adjusted density (cells / mL) was uniformly mixed and added to each 96-well cell culture plate at a rate of 100 μL / well. Only 200 μL of PBS was added to the outer wells of the 96-well plate. The culture plates were incubated in an incubator for 24 hours (37°C, 5% CO2). (4) Preparation of the compound: The compound was dissolved in DMSO (dimethyl sulfoxide, SIGMA) to prepare a 2 mM stock solution. A 2 mM small molecule compound sample stock solution was diluted to 600 nM with cell medium containing 2% FBS, filtered through a 0.22 μM filter, and sterilized. Then, 300 μL of each test sample was added to the first row of a 96-well U-bottom dispenser plate to achieve a sample concentration of 600 nM. 210 μL of cell medium containing 2% FBS was added to each well from the second to the tenth row. 70 μL of sample was transferred from the first row to the 210 μL of cell medium in the second row, mixed uniformly, and then 70 μL was transferred to the third row, and this process was continued up to the ninth row. (5) Sample addition procedure: 100 μL of each prepared test sample at different concentrations was added to the culture plate, and two overlapping wells were created for each sample. The culture plate was incubated in an incubator for 6 days (37°C, 5% CO2). (6) Chromogenic procedure: Remove the 96-well cell culture plate, remove the cell medium supernatant, add 100 μL of basal medium (without FBS) containing 10% CCK8, and incubate in an incubator for approximately 2 hours (37°C, 5% CO2). (7) Plate reading procedure: Remove the 96-well cell culture plate and place it in the microplate reader (MD SpectraMax i3X) and A4 50 We measured it. (8) Data analysis: Data was processed and analyzed using Microsoft Excel and Graphpad Prism 5. The results of the above tests are summarized in Table 1.

[0350] [Table 1]

[0351] Conclusion: The small molecule fragments in this disclosure exhibit significant growth inhibitory activity against A549, SK-BR-3, and NCI-N87 cells. Compounds 1, 2, and 3 showed significantly superior in vitro growth inhibitory effects against A549, SK-BR-3, and NCI-N87 cells at the same dose compared to reference compound 1. Test Example 2: In vitro growth inhibition study of the antibody-drug conjugate of this disclosure against HER2-targeted tumor cells

[0352] 1. Purpose of the examination The objective of this experiment was to detect the in vitro growth inhibitory activity of the HER2-targeting antibody-drug conjugates disclosed herein against SK-BR-3 cells (human breast cancer cells, Wuhan Procell, catalog number: CL-0211) and NCI-N87 cells (human gastric cancer cells, Cell Resources Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, catalog number: 3111C0001CCC000481). Cells were treated in vitro with different concentrations of the conjugate and cultured for 6 days, after which cell proliferation was detected using the CCK8 (Cell Counting Kit-8, catalog number: TS547) reagent. In vitro activity was measured by IC50. 50 The evaluation was based on the values.

[0353] 2. Experimental Method The following tests were conducted using the following method as an example for testing in vitro growth inhibitory activity against SK-BR-3 cells and NCI-N87 cells. This method is applicable to, but not limited to, in vitro growth inhibitory activity testing against other tumor cells (such as HCC1569, JIMT-1, and DIFI). (1) Cell culture: SK-BR-3 cells and NCI-N87 cells were cultured in RPMI 1640 medium containing 10% FBS (Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: L210KJ). (2) Cell preparation: Cells in the logarithmic growth phase were washed once with PBS (phosphate buffer, Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: E211004), then 1 mL of trypsin (0.25% trypsin-EDTA (1x), Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: A121002) was added and digested for 2-3 minutes. After the cells were completely digested, 10 mL of cell culture medium was added to elute the digested cells, and the cells were centrifuged at 300 g for 5 minutes, and the supernatant was discarded. Next, 10 mL of cell culture medium was added to resuspend the cells and prepare a single-cell suspension. (3) Cell plating: Mix the single-cell suspension uniformly and increase the viable cell density to 3 × 10⁻⁶ with cell culture medium. 4 The cell suspension, adjusted to the required cell / mL density, was uniformly mixed and added to each 96-well cell culture plate at a rate of 100 μL / well. Only 200 μL of PBS was added to the outer wells of the 96-well plate. The culture plates were incubated in an incubator for 24 hours (37°C, 5% CO2). (4) Preparation of test samples: The test samples were diluted to 400 nM in cell medium containing 2% FBS. Then, 300 μL of each sample was added to the first row of a 96-well U-bottom dispensing plate to achieve a sample concentration of 400 nM. 210 μL of cell medium containing 2% FBS was added to each well from the second to the tenth row. 70 μL of sample was transferred from the first row to the 210 μL of cell medium in the second row, mixed uniformly, and then 70 μL was transferred to the third row. This process was continued up to the ninth row. (5) Sample addition procedure: 100 μL of each prepared test sample at different concentrations was added to the culture plate, and two overlapping wells were created for each sample. The culture plate was incubated in an incubator for 6 days (37°C, 5% CO2). (6) Chromogenic procedure: Remove the 96-well cell culture plate, remove the cell medium supernatant, add 100 μL of basal medium (without FBS) containing 10% CCK8 to each well, and incubate at room temperature for 2 hours. (7) Plate reading procedure: Remove the 96-well cell culture plate and place it in the microplate reader (SpectraMax i3X) on A4. 50 We measured it. (8) Data analysis: Data was processed and analyzed using Microsoft Excel and Graphpad Prism 5. The results of the above tests are summarized in Table 2.

[0354] [Table 2]

[0355] Conclusion: The HER2-targeting antibody-drug conjugates described herein exhibit significant growth inhibitory activity against HER2-positive cells SK-BR-3 and NCI-N87. Test Example 3: In vitro growth inhibition study of the antibody-drug conjugate of this disclosure against EGFR-targeted tumor cells 1. Purpose of the examination

[0356] The objective of this experiment was to detect the in vitro growth inhibitory activity of the EGFR-targeting antibody-drug conjugates disclosed herein against MDA-MB-468 cells (human breast cancer cells, Cell Center, Shanghai Academy of Biosciences, Chinese Academy of Sciences, catalog number: 3131C0001000700120), SK-BR-3 cells (human breast cancer cells, Wuhan Procell, catalog number: CL-0211), and SW620 cells (human colon cancer cells, Biofeng, bc067). Cells were treated in vitro with different concentrations of the conjugate and cultured for 6 days, after which cell proliferation was detected using the CCK8 (Cell Counting Kit-8, catalog number: TS547) reagent. In vitro activity was measured by IC50. 50 The evaluation was based on the values. 2. Experimental method:

[0357] The following tests were conducted using the following method as an example to test in vitro growth inhibitory activity against MDA-MB-468 cells, SK-BR-3 cells, and SW620 cells. This method is applicable to, but not limited to, in vitro growth inhibitory activity tests against other tumor cells (such as HCC1569, JIMT-1, and DIFI). (1) Cell culture: MDA-MB-468 cells and SW620 cells were cultured in L-15 medium containing 10% FBS (Gibco, catalog number: 11415-064). SK-BR-3 cells were cultured in RPMI 1640 medium containing 10% FBS (Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: L210KJ). (2) Cell preparation: Cells in the logarithmic growth phase were washed once with PBS (phosphate buffer, Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: E211004). Next, 1 mL of trypsin (0.25% trypsin-EDTA (1x), Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: A121002) was added and digested for 2-3 minutes. After the cells were completely digested, 10 mL of the corresponding cell culture medium containing 10% FBS was added to elute the digested cells, and the mixture was centrifuged at 300 g for 5 minutes, and the supernatant was discarded. Next, 10 mL of cell culture medium was added to resuspend the cells and prepare a single-cell suspension. (3) Cell plating: Mix the single-cell suspension uniformly and plate the viable cell density to 3 × 10 in the corresponding cell culture medium containing 2% FBS. 4 The cell suspension, adjusted to the required cell / mL and density, was uniformly mixed and added to each 96-well cell culture plate at a rate of 100 μL / well. Only 200 μL of PBS was added to the outer wells of the 96-well plate. The MDA-MB-468 and SW620 cell culture plates were incubated in a CO2-free incubator for 24 hours (37°C), and the SK-BR-3 cell culture plate was incubated in a 5% CO2 incubator for 24 hours (37°C). (4) Preparation of test samples: The test sample was diluted to 400 nM in the corresponding cell medium containing 2% FBS. 300 μL of the sample was added to the first row of a 96-well U-bottom dispensing plate to achieve a sample concentration of 400 nM. 210 μL of the corresponding cell medium containing FBS was added to each well from the second to the tenth row. 70 μL of the sample was transferred from the first row to the 210 μL of cell medium in the second row, mixed uniformly, and then 70 μL was transferred to the third row. This process was continued up to the ninth row. (5) Sample addition procedure: 100 μL of each prepared test sample at different concentrations was added to the culture plate, and two overlapping wells were set up for each sample. The MDA-MB-468 cell culture plate and the SW620 cell culture plate were cultured in a CO2-free incubator for 6 days (37°C), and the SK-BR-3 cell culture plate was cultured in a 5% CO2 incubator for 6 days (37°C). (6) Chromogenic procedure: Remove the 96-well cell culture plate, remove the cell medium supernatant, add 100 μL of 10% CCK8 solution (prepared in RPMI 1640 basal medium, without FBS) to each well, and incubate at room temperature for 2 hours. (7) Plate reading procedure: Remove the 96-well cell culture plate and place it in the microplate reader (SpectraMax i3X), then use the microplate reader to read A4 50 We measured it. (8) Data analysis: Data was processed and analyzed using Microsoft Excel and Graphpad Prism 5. The results of the above tests are summarized in Table 3.

[0358] [Table 3]

[0359] Conclusion: The EGFR-targeting antibody-drug conjugates described herein exhibit significant growth inhibitory activity against EGFR-positive cells MDA-MB-468 and weak growth inhibitory activity against EGFR-negative cells SW620, demonstrating excellent selectivity. Study Example 4: In vitro growth inhibition study of antibody-drug conjugates of this disclosure against HER2-targeted tumor cells 2

[0360] 1. Purpose of the examination The objective of this experiment was to detect the in vitro growth inhibitory activity of the HER2-targeting antibody-drug conjugates disclosed herein against SK-BR-3 cells (human breast cancer cells, Wuhan Procell, catalog number: CL-0211) and MDA-MB-468 cells (human breast cancer cells, Cell Center, Shanghai Academy of Biosciences, Chinese Academy of Sciences, catalog number: 3131C0001000700120). Cells were treated in vitro with different concentrations of the conjugate and cultured for 6 days, after which cell proliferation was detected using the CCK8 (Cell Counting Kit-8, catalog number: TS547) reagent. In vitro activity was measured by IC50. 50 The evaluation was based on the values.

[0361] 2. Experimental Method The following tests were conducted using the following method as an example for testing in vitro growth inhibitory activity against SK-BR-3 cells and MDA-MB-468 cells. This method is applicable to, but not limited to, in vitro growth inhibitory activity testing against other tumor cells (such as HCC1569, JIMT-1, and DIFI). (1) Cell culture: SK-BR-3 cells and MDA-MB-468 cells were cultured in RPMI 1640 medium containing 2% FBS (Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: L210KJ). (2) Cell preparation: Cells in the logarithmic growth phase were washed once with PBS (phosphate buffer, Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: E211004). Next, 1 mL of trypsin (0.25% trypsin-EDTA (1x), Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: A121002) was added and digested for 2-3 minutes. After the cells were completely digested, 10 mL of cell culture medium was added to elute the digested cells, and the cells were centrifuged at 300 g for 5 minutes, and the supernatant was discarded. Next, 10 mL of cell culture medium was added to resuspend the cells and prepare a single-cell suspension. (3) Cell plating: Mix the single-cell suspension uniformly and increase the viable cell density to 3 × 10⁻⁶ with cell culture medium. 4 The cell suspension, adjusted to the required cell / mL density, was uniformly mixed and added to each 96-well cell culture plate at a rate of 100 μL / well. Only 200 μL of PBS was added to the outer wells of the 96-well plate. The culture plates were incubated in an incubator for 24 hours (37°C, 5% CO2). (4) Preparation of test samples: The test samples were diluted to 400 nM in cell medium containing 2% FBS, and 300 μL of each sample was added to the first row of a 96-well U-bottom dispensing plate to achieve a sample concentration of 400 nM. 210 μL of cell medium containing 2% FBS was added to each well from the second to the tenth row. 70 μL of sample was transferred from the first row to the 210 μL of cell medium in the second row, mixed uniformly, and then 70 μL was transferred to the third row, and this process was continued up to the ninth row. (5) Sample addition procedure: 100 μL of each prepared test sample at different concentrations was added to the culture plate, and two overlapping wells were created for each sample. The culture plate was incubated in an incubator for 6 days (37°C, 5% CO2). (6) Chromogenic procedure: Remove the 96-well cell culture plate, remove the cell medium supernatant, add 100 μL of 10% CCK8 (prepared in RPMI1640 basal medium, without FBS) solution to each well, and incubate at room temperature for 2 hours. (7) Plate reading procedure: Remove the 96-well cell culture plate and place it in the microplate reader (SpectraMax i3X) on A4. 50 We measured it. (8) Data analysis: Data was processed and analyzed using Microsoft Excel and Graphpad Prism 5. The results of the above tests are summarized in Table 4.

[0362] [Table 4]

[0363] Conclusion: The HER2-targeting antibody-drug conjugates of this disclosure exhibit significant growth inhibitory activity against HER2-positive SK-BR-3 cells. ADC-1 and ADC-74 showed superior in vitro growth inhibitory effects against SK-BR-3 cells at the same dose compared to controls 2 and 4. On the other hand, they showed weak growth inhibitory activity against HER2-negative MDA-MB-468 cells, demonstrating good selectivity. Test Example 5: Testing of bystander killing activity of the antibody-drug conjugate of this disclosure against HER2-targeted tumor cells

[0364] HER2-positive cells SK-BR-3 (human breast cancer cells, Wuhan Procell, catalog number: CL-0211) and HER2-negative cells MDA-MB-468 (human breast cancer cells, Cell Center, Shanghai Academy of Biosciences, Chinese Academy of Sciences, catalog number: 3131C0001000700120) were subjected to 1.2 × 10⁶ measurements each using RPMI-1640 + 10% FBS. 5 cells / ml and 4×10 4The cell density was adjusted to cells / ml. SK-BR-3 cells and MDA-MB-468 cells were added to a 6-well plate in 1 mL each, mixed at 37°C and 5% CO2, and cultured overnight. Sample ADC-113 was prepared to a concentration of 4.5 μg / mL (30 nM), and 1 mL was added to the cells, resulting in a total volume of 3 mL and a final concentration of 10 nM. A solvent control group was set up and cultured at 37°C and 5% CO2 for 5 days. Trypsin (0.25% trypsin-EDTA (1x), Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: A121002) was added to the 6-well plate for digestion, 1 mL of FACS buffer (PBS + 4% FBS) was added for resuspending, and the cells were stained with trypan blue and counted. The remaining cells were centrifuged, trastuzumab was diluted to 10 μg / mL in FACS buffer, and the cells were resuspended in 200 μL of antibody solution and incubated on ice for 30 minutes. After centrifugation, the supernatant was discarded and the cells were washed once with 1 mL of FACS buffer. 200 μL of AF647-labeled goat anti-human Fc antibody (Jackson, catalog number: 109-606-170) solution was added and incubated on ice for 15 minutes. 5 μg / mL PI (Sigma, catalog number: 31845) solution was added and incubated on ice for 5 minutes. After centrifugation, the supernatant was discarded and the cells were washed once with 1 mL of FACS buffer. The cells were resuspended in 400 μL of PBS and detected and analyzed using a BD Celesta flow cytometer. Based on the flow cytometry and cell counting results, the proportion and number of the two cell types were determined. The above test results are summarized in Figure 1. This demonstrates that the antibody-drug conjugates of this disclosure have superior bystander-killing activity. ADC-1, ADC-10, ADC-74, and ADC-75 showed superior bystander-killing activity against HER2-targeted tumor cells compared to reference samples 2 and 4 at the same dose. Test Example 6: Testing of bystander killing activity of the antibody-drug conjugate of this disclosure against EGFR-targeted tumor cells

[0365] EGFR-positive cells MDA-MB-468 (human breast cancer cells, Cell Center, Shanghai Institute of Biosciences, Chinese Academy of Sciences, catalog number: 3131C0001000700120) and EGFR-negative cells SW620 (human colorectal cancer cells, Biofeng, bc067) were subjected to 1.2 × 10⁶ measurements each using RPMI-1640 + 10% FBS. 5 cells / ml and 4×10 4 The cell density was adjusted to cells / ml. 1 mL each of MDA-MB-468 and SW620 cells were added to a 6-well plate and incubated overnight at 37°C and 5% CO2. The ADC sample was prepared to a concentration of 4.5 μg / mL (30 nM), and 1 mL was added to the cells, resulting in a total volume of 3 mL and a final concentration of 10 nM. A solvent control group was set up and cultured at 37°C and 5% CO2 for 5 days. Trypsin (0.25% trypsin-EDTA (1x), Shanghai Yuanpei Biotechnology Co., Ltd., catalog number: A121002) was added to the 6-well plate for digestion, and the cells were resuspended in 1 mL of FACS buffer (PBS + 4% FBS). Cells were stained with trypan blue and counted. The remaining cells were centrifuged, Nimotuzumab was diluted to 10 μg / mL in FACS buffer, and the cells were resuspended in 200 μL of antibody solution and incubated on ice for 30 minutes. After centrifugation, the supernatant was discarded and the cells were washed once with 1 mL of FACS buffer. 200 μL of AF647-labeled goat anti-human Fc antibody (Jackson, catalog number: 109-606-170) solution was added and incubated on ice for 15 minutes. 5 μg / mL PI (Sigma, catalog number: 31845) solution was added and incubated on ice for 5 minutes. After centrifugation, the supernatant was discarded and the cells were washed once with 1 mL of FACS buffer. The cells were resuspended in 400 μL of PBS and detected and analyzed using a BD Celesta flow cytometer. Based on the flow cytometry and cell counting results, the proportion and number of the two cell types were determined. The above test results are summarized in Figure 2. This shows that the Nimotuzumab antibody-drug conjugates of this disclosure have superior bystander-killing activity. ADC-72 and ADC-73 showed significantly superior bystander-killing activity against EGFR-targeted tumor cells compared to reference 3 at the same dose.

[0366] The embodiments of the technical solutions of this disclosure have been described exemplarily. It should be understood that the scope of protection of this disclosure is not limited to the embodiments described above. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art without departing from the spirit and principles of this disclosure should also be included in the scope of protection of the claims of this application.

Claims

1. Ligand drug conjugates represented by the following formula (C), their stereoisomers, racemates, tautomers, isotopologs, isotopic markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof. Tp-L-G (C) (Here, Tp is the targeting portion, L is selected from chemical bonds or linkers. G is a group represented by the following formula (G), 【Chemistry 1】 Here, A does not exist, or there is no substitution or one, two or more Rs. Ａ The following groups are optionally substituted by: alkylene groups, alkenylene groups, alkylene groups, cycloalkyl groups, aryl groups, heteroaryl groups, heterocyclyl groups, or combinations of two or more of these groups, and the alkylene groups, alkenylene groups, alkylene groups, cycloalkyl groups, aryl groups, heteroaryl groups, heterocyclyl groups, or combinations of two or more of these groups are -O-, -S-, -NR ５－ , -NR ６ C(=O)-, -C(=O)NR ６ -, -C(=O)-, -NR ７ C(=O)NR ８ - or -OC (=O) - are not separated by one, two or more groups selected from these, or may be separated by them as desired. R １ This is either unsubstituted or with one, two, or more Rs. Ｂ The following groups are optionally substituted by: selected from cycloalkyl groups, cycloalkylalkyl groups, cycloalkyloxy groups, heterocyclyl groups, heterocyclylalkyl groups, and heterocyclyloxy groups. X is selected from O or S, Z is selected from 0 or 1. R ２ is selected from hydrogen, deuterium, halogen, hydroxy group, mercapto group, amino group, cyano group, and the following groups unsubstituted or optionally substituted by one, two or more R Ｃ : alkyl group, alkyloxy group, cycloalkyl group, cycloalkylalkyl group, cycloalkyloxy group, R ２２ R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R groups. Ｃ The following groups are optionally substituted by: alkyl groups, alkyloxy groups, cycloalkyl groups, cycloalkylalkyl groups, and cycloalkyloxy groups, selected from the above. R ３ R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R groups. Ｃ The following groups are optionally substituted by: alkyl groups, alkyloxy groups, cycloalkyl groups, cycloalkylalkyl groups, and cycloalkyloxy groups, selected from the above. R ４ R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R groups. Ｃ The following groups are optionally substituted by: alkyl groups, alkyloxy groups, cycloalkyl groups, cycloalkylalkyl groups, and cycloalkyloxy groups, selected from the above. Alternatively, R ２ , R ３ These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. Ｄ Forms a ring structure arbitrarily substituted by, Alternatively, R ３ , R ４ These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. Ｄ Forms a ring structure arbitrarily substituted by, Alternatively, R ２２ , R ４ These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. Ｄ Forms a ring structure arbitrarily substituted by, B does not exist, or -O-, -S-, -S(=O)-, -C(=O)-, -NR ５ -, -C = N - NR ９ -, -C=N-O-, or -NR １０ -NR １１ - Selected from, R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ These are the same or different, and each independently consists of hydrogen, deuterium, unsubstituted or one, two or more R atoms. Ｅ The following groups are optionally substituted by: alkyl groups, cycloalkyl groups, cycloalkylalkyl groups, aryl groups, arylalkyl groups, heteroaryl groups, heteroarylalkyl groups, heterocyclyl groups, heterocyclylalkyl groups, HC(=O)-, alkyl C(=O)-, cycloalkyl C(=O)NH-, heterocyclyl C(=O)NH-, aryl C(=O)NH-, and heteroaryl C(=O)NH-, selected from these. Each R Ａ , R Ｂ , R Ｃ , R Ｄ , R Ｅ These are the same or different, and each independently consists of a deuterated group, halogen, hydroxyl group, cyano group, nitro group, oxo group (=O), unsubstituted or one, two or more R groups. Ｆ The following groups optionally substituted by: alkyl group, alkyloxy group, cycloalkyl group, cycloalkylalkyl group, cycloalkyloxy group, aryl group, arylalkyl group, aryloxy group, heteroaryl group, heteroarylalkyl group, heteroaryloxy group, heterocyclyl group, heterocyclylalkyl group, heterocyclyloxy group, NH ２ Selected from HC(=O)NH-, alkylC(=O)NH-, cycloalkylC(=O)NH-, heterocyclylC(=O)NH-, arylC(=O)NH-, and heteroarylC(=O)NH-, Each R Ｆ These are the same or different, and each independently consists of a deuterated group, halogen, hydroxyl group, cyano group, nitro group, oxo group (=O), alkyl group, alkyloxy group, cycloalkyl group, cycloalkylalkyl group, cycloalkyloxy group, aryl group, arylalkyl group, aryloxy group, heteroaryl group, heteroarylalkyl group, heteroaryloxy group, heterocyclyl group, heterocyclylalkyl group, heterocyclyloxy group, NH ２ Selected from HC(=O)NH-, alkylC(=O)NH-, cycloalkylC(=O)NH-, heterocyclylC(=O)NH-, arylC(=O)NH-, and heteroarylC(=O)NH-, The wavy line indicates the connection point with L.

2. The bases in formula (G) are independently selected from the following definitions: Here, A does not exist, or there is no substitution or one, two or more Rs. Ａ The following bases are optionally substituted by: C １～１０ Alkylene group, C ２～１０ Alkenylene group, C ２～１０ Alkynylene group, C ３～１０ Cycloalkyl groups, C ６～１２ Selected from an aryl group, a 5-12 membered heteroaryl group, a 5-12 membered heterocyclyl group, or a combination of two or more of these groups, the C １～１０ Alkylene group, C ２～１０ Alkenylene group, C ２～１０ Alkynylene group, C ３～１０ Cycloalkyl groups, C ６～１２ An aryl group, a 5- to 12-membered heteroaryl group, a 5- to 12-membered heterocyclyl group, or a combination of two or more of these groups is classified as -O-, -S-, -NR ５－ , -NR ６ C(=O)-, -C(=O)NR ６ -, -C(=O)-, -NR ７ C(=O)NR ８ - or -OC (=O) - may or may not be separated by one, two or more groups selected from -OC (=O), preferably A is absent, unsubstituted or one, two or more R Ａ The following bases are optionally substituted by: C １～６ Alkylene group, C ２～６ Alkenylene group, C ２～６ Alkynylene group, C ３～６ Cycloalkyl groups, C ６～１０ Selected from an aryl group, a 5-10 membered heteroaryl group, a 5-10 membered heterocyclyl group, or a combination of two or more of these groups, the C １～６ Alkylene group, C ２～６ Alkenylene group, C ２～６ Alkynylene group, C ３～６ Cycloalkyl groups, C ６～１０ An aryl group, a 5-10 membered heteroaryl group, a 5-10 membered heterocyclyl group, or a combination of two or more of these groups is classified as -O-, -S-, -NR ５－ , -NR ６ C(=O)-, -C(=O)NR ６ -, -C(=O)-, -NR ７ C(=O)NR ８ - or -OC (=O) - are not separated by one, two or more groups selected from these, or may be separated by them as desired. R １ is any of the following groups, which is unsubstituted or optionally substituted by one, two or more R Ｂ : C ３～１０ cycloalkyl, C ３～１０ cycloalkyl C １～１０ alkyl, C ３～１０ cycloalkyloxy, a 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl C １～１０ alkyl, or 3- to 10-membered heterocyclyloxy; preferably, R １ is any of the following groups, which is unsubstituted or optionally substituted by one, two or more R Ｂ : C ３～６ cycloalkyl, C ３～６ cycloalkyl C １～６ alkyl, C ３～６ cycloalkyloxy, a 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl C １～６ alkyl, or 3- to 6-membered heterocyclyloxy, X is selected from O or S, Z is selected from 0 or 1. R ２ is selected from hydrogen, deuterium, halogen, hydroxy group, mercapto group, amino group, cyano group, and the following groups unsubstituted or optionally substituted with one, two or more R Ｃ : C ３～１０ alkyl group, C ３～１０ alkyloxy group, C ３～１０ cycloalkyl group, C ３～１０ cycloalkyl C １～１０ alkyl group, C ３～１０ cycloalkyloxy group; preferably, R ２ is selected from hydrogen, deuterium, halogen, hydroxy group, mercapto group, amino group, cyano group, and the following groups unsubstituted or optionally substituted with one, two or more R Ｃ : C １～６ alkyl group, C １～６ alkyloxy group, C ３～６ cycloalkyl group, C ３～６ cycloalkyl C １～６ alkyl group, C ３～６ cycloalkyloxy group, R ２２ R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R groups. Ｃ The following bases are optionally substituted by: C ３～１０ alkyl group, C ３～１０ Alkyloxy group, C ３～１０ Cycloalkyl groups, C ３～１０ Cycloalkyl C １～１０ alkyl group, C ３～１０ Selected from cycloalkyloxy groups, preferably R ２ R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R groups. Ｃ The following bases are optionally substituted by: C １～６ alkyl group, C １～６ Alkyloxy group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl C １～６ alkyl group, C ３～６ Selected from cycloalkyloxy groups, R ３ R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R groups. Ｃ The following bases are optionally substituted by: C １～１０ alkyl group, C １～１０ Alkyloxy group, C ３～１０ Cycloalkyl groups, C ３～１０ Cycloalkyl C １～１０ alkyl group, C ３～１０ Selected from cycloalkyloxy groups, preferably R ３ R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R groups. Ｃ The following bases are optionally substituted by: C １～６ alkyl group, C １～６ Alkyloxy group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl C １～６ alkyl group, C ３～６ Selected from cycloalkyloxy groups, R ４ R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R groups. Ｃ The following bases are optionally substituted by: C １～１０ alkyl group, C １～１０ Alkyloxy group, C ３～１０ Cycloalkyl groups, C ３～１０ Cycloalkyl C １～１０ alkyl group, C ３～１０ Selected from cycloalkyloxy groups, preferably R ４ R is hydrogen, deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, unsubstituted or one, two or more R groups. Ｃ The following bases are optionally substituted by: C １～６ alkyl group, C １～６ Alkyloxy group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl C １～６ alkyl group, C ３～６ Selected from cycloalkyloxy groups, Alternatively, R ２ , R ３ These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. Ｄ A 4- to 10-membered ring structure is formed by which the 4- to 10-membered ring structure may be selected from, for example, 4, 5, 6, 7, 8, 9, or 10-membered heteromonocyclic hydrocarbon groups, heterodicyclic hydrocarbon groups, monocyclic hydrocarbon groups, and bicyclic hydrocarbon groups, wherein the heteromonocyclic hydrocarbon group and heterodicyclic hydrocarbon group contain one, two or more O, S, N, or carbonyl groups, or any combination thereof. Alternatively, R ３ , R ４ These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. Ｄ A 4- to 10-membered ring structure is formed by which the 4- to 10-membered ring structure may be selected from, for example, 4, 5, 6, 7, 8, 9, or 10-membered monocyclic hydrocarbon groups, bicyclic hydrocarbon groups, heteromonocyclic hydrocarbon groups, and heterodicyclic hydrocarbon groups, wherein the heteromonocyclic hydrocarbon group and heterodicyclic hydrocarbon group contain one, two, or more O, S, N, or carbonyl groups, or any combination thereof. Alternatively, R ２２ , R ４ These, along with the atoms linked to them, are either unsubstituted or have one, two, or more R atoms. Ｄ A 4- to 10-membered ring structure is formed by which the 4- to 10-membered ring structure may be selected from, for example, 4, 5, 6, 7, 8, 9, or 10-membered monocyclic hydrocarbon groups, bicyclic hydrocarbon groups, heteromonocyclic hydrocarbon groups, and heterodicyclic hydrocarbon groups, wherein the heteromonocyclic hydrocarbon group and heterodicyclic hydrocarbon group contain one, two, or more O, S, N, or carbonyl groups, or any combination thereof. B does not exist, or -O-, -S-, -S(=O)-, -C(=O)-, -NR ５ -, -C = N - NR ９ -, -C=N-O-, or -NR １０ -NR １１ - Selected from, R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ These are the same or different, and each independently consists of hydrogen, deuterium, unsubstituted or one, two or more R atoms. Ｅ The following bases are optionally substituted by: C １～１０ alkyl group, C ３～１０ Cycloalkyl groups, C ３～１０ Cycloalkyl C １～１０ alkyl group, C ６～１２ Aryl group, C ６～１２ Aryl C １～１０ Alkyl group, 5-12 member heteroaryl group, 5-12 member heteroaryl C １～１０ Alkyl group, 5-12 membered heterocyclyl group, 5-12 membered heterocyclyl C １～１０ Alkyl alkyl group, HC(=O)-, C １～１０ Alkyl C(=O)-, C ３～１０ Cycloalkyl C(=O)NH-, 5-12 member heterocyclyl C(=O)NH-, C ６～１２ Selected from aryl C(=O)NH- and 5- to 12-membered heteroaryl C(=O)NH-, preferably R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ These are the same or different, and each independently consists of hydrogen, deuterium, unsubstituted or one, two or more R atoms. Ｅ The following bases are optionally substituted by: C １～６ alkyl group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl C １～６ alkyl group, C ６～１０ Aryl group, C ６～１０ Aryl C １～６ Alkyl group, 5-6 member heteroaryl group, 5-6 member heteroaryl C １～６ Alkyl group, 5-6 membered heterocyclyl group, 5-6 membered heterocyclyl C １～６ Alkyl alkyl group, HC(=O)-, C １～６ Alkyl C(=O)-, C ３～６ Cycloalkyl C(=O)NH-, 5-6 member heterocyclyl C(=O)NH-, C ６～１０ Selected from aryl C(=O)NH- and 5-6 member heteroaryl C(=O)NH-, Each R Ａ , R Ｂ , R Ｃ , R Ｄ , R Ｅ These are the same or different, and each independently contains a deuterated group, halogen, hydroxyl group, cyano group, nitro group, unsubstituted or one, two or more R groups. Ｆ The following bases are optionally substituted by: C １～１０ alkyl group, C １～１０ Alkyloxy group, C ３～１０ Cycloalkyl groups, C ３～１０ Cycloalkyl C １～１０ alkyl group, C ３～１０ Cycloalkyloxy group, C ６～１２ Aryl group, C ６～１２ Aryl C １～１０ alkyl group, C ６～１２ Aryloxy group, 5-12 membered heteroaryl group, 5-12 membered heteroaryl C １～１０ Alkyl group, 5-12 member heteroaryloxy group, 5-12 member heterocyclyl group, 5-12 member heterocyclyl C １～１０ Alkyl group, 5-12 member heterocyclyloxy group, NH ２ , HC(=O)NH-, C １～１０ Alkyl C(=O)NH-, C ３～１０ Cycloalkyl C(=O)NH-, 5-12 member heterocyclyl C(=O)NH-, C ６～１２ Selected from aryl C(=O)NH- and 5- to 12-membered heteroaryl C(=O)NH-, preferably each R Ａ , R Ｂ , R Ｃ , R Ｄ , R Ｅ These are the same or different, and each independently contains a deuterated group, halogen, hydroxyl group, cyano group, nitro group, unsubstituted or one, two or more R groups. Ｆ The following bases are optionally substituted by: C １～６ alkyl group, C １～６ Alkyloxy group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl C １～６ alkyl group, C ３～６ Cycloalkyloxy group, C ６～１０ Aryl group, C ６～１０ Aryl C １～６ alkyl group, C ６～１０ Aryloxy group, 5-6 member heteroaryl group, 5-6 member heteroaryl C １～６ Alkyl group, 5-6 member heteroaryloxy group, 5-6 member heterocyclyl group, 5-6 member heterocyclyl C １～６ Alkyl group, 5-6 member heterocyclyloxy group, NH ２ , HC(=O)NH-, C １～６ Alkyl C(=O)NH-, C ３～６ Cycloalkyl C(=O)NH-, 5-6 member heterocyclyl C(=O)NH-, C ６～１０ Selected from aryl C(=O)NH- and 5-6 member heteroaryl C(=O)NH-, Each R Ｆ These are the same or different, and each is independently a deuterated group, halogen, hydroxyl group, cyano group, nitro group, alkyl group, C １～１０ Alkyloxy group, C ３～１０ Cycloalkyl groups, C ３～１０ Cycloalkyl C １～１０ alkyl group, C ３～１０ Cycloalkyloxy group, C ６～１２ Aryl group, C ６～１２ Aryl C １～１０ alkyl group, C ６～１２ Aryloxy group, 5-12 membered heteroaryl group, 5-12 membered heteroaryl C １～１０ Alkyl group, 5-12 member heteroaryloxy group, 5-12 member heterocyclyl group, 5-12 member heterocyclyl C １～１０ Alkyl group, 5-12 member heterocyclyloxy group, NH ２ , HC(=O)NH-, C １～１０ Alkyl C(=O)NH-, C ３～１０ Cycloalkyl C(=O)NH-, 5-12 member heterocyclyl C(=O)NH-, C ６～１２ Selected from aryl C(=O)NH- and 5- to 12-membered heteroaryl C(=O)NH-, preferably each R Ｆ These are the same or different, and each is independently a deuterated group, halogen, hydroxyl group, cyano group, nitro group, alkyl group, C １～６ Alkyloxy group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl C １～６ alkyl group, C ３～６ Cycloalkyloxy group, C ６～１０ Aryl group, C ６～１０ Aryl C １～６ alkyl group, C ６～１０ Aryloxy group, 5-6 member heteroaryl group, 5-6 member heteroaryl C １～６ Alkyl group, 5-6 member heteroaryloxy group, 5-6 member heterocyclyl group, 5-6 member heterocyclyl C １～６ Alkyl group, 5-6 member heterocyclyloxy group, NH ２ , HC(=O)NH-, C １～６ Alkyl C(=O)NH-, C ３～６ Cycloalkyl C(=O)NH-, 5-6 member heterocyclyl C(=O)NH-, C ６～１０ A ligand drug conjugate according to claim 1, selected from aryl C(=O)NH- and 5-6 member heteroaryl C(=O)NH-, stereoisomers thereof, racemates, tautomers, isotopologs, isotopic markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof.

3. A is either absent or one selected from the following substructures, wherein the substructure is unsubstituted or contains one, two or more R Ａ A ligand drug conjugate according to any one of claims 1 to 2, stereoisomers, racemates, tautomers, isotopologs, isotopic markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof, which may be optionally substituted by the above. -(CH ２ ) ｎ１ -、-O(CH ２ ) ｎ２ -、-S(CH ２ ) ｎ３ -、-NR ５ (CH ２ ) ｎ４ -、-NR ６ C(=O)(CH ２ ) ｎ５ -、-C(=O)(CH ２ ) ｎ６ -、-NR ７ C(=O)NR ８ (CH ２ ) ｎ７ -、-OC(=O)(CH ２ ) ｎ８ -、-C=C(CH ２ ) ｎ９ -、-C≡C(CH ２ ) ｎ１０ -、 【Chemistry 2】 (n1, n2, n3, n4, n5, n6, n7, n8, n9, n10 are each independent integers selected from 0 to 6, R １ This is either unsubstituted or with one, two, or more Rs. Ｂ The following bases are optionally substituted by: C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl C １～６ Selected from alkyl groups, for example, R １ This is either unsubstituted or with one, two, or more Rs. Ｂ Selected from the following bases, which are arbitrarily substituted by: 【Transformation 3】 R ２ It is selected from hydrogen, R ２２ It is selected from hydrogen, R ３ This is either unsubstituted or with one, two, or more Rs. Ｃ C arbitrarily substituted by １～６ Selected from alkyl groups, for example, R ３ The group is selected from a methyl group, an ethyl group, and a propyl group. R ４ It is selected from halogens, B does not exist, or -O-, -S-, NR ５ Selected from, R ５ H, deuterium, C １～６ alkyl group, C ３～６ Selected from cycloalkyl groups, Alternatively, R ３ , R ４ Together with the benzene rings linked thereto, these form one of the following substructures, and the substructure is unsubstituted or has one, two or more R Ｄ It may be optionally replaced by, 【Chemistry 4】 Here, R Ｄ (Each has independently the definition described in any of claims 1 to 2.)

4. A is either absent or one selected from the following substructures, wherein the substructure is unsubstituted or contains one, two or more R Ａ A ligand drug conjugate according to any one of claims 1 to 3, characterized in that it may be optionally substituted by a ligand, stereoisomer thereof, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate thereof, or a pharmaceutically acceptable salt thereof. 【Transformation 5】 (B does not exist, or -O-, -S-, NR) ５ Selected from, R ５ H, deuterium, C １～６ alkyl group, C ３～６ (Selected from cycloalkyl groups.)

5. G is selected from the group represented by the following formula (G-1) or (G-2), wherein the ligand drug conjugate, stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4. 【Transformation 6】 (Here, A, B, R １ , R ２ , R ２２ , R ３ , R ４ (Each has independently had the definition described in any one of claims 1 to 4.)

6. G is selected from the group represented by formula (G-3), (G-4), (G-5), or (G-6), and is a ligand drug conjugate according to any one of claims 1 to 4, stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof. 【Transformation 7】 (Here, A, B, R １ (This has the definition described in any one of claims 1 to 4.)

7. G is a ligand drug conjugate according to any one of claims 1 to 4, selected from the following groups, stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof. 【Transformation 8】 (Here, A, B, R ２ , R ２２ , R ３ , R ４ (Each has independently had the definition described in any one of claims 1 to 4.)

8. G is a ligand drug conjugate according to any one of claims 1 to 4, selected from the following groups, stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof. 【Chemistry 9】 (Here, A, B, R ２ , R ２２ , R ３ , R ４ (Each has independently had the definition described in any one of claims 1 to 4.)

9. G is a ligand drug conjugate according to any one of claims 1 to 4, selected from the following groups, stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof. 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】

10. L is selected from a chemical bond or a linker represented by formula (L) as defined below, the ligand drug conjugate according to any one of claims 1 to 4, its stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate or pharmaceutically acceptable salt thereof. #L １ -8 ２ -8 ３ -8 ４ * (7) (Here, L １ This is the linking portion with the targeting portion Tp, and the reactive group L １ ' is formed by the targeted portion Tp, and # represents the connection site with the targeted portion Tp. For example, L １ If ' is a pyrimidinyl group or a maleimide group, L １ It has the following structure: 【Chemistry 13】 L ２ It does not exist, or L １ and L ３ This is the spacer part, L ３ This is the peptide portion, L ４ It is either absent or is a linking portion between the peptide portion and the biologically active molecule G, and is a reactive group L. ４ It is produced by reacting ' with biologically active molecule G or an intermediate thereof, and * represents the linkage site with biologically active molecule G. Optional, Between the above parts of L, preferably L １ and L ２ Between, or L ２ and L ３ Between, or L ２ Replace with L ２ By inserting it, the following hydrophilic portion is included, Here, the hydrophilic portion is a divalent unit substituted with one, two or more hydrophilic groups, for example, a phenylene group substituted with one, two or more hydrophilic groups, or an amino acid residue substituted with one, two or more hydrophilic groups, preferably, 【Chemistry 14】 The hydrophilic portion is a divalent unit formed by the hydrophilic group itself, for example, 【Chemistry 15】 or - (CH ２ CH ２ O) ｐ - may be, R １２ , R １２ ' are the same or different, at least one of which is selected from hydrophilic groups and the other is one of the following substituents: hydrogen, halogen, cyano group, amino group, nitro group, unsubstituted or one, two or more R ｚｇ C arbitrarily substituted by １～１０ alkyl group, C １～１０ Alkyloxy group, C ３～１０ Cycloalkyl groups, C ３～１０ Cycloalkyl C １～１０ alkyl group, C ３～１０ Selected from cycloalkyloxy groups, The hydrophilic group is optionally substituted with a polyethylene glycol group, a polyethylene glycol divalent unit, or 1 to 10 hydroxyl groups. １～１０ A group containing an alkyl group, a sugar ring, or a heterocyclyl divalent unit containing a nitrogen atom, selected from, for example, a piperidinyl group or a piperazyl group, preferably a polyethylene glycol group, more preferably -(CH ２ CH ２ O) ｐ -C １～１０ Alkyl alkyl group, -C(=O)-NH-(CH ２ CH ２ O) ｐ -C １～１０ Alkyl alkyl group, or -NH-(CH ２ CH ２ O) ｐ -C １～１０ C is an alkyl group, or preferably optionally substituted with 1 to 10 hydroxyl groups. １～１０ Alkyl alkyl groups, more preferably 【Chemistry 16】 And, Each p is the same or different, and independently selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. Each R ｚｇ They are the same or different, and each is independently a halogen, hydroxyl group, amino group, cyano group, nitro group, C １～１０ alkyl group, C １～１０ Alkyloxy group, C ３～１０ Cycloalkyl groups, C ３～１０ Cycloalkyl C １～１０ alkyl group, C ３～１０ Selected from cycloalkyloxy groups, Preferably, each R ｚｇ They are the same or different, and each is independently a halogen, hydroxyl group, amino group, cyano group, nitro group, C １～６ alkyl group, C １～６ Alkyloxy group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl C １～６ alkyl group, C ３～６ Selected from cycloalkyloxy groups, The hydrophilic portion defined above may or may not exist. L １ -L ４ Alternatively, the hydrophilic portion may be linked via any chemical bond, such as a direct bond, an ester bond (-CO-O-), an amide bond (-CO-NH-), an ether bond (-O-), a thioether bond (-S-), a carbamate bond (-N-CO-O-), or a ureid group (-O-CO-O-). Preferably, the hydrogen atoms in each peptide bond or amide bond in L may be optionally substituted with methyl groups.

11. L １ This is any group L that reacts with the targeting portion Tp. １ ' is formed by L １ ' is preferably a mercapto-reactive group, an amino-reactive group, a carboxy-reactive group, a dithiol crosslinking group, etc., and for antibodies introducing non-natural amino acids, it may be selected from click chemistry-reactive groups, such as ketones, hydrazines or hydrazides, azides, alkynes, cyclopropenes or dienes, and if the Tp portion is an antibody, the linking site comprises any suitable amino acid residue or an N297 glycan complex of the CH2 domain, such as fucose, galactose, N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), and sialic acid (SA) introduced by glycoengineering, and the linking reaction comprises a chemical or enzymatic reaction, for example, transferring an amine-containing drug linker or reactive spacer to a deglycosylated antibody using transglutaminase (MTGase). L １ ' is preferably a mercapto-reactive group, L １ ' is preferably a mercapto-reactive group having the following structure, Hal-Het- Haal is a halogen, OMs, OTs, OTf, nitro group, and one, two or more R groups. ｚ８ The following bases are optionally substituted by: C １～１０ Alkylthioether group, C ６～１２ Arylthioether group, 5-12 membered heteroarylthioether group, C １～１０ Alkyl sulfoxide group, C ６～１２ Aryl sulfoxide group, 5-12 member heteroaryl sulfoxide group, C １～１０ Alkyl sulfonyl group, C ６～１２ Selected from arylsulfonyl groups and 5-12 membered heteroarylsulfonyl groups, where R ｚ８ These are independently H (hydrogen), D (deuterium), halogen, CN, nitro group, and C １～６ Alkyl, Halo C １～６ alkyl group, C １～６ Alkoxy group, C ６～１２ Selected from 5-membered aryl groups and 5- to 12-membered heteroaryl groups, Het has one, two, or more R ｚ９ Selected from 5- to 12-membered heteroaryl groups optionally substituted by, where R ｚ９ These are independently H (hydrogen), D (deuterium), halogen, CN, nitro group, and C １～１０ Alkyl groups, and halo C １～１０ Selected from alkyl groups, preferably Het has one, two or more R ｚ９ Selected from 5- to 10-membered heteroaryl groups optionally substituted by, where R ｚ９ These are independently H (hydrogen), D (deuterium), halogen, CN, nitro group, and C １～４ Alkyl groups, and halo C １～４ Selected from alkyl groups, In a preferred embodiment, Haal is preferably a methanesulfonyl group, and Het is preferably a pyrimidine. In a preferred embodiment, Hal-Het- is as follows: 【Chemistry 17】 Corresponding L １ The structure is as follows: [Chemistry 18] Furthermore, L １ '-L ２ Preferably, it has the following structure: 【Chemistry 19】 q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. R ｚ４ and R ｚ５ H and C are the same or different, and are independent of each other. １～４ alkyl group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl-C １～４ Selected from alkyl groups, or R ｚ４ or R ｚ５ C ３～６ Forms a cycloalkyl group, L １ '-L ２ More preferably, the structure is as follows: 【Chemistry 20】 Or, L １ ' is more preferably a maleimide group or a substituted maleimide group, and L １ -L ２ Preferably, it has the following structure: A fragment produced from (N-maleimidomethyl)carboxylate-N-hydroxysuccinimide ester having the following structure, 【Chemistry 21】 (q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8) Alternatively, a fragment produced from m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) having the following structure, 【Chemistry 22】 A fragment produced from 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate succinimide (SMCC) having the following structure, 【Chemistry 23】 The ligand drug conjugate according to claim 10, its stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate, or pharmaceutically acceptable salt thereof.

12. L ２ C does not exist. １～１０ Alkylene group, C ２～１０ Alkenylene group, C ２～１０ Alkynylene group, C ３～１０ Cycloalkyl groups, C ６～１２ Selected from an aryl group, a 5-12 membered heteroaryl group, a 5-12 membered heterocyclyl group, or a combination of two or more of these groups, the C １～１０ Alkylene group, C ２～１０ Alkenylene group, C ２～１０ Alkynylene group, C ３～１０ Cycloalkyl groups, C ６～１２ The aryl group, the 5-12 membered heteroaryl group, the 5-12 membered heterocyclyl group, or a combination of two or more of these groups may not be separated by a carbonyl group, O, S, or N atom, or may be separated as such. １～１０ Alkylene group, C ２～１０ Alkenylene group, C ２～１０ Alkynylene group, C ３～１０ Cycloalkyl groups, C ６～１２ An aryl group, a 5-12 membered heteroaryl group, a 5-12 membered heterocyclyl group, or a combination of two or more of these groups is C １～６ alkyl group, C ３～６ Cycloalkyl groups, halogen atoms, halo C １～６ It may be optionally substituted with an alkyl group, and optionally, the C １～６ Alkyl group, or halo C １～６ Alkyl groups, along with the C atoms linked to them, are C ３～６ A cycloalkyl group may be formed, L ２ L is formed via any functional group or covalent bond. １ or L ３ The fragments are joined together, Preferably, L ２ is, -(CH ２ ) ｑ -, -C(=O)-NH-(CH ２ ) ｑ -C(=O)-, -(CH ２ ) ｑ -C(=O)-, -(CH ２ ) ｑ -NH-C(=O)-, -(CH ２ ) ｑ -NCH ３ -C(=O)-, -(C≡C)-(CH ２ ) ｑ -C(R ｚ４ R ｚ５ )-C(=O)- or -Cy-(CH ２ ) ｑ -C(R ｚ４ R ｚ５ ) - C (= O) - is selected, where q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. Here, Cy is a 5-12 membered heteroaryl group or heterocyclyl group optionally containing an S, O, or N heteroatom, and also H (hydrogen), D (deuterium), halogen, CN, nitro group, C １～４ Alkyl groups, and halo C １～４ The group is optionally substituted with an alkyl group, preferably at least three atoms of Cy are nitrogen, more preferably three consecutive atoms of Cy are nitrogen, and even more preferably Cy is a 1,2,3-triazolyl group. Preferably, R ｚ４ and R ｚ５ H and C are the same or different, and are independent of each other. １～４ alkyl group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl-C １～４ Selected from alkyl groups, or R ｚ４ or R ｚ５ C ３～６ Forms a cycloalkyl group, Preferably, L ２ is -NHC(=O)-, -NCH ３ via C(=O)- or -C(=O)-, peptide fragment L ３ A ligand drug conjugate according to claim 10, linked to the N-terminus of, stereoisomers, racemates, tautomers, isotopologs, isotopic markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof.

13. L ３ The peptide group is selected from a divalent peptide group containing 2 to 8 arbitrarily placed natural or non-natural, L-type or D-type amino acid residues, each of which is the same or different, and each is independently one of the following amino acid residues: alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Ile). Nin (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolidine (Pyl), homoserine, homocysteine, demethylpyrrolidine, selected from analogs of the above amino acids, or AA １ Selected from the amino acid residues shown, or their stereoisomers, 【Chemistry 24】 Here, R Ｇ and R Ｈ H is not H at the same time, and each is independent of H, 【Chemistry 25】 Selected from, Alternatively, R Ｇ and R Ｈ These, along with the carbon atoms they jointly link, are either unsubstituted or have one, two, or more R atoms. Ｌ C arbitrarily substituted by ３～１０ Forming a cycloalkyl group or a 3-10 membered heterocyclyl group, r and r1 are each independent integers selected from 0 to 10. R Ｉ , R Ｊ , R Ｋ Each of these is independently H, unsubstituted, or one, two or more R Ｍ C arbitrarily substituted by １～６ alkyl group, C ３～１０ Cycloalkyl groups, C ３～１０ Cycloalkyl C １～１０ Selected from alkyl groups and ester groups, Alternatively, R Ｉ and R Ｊ These, along with the nitrogen atom they collectively link, are either unsubstituted or have one, two, or more R atoms. Ｌ This forms a 4- to 10-membered heterocyclyl group which is optionally substituted by R Ｍ , R Ｌ These are the same or different, and each independently consists of a deuterated group, halogen, hydroxyl group, cyano group, nitro group, alkyl group, alkyloxy group, cycloalkyl group, cycloalkylalkyl group, cycloalkyloxy group, aryl group, arylalkyl group, aryloxy group, heteroaryl group, heteroarylalkyl group, heteroaryloxy group, heterocyclyl group, heterocyclylalkyl group, heterocyclyloxy group, NH ２ Selected from alkylamino groups, dialkyl amino acids, HC(=O)NH-, alkyl C(=O)NH-, cycloalkyl C(=O)NH-, heterocyclyl C(=O)NH-, aryl C(=O)NH-, and heteroaryl C(=O)NH-, two R groups linked to the same carbon atom are optionally selected. Ｍ or R Ｌ C ３～６ Forms a cycloalkyl group, More preferably, L ３ This refers to optionally substituted or unnatural, L-type or D-type amino acid residues, or AA １ A combination of 2, 3, 4, 5, or 6 amino acid residues is selected from a divalent peptide group, where each of the amino acid residues is the same or different and independently consists of the following amino acids: alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Lys), and methyl phosphate. (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolidine (Pyl), homoserine, homocysteine, demethylpyrrolidine, analogs of the above amino acids or AA １ Selected from, for example, -ValCit-; -ValAA １ -;-CitVal-;-AlaAla-;-AlaCit-;-CitAla-;-AsnCit-;-CitAsn-;-CitCit-;-ValGlu-;-GluVal-;-SerCit-;-CitSer-;-L ysCit-;-CitLys-;-AspCit-;-CitAsp-;-AlaVal-;-ValAla-;-PheAla-;-AlaPhe-;-PheLys-;-LysPhe-;-ValLys-;-GlyAA １ -;-LysVal-;-AlaLys-;-LysAla-;-PheCit-;-CitPhe-;-LeuCit-;-CitLeu-;-IleCit-; -CitIle-;-PheArg-;-ArgPhe-;-CitTrp-;-TrpCit-;-AlaAlaAla-;-PhePheLys-;-ValAA １ Gly-;-AlaAA １ Gly-;- GlyAA １ Gly-;-LysPhePhe-;-DPhePheLys-;-DLysPhePhe-;-GlyPheLys-;-LysPheGly-;-GlyPheLeuGly-;-GlyLeuPheGly-;-AlaLeuAlaLeu-;-GlyGlyGly-;-GlyGlyGlyGly-;-GlyPheValGly-;-GlyValPheGly-;-GlyGlyPheGly-;-GlyGlyValGly-であり、 AA １ In the amino acid residues, preferably, r and r1 are each independent integers selected from 0 to 5. R Ｇ and R Ｈ Of these, one is H, and the other is 【Chemistry 26】 Selected from, Alternatively, R Ｇ and R Ｈ These, along with the carbon atoms they jointly link, are either unsubstituted or have one, two, or more R atoms. Ｌ This forms a 5-6 member heterocyclyl group which is optionally substituted by R Ｉ , R Ｊ , R Ｋ Each of these is independently H, unsubstituted, or one, two or more R Ｍ Methyl groups, ethyl groups, n-propyl groups, n-butyl groups, C, which are optionally substituted by ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl C １～６ Alkyl alkyl group, -COOCH ３ COOCH ２ CH ３ , -COOCH ２ CH ２ CH ３ , -COOCH(CH ３ ) ２ , -COOC(CH ３ ) ３ , and -COOCH ２ CH ２ CH ２ CH ３ Selected from, Alternatively, R Ｉ and R Ｊ These, along with the nitrogen atom they collectively link, are either unsubstituted or have one, two, or more R atoms. Ｌ This forms a 5-6 member heterocyclyl group which is optionally substituted by Most preferably, L ３ is, -ValAA １ Selected from Gly-, Here, AA １ In the amino acid residue, r is 0 and r1 is 4. R Ｇ and R Ｈ Of these, one is H, and the other is 【Chemistry 27】 Selected from, Alternatively, R Ｇ and R Ｈ These, along with the carbon atoms that are linked together, 【Chemistry 28】 This forms, where * is R Ｇ and R Ｈ This represents carbon atoms that are linked together, R Ｉ , R Ｊ , R Ｋ Each of these is independently H, unsubstituted, or one, two or more R Ｍ Methyl groups, ethyl groups, n-propyl groups, n-butyl groups, C are substituted by C. ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl C １～４ Selected from alkyl groups, Alternatively, R Ｉ and R Ｊ These, along with the nitrogen atoms that are linked together, 【Chemistry 29】 A ligand drug conjugate according to claim 10, stereoisomers, racemates, tautomers, isotopologs, isotopic markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof, forming a ligand drug conjugate according to claim 10.

14. AA １ The ligand drug conjugate according to any one of claims 10 to 13, characterized in that the amino acid residue is one selected from the following substructures, stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof. 【Transformation 30】 【Chemistry 31】

15. L ４ It does not exist, or is selected from the following: 【Chemistry 32】 More preferably, L ４ teeth, 【Transformation 33】 And, Most preferably, L ４ teeth, 【Transformation 34】 The ligand drug conjugate according to claim 10, its stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate, or pharmaceutically acceptable salt thereof.

16. L １ This is a structure in which a maleimide group, a substituted maleimide group, or a mercapto-reactive group selected from Hal-Het- is bonded to Tp. L １ and L ２ Between, or L ２ and L ３ Between, or L ２ Replace with L ２ A ligand drug conjugate according to any one of claims 10 to 15, comprising the hydrophilic portion by insertion, stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof.

17. L １ The ligand drug conjugate according to any one of claims 10 to 15, wherein a mercapto-reactive group selected from a maleimide group or a substituted maleimide group is bonded to Tp, stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof.

18. L １ This is a structure in which a mercapto-reactive group selected from Hal-Het- is bound to Tp, L ４ teeth, 【Chemistry 35】 The ligand drug conjugate according to any one of claims 10 to 15, its stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate, or pharmaceutically acceptable salt thereof.

19. L １ -L ２ L has the following structure １ '-L ２ This is formed by combining with Tp, 【Transformation 36】 q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. R ｚ４ and R ｚ５ H and C are the same or different, and are independent of each other. １～４ alkyl group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl-C １～４ Selected from alkyl groups, or R ｚ４ or R ｚ５ C ３～６ A cycloalkyl group is formed, where R ｚ４ or R ｚ５ At least one of them is not H, More preferably, R ｚ４ or R ｚ５ C ３～６ Forms a cycloalkyl group, L １ -L ２ Most preferably, 【Chemistry 37】 A ligand drug conjugate according to any one of claims 10 to 15, wherein the compound is bound to Tp, a stereoisomer thereof, a racemate, a tautomer, an isotopolog, an isotope marker, a nitrogen oxide, a prodrug, a solvate thereof, or a pharmaceutically acceptable salt thereof.

20. Tp is a targeting site selected from small molecule ligands, proteins, polypeptides, and non-protein reagents (e.g., sugars, RNA, or DNA). 4000000000000000000000000000000000000000000000000000 000 000 00 505 55% girls 455% 2000 to 2020 in 22,300,000,000,000,000,000,000,000 receptor1、u 138、3420、3419、3300、33042006、3800 4、4issue factor、ｭucin116、･ndothei recceptorraｳTEA?0MMMMy9v@ C、PSM｡、33CD79b、3D22、oodium phoosphat cotraasporter 23、10073、44 glycoprotein、213-16、1 02、3333、3446612、3474、3444 6、.44-11、442334442、425、51 The 5b、PSCA hlg、ETTBR、*371783、344. 2014, 300,000,000,000,000,000 1,347,222, 832, 740, 3,200,000,000,000,000,000,000. ph322、|33,17659、0332、 1542、32200-2、34795、38 325, 2003, 02857 2、, 164、0522211、3244222、4 5832、インテグリンα4β6、α4β7、007022、0702222222 6、DLL3、44444、Pcadher in、EpCAM、p03AD、34223、 LYDD 3、666!!!(,08A4(!! 21, 3, 9, 4, 4, 6, 44, 58,000 The 4.12-122-121-212-121-21TH、SHR40、SHR454(SHR)、SHR4 0(SYS)、SHR80、SHR10、SHRY、 JSH、LOVE86、SH47、SH3S1、2 THIRCH、SHR5、1005、1001 LOVE、ROSE2、LOVE71、LOVE、LOVE 15、SHR8、SHR10、SHR10 CYS、SYS1、SYSYS、SYSY、SYS3 、SHYS、S1SY、SHYS、SHYS44、 JOHN3、DYS3、DY10、S 45、SHASH10、SHASH11、CHASH、S 22、SYS10、SYS2、DYS4、SYS3 33、SH1、SH11、SH11、SHA1 2. CHR11 CHR11 CHRIC3 0、HY1、SAS33、CHARH、CHAS5S、 CHEER3、HYD14、SHORE1、SHORE 、CHS4、SH1、SH11、SH2、S WHY、HYS1、HYS2、SYS 21、HAR13、SHOSHKH、HAR1 6、DY2、DY10、DY143 Happy Birthday to you. Preferably, Tp is a small molecule ligand, such as a folic acid derivative, a glutamate urea derivative, a somatostatin derivative, an aryl sulfonamide derivative (e.g., a carbonic anhydrase IX inhibitor), an ICG dye, a cyanine dye, or a derivative thereof. Preferably, Tp is selected from an antibody or its antigen-binding fragment, and the antibody is selected from a chimeric antibody, a humanized antibody, or a fully human antibody, preferably a monoclonal antibody. Preferably, the antibody or antigen-binding fragment thereof is anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti- Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-MUCl antibody, anti-Lewis At least one antibody or its antigen-binding fragment selected from Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, or anti-Mesothelin antibody, wherein the antibody may be a bispecific antibody or a multispecific antibody. More preferably, the antibody or its antigen-binding fragment is at least one antibody or its antigen-binding fragment selected from Trastuzumab, Pertuzumab, Nimotuzumab, Enoblituzumab, Emibetuzumab, Inotuzumab, Pinatuzumab, Brentuximab, Gemtuzumab, Bivatuzumab, Lorvotuzumab, cBR96, and Glembatumumab, the ligand drug conjugate according to any one of claims 1 to 19, its stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate or pharmaceutically acceptable salt thereof.

21. The aforementioned complex, its linker, or linker-drug is one selected from the following: Herein, u is an integer selected from 0 to 10, G has the definition described in any one of claims 1 to 20, and LG has the definition described in any one of claims 1 to 20, wherein the ligand drug conjugate, stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate or pharmaceutically acceptable salt thereof. Table 1(1) 【Table 1(2)】 【Table 1(3)】 Table 1(4) 【Table 1(5)】 Table 1(6) Table 1(7) 【Table 1(8)】 【Table 1(9)】 【Table 1(10)】

22. The complex is a ligand drug complex according to any one of claims 1 to 20, having a structure represented by the following formula, stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate, or pharmaceutically acceptable salt thereof. 【Transformation 38】 (Here, R １ , R ２ , R ２２ , R ３ , R ４ , R Ｇ , R Ｈ ,A,B,X,Z,L １ , L ２ (Tp has the definition described in any one of claims 1 to 20.)

23. The complex is a ligand drug complex according to any one of claims 1 to 20, having a structure represented by the following formula, stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate, or pharmaceutically acceptable salt thereof. 【Chemistry 39】 (Here, A, B, R ３ , R ４ , L １ , L ２ (Tp has the definition described in any one of claims 1 to 20.)

24. The complex is a ligand drug complex according to any one of claims 1 to 20, having a structure represented by the following formula, stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate, or pharmaceutically acceptable salt thereof. 【Chemistry 40】 (Here, A, B, L １ , L ２ (Tp has the definition described in any one of claims 1 to 20.)

25. The complex is one selected from the following: a ligand drug complex according to any one of claims 1 to 20, a stereoisomer thereof, a racemate, a tautomer, an isotopolog, an isotope marker, a nitrogen oxide, a prodrug, a solvate thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 (Here, R ３ , R ４ Each of these independently has the definition described in any one of claims 1 to 20, u is an integer selected from 0 to 10. r2 is an integer selected from 0 to 4, and r3 and r4 are integers independently selected from 0 to 3. K is either C or N, R ｚ６ , R ｚ７ They are the same or different, and each is independently selected from hydrogen, an amino group, an alkylamino group, or a dialkylamino group, an alkyl group, an alkyloxy group, a cycloalkyl group, a cycloalkylalkyl group, or a cycloalkyloxy group. Alternatively, R ｚ６ , R ｚ７ These, together with the atoms linked to them, form a ring structure, preferably C １～４ A 5-6 membered heterocyclyl group is optionally substituted with an alkyl group, and the 5-6 membered heterocyclyl group is preferably a piperidinyl group or a piperazylic group. mAb stands for monoclonal antibody, y represents the average number (DAR) of small molecule drugs linked to each monoclonal antibody, and may be an integer or decimal, for example, an integer or decimal from 1 to 50, an integer or decimal from 1 to 20, or an integer or decimal from 1 to 10.

26. The aforementioned complex is one selected from the following: y represents the average number (DAR) of small molecule drugs linked to each monoclonal antibody, and may be an integer or decimal, for example, an integer or decimal from 1 to 50, an integer or decimal from 1 to 20, or an integer or decimal from 1 to 10, as described in any one of claims 1 to 25, the ligand drug conjugate thereof, stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof. 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Transformation 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 [[Chem. 66]]

27. A method for preparing a ligand drug conjugate according to any one of claims 1 to 26, its stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate, or a pharmaceutically acceptable salt thereof, Method A includes the following steps: Step 1: L １ '-L ２ -L ３ -L ４ Provides a linker indicated by '(L)', Preferably, in the linker described above, L ４ 'teeth, 【Transformation 67】 It is acetate, More preferably, L ４ 'teeth, 【Transformation 68】 It is acetate, Step 2: The linker is reacted with the compound of formula (GH) to form L １ '-L ２ -L ３ -L ４ -G(C') bonded intermediate is obtained, The structure of equation (GH) is shown below, 【Transformation 69】 (Here, A, B, Z, X, R １ , R ２ , R ３ , R ４ , L １ ', L １ , L ２ , L ３ , L ４ , L ４ (' independently has the definition set out in any one of claims 1 to 26.) Preferably, the preparation method further includes a third step of binding the binding intermediate of formula (C') to the targeting moiety Tp, Alternatively, the above method is Method B, which includes the following steps: Step 1: L ４ A linker fragment containing ' is provided, and the L ４ ' is as defined above, Step 2: L ４ A linker fragment containing ' is combined with a compound of formula (GH), L ４ A linker fragment containing ' is obtained - G intermediate, Step 3: Provide another linker fragment and react it with the above intermediate to form a complete linker L １ '-L ２ -L ３ -L ４ -G(C') bond intermediate is formed, Preferably, L ４ Linker fragments containing ' are 【Transformation 70】 B reacts with the -O- GH to form a linkage via an ether bond. Preferably, another linker fragment is 【Chemistry 71】 And, Preferably, the preparation method further includes a fourth step of binding the binding intermediate of formula (C') to the targeting portion Tp, A method characterized by the ability to optionally protect the functional groups of a reaction substrate with protecting groups known in the art to ensure the reaction proceeds smoothly, and to remove the protecting groups after the reaction is complete.

28. Compounds represented by the following formula (GH), their stereoisomers, racemates, tautomers, isotopologs, isotopic markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof. 【Chemistry 72】 (Here, A, B, X, Z, R １ , R ２ , R ２２ , R ３ , R ４ Each of these terms independently has the definition described in any one of claims 1 to 26.

29. The compound represented by formula (GH) may be selected from the compound represented by formula (GH-1) below, according to claim 28, its stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate or pharmaceutically acceptable salt thereof. 【Transformation 73】 (Here, A, B, Z, R １ , R ２ , R ２２ , R ３ , R ４ Each of these terms independently has the definition described in claim 28.

30. The compound represented by formula (GH) may be selected from the compound represented by formula (GH-2) below, according to claim 28, its stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate or pharmaceutically acceptable salt thereof. 【Chemistry 74】 (Here, A, B, Z, R １ , R ２ , R ２２ , R ３ , R ４ Each of these terms independently has the definition described in claim 28.

31. The compound is selected from the following compounds: the compound according to claim 28, its stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate, or pharmaceutically acceptable salt thereof. 【Chemistry 75】 【Transformation 76】

32. The method for preparing a compound of formula (GH), its stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates, or pharmaceutically acceptable salts thereof, according to 28, further comprising the step of reacting a compound of formula (i) with a compound of formula (ii) to obtain a compound of formula (G'). [Chem 77] (Here, T is, 【Transformation 78】 Alternatively, by reaction methods such as oxidation and reduction 【Transformation 79】 It is a base that can be converted, Preferably, a group containing an active functional group such as an alkenyl group, aldehyde group, carbonyl group, or nitro group is selected as T. Preferably, when the active functional group is a carbon-containing structure such as an alkenyl group, aldehyde group, or carbonyl group, the residue obtained by removing the active functional group from T has one less carbon atom than A. When the active functional group is a nitro group, the residue obtained by removing the nitro group from T is A.

33. A method for preparing a compound of formula (GH), a stereoisomer thereof, a racemate, a tautomer, an isotopolog, an isotope marker, a nitrogen oxide, a prodrug, a solvate thereof, or a pharmaceutically acceptable salt thereof, according to claim 28, comprising the step of reacting a compound of formula (G') to obtain a compound of formula (GH). 【Chemistry 80】 (Here, A, B, R １ , R ２ , R ２２ , R ３ , R ４ X and Z independently have the definitions set out in any one of claims 28 to 31. Here, T is determined by reaction methods such as oxidation and reduction. 【Chemistry 81】 It is a base that can be converted, Preferably, a group containing an active functional group such as an alkenyl group, aldehyde group, carbonyl group, or nitro group is selected as T. Preferably, when the active functional group is a carbon-containing structure such as an alkenyl group, aldehyde group, or carbonyl group, the residue obtained by removing the active functional group from T has one less carbon atom than A. When the active functional group is a nitro group, the residue obtained by removing the nitro group from T is A.

34. The compound represented by formula (i). 【Chemistry 82】 (Here, R １ X and Z independently have the definitions set out in any one of claims 28 to 31.

35. The compound represented by formula (G'). 【Chemistry 83】 (Here, R １ , R ２ , R ２２ , R ３ , R ４ X, Z, and T each independently have the definitions set forth in any one of claims 28 to 32.

36. A complex with the following structure. Tp-L-D (D) (Here, Tp is the targeting portion, D is a biologically active molecular fragment, preferably a molecular fragment having antitumor biological activity. however, L is selected from the linkers shown in equation (L), #L １ -8 ２ -8 ３ -8 ４ * (7) Here, L １ This is the linking portion with the targeting portion Tp, and the reactive group L １ ' is formed by the targeted portion Tp, and # represents the connection point with the Tp portion, L １ Preferably, 【Chemical 84】 And, L ２ is -(C≡C)-(CH ２ ) ｑ -C(R ｚ４ R ｚ５ )-C(=O)- or-(CH ２ ) ｑ -C(R ｚ４ R ｚ５ ) - C (= O) - are selected, Here, L １ '-L ２ It has the following structure: 【Chemical 85】 q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. R ｚ４ and R ｚ５ H and C are the same or different, and are independent of each other. １～４ alkyl group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl-C １～４ Selected from alkyl groups, or R ｚ４ or R ｚ５ C ３～６ A cycloalkyl group is formed, where R ｚ４ or R ｚ５ At least one of them is not H, or, L ２ is -(C≡C)-(CH ２ ) ｑ -C (=O)- is selected, L ２ and L ３ A hydrophilic portion as defined in claim 10 is included between the two, [Chem. 86] L ３ is, -ValAA １ Gly-, and here, AA １ This is as defined in any one of claims 13 to 14, L ４ It is either absent or is a linking portion between the peptide portion and the biologically active molecule D, and the reactive group L ４ (This is produced by reacting ' with a biologically active molecule, and * represents the linkage site with biologically active molecule D.)

37. Biologically active molecule D is a compound having biological activity or potential biological activity, as described in or disclosed in the Chinese, American, or European pharmacopoeia. The aforementioned drug may be selected from cytotoxic agents, cell proliferation inhibitors, or immunosuppressants, preferably antitubulin agents, tubulin inhibitors, DNA sulcus binding agents, DNA replication inhibitors, alkylating agents, antibiotics, folate antagonists, antimetabolites, chemotherapy sensitivity agents, topoisomerase inhibitors, vinca alkaloids, and the like. More preferably, the complex according to claim 36 comprises auristatin, camptothecin, duocalmycin, etoposide, meitansine and meitansine alkaloids, taxane, benzodiazepines or benzodiazepine-containing drugs, and vinca alkaloids.

38. A pharmaceutical composition, A ligand drug conjugate represented by formula (C) as described in any one of claims 1 to 26, its stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate or pharmaceutically acceptable salt thereof, and / or Compounds represented by formula (GH) as described in any one of claims 28-31, stereoisomers, racemates, tautomers, isotopologs, isotopic markers, nitrogen oxides, prodrugs, solvates or pharmaceutically acceptable salts thereof, and / or A ligand drug conjugate represented by formula (D) as described in any one of claims 36 to 37, comprising at least one selected from its stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate, or pharmaceutically acceptable salt thereof, Preferably, the pharmaceutical composition contains the compound represented by formula (GH), its stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates or pharmaceutically acceptable salts thereof, and the ligand drug conjugate represented by formula (C) or (D), its stereoisomers, racemates, tautomers, isotopologs, isotope markers, nitrogen oxides, prodrugs, solvates or pharmaceutically acceptable salts thereof, all present in therapeutically effective amounts.

39. The use of a compound represented by formula (GH) as described in any one of claims 28 to 31, its stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate or a pharmaceutically acceptable salt thereof, or a ligand drug conjugate represented by formula (C) as described in any one of claims 1 to 26 or a ligand drug conjugate represented by formula (D) as described in any one of claims 36 to 37, its stereoisomer, racemate, tautomer, isotopolog, isotope marker, nitrogen oxide, prodrug, solvate or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in claim 38, Used for the prevention and / or treatment of diseases or conditions, and / or for the preparation of drugs. Preferably, the disease or condition may be selected from tumors, such as solid tumors or hematological cancers.

40. The aforementioned drug is used for the prevention and / or treatment of a disease or illness. Preferably, the disease or condition may be selected from tumors, such as solid tumors or hematological cancers. The solid tumors are selected from malignant tumors of various organ systems, such as sarcomas, adenocarcinomas, germ cell tumors, and cancers that may affect the liver, lungs, breasts, lymph nodes, bile ducts (e.g., colon), genitourinary tract (e.g., kidneys, urothelial cells), prostate, and pharynx, and adenocarcinomas include, for example, most colon cancers, rectal cancers, renal cell carcinomas, liver cancers, small cell lung cancers, non-small cell lung cancers, small intestine cancers, and esophageal cancers. The use according to claim 39, wherein the blood cancer is selected from leukemia, lymphoma, and malignant lymphoproliferative disorders that affect the blood, bone marrow, and lymphatic system.

41. A compound of a linker having the following structure and a drug. L １ ’-L ２ -L ３ -L ４ -G(C’) (Here, G is as defined in any of claims 1 to 9, L １ ', L ２ , L ３ , L ４ (This is as defined in any of claims 10 to 19.)

42. The compound is selected from the following, and is a compound of the linker and drug according to claim 41. 【Chemistry 87】 [Chem. 88] 【Chemistry 89】 [Chemical 90] 【Chemistry 91】 【Chemistry 92】 【Chemistry 93】 【Chemistry 94】 【Chemical 95】 【Chemistry 96】 【Chemistry 97】 【Chem.98】 [Chemical 99] 【Chemistry 100】 【Chemistry 101】 【Chemical Engineering 102】 【Chemistry 103】 【Chemical 104】 【Chemistry 105】

43. A compound of a linker having the following structure and a drug. L １ '-L ２ -8 ３ -8 ４ -0 (Here, D is as defined in claims 36-37, L １ ' is a reactive group, preferably, 【Chemistry 106】 And, L ２ is -(C≡C)-(CH ２ ) ｑ -C(R ｚ４ R ｚ５ )-C(=O)- or-(CH ２ ) ｑ -C(R ｚ４ R ｚ５ ) - C (= O) is selected, Here, L １ '-L ２ It has the following structure: 【Chemistry 107】 q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. R ｚ４ and R ｚ５ H and C are the same or different, and are independent of each other. １～４ Alkyl alkyl group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl-C １～４ Selected from alkyl groups, or R ｚ４ or R ｚ５ C ３～６ A cycloalkyl group is formed, where R ｚ４ or R ｚ５ At least one of them is not H, or, L ２ is -(C≡C)-(CH ２ ) ｑ -C (=O)- is selected, L ２ and L ３ A hydrophilic portion as defined in claim 10 is included between the two, 【Chemistry 108】 L ３ is, -ValAA １ Gly-, and here, AA １ This is as defined above, L ４ It is either absent or is a linking portion between the peptide portion and the biologically active molecule D, and the reactive group L ４ It is produced by reacting ' with a biologically active molecule, and * represents the linkage site with the biologically active molecule D. Optional, L １ and L ２ Between, or L ２ and L ３ Between, or L ２ A form that replaces L ２ (The hydrophilic portion defined in claim 10 is included in a form that is inserted into the structure.)

44. A linker with the following structure. L １ '-L ２ -8 ３ -8 ４ '(L') (Here Here, L １ ' is a reactive group, preferably, 【Chemistry 109】 And, L ２ is -(C≡C)-(CH ２ ) ｑ -C(R ｚ４ R ｚ５ )-C(=O)- or-(CH ２ ) ｑ -C(R ｚ４ R ｚ５ ) - C (= O) is selected, Here, L １ '-L ２ It has the following structure: L １ '-L ２ teeth, 【Chemical 110】 And, R ｚ４ and R ｚ５ H and C are the same or different, and are independent of each other. １～４ Alkyl alkyl group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl-C １～４ Selected from alkyl groups, or R ｚ４ or R ｚ５ C ３～６ A cycloalkyl group is formed, where R ｚ４ or R ｚ５ At least one of them is not H, and q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. or, L ２ is -(C≡C)-(CH ２ ) ｑ -C (=O)- is selected, L ２ and L ３ A hydrophilic portion as defined in claim 10 is included between the two, 【Chemistry 111】 and, L3 is -ValAA １ Gly-, and here, AA １ It has the definition described in any one of claims 13 to 14, L' is preferably the following: 【Chemistry 112】 【Chemistry 113】 Here, OSu represents succinimide active ester. 【Chemistry 114】

45. A bonding intermediate with the following structure. 【Chemical 115】 (Here, G Ｎ is H or any amino group protecting group, A, R １ , R ２ , R ２２ , R ３ , R ４ X and Z independently have the definitions set out in any one of claims 28 to 31.

46. Linker fragment compounds. L １ '-L ２ -Valal｡｡ １ '(L'') (Here Here, L １ ' is a reactive group, preferably, 【Chemistry 116】 And, L ２ is -(C≡C)-(CH ２ ) ｑ -C(R ｚ４ R ｚ５ )-C(=O)- or-(CH ２ ) ｑ -C(R ｚ４ R ｚ５ ) - C (= O) is selected, Here, L １ '-L ２ It has the following structure: L １ '-L ２ teeth, 【Chemistry 117】 And, R ｚ４ and R ｚ５ H and C are the same or different, and are independent of each other. １～４ Alkyl alkyl group, C ３～６ Cycloalkyl groups, C ３～６ Cycloalkyl-C １～４ Selected from alkyl groups, or R ｚ４ or R ｚ５ C ３～６ A cycloalkyl group is formed, where R ｚ４ or R ｚ５ At least one of them is not H, q is an integer selected from 0 to 10, preferably 1, 2, 3, 4, 5, 6, 7, or 8. or, L ２ is -(C≡C)-(CH ２ ) ｑ -C (=O)- is selected, L ２ and L ３ A hydrophilic portion as defined in claim 10 is included between the two, 【Chemistry 118】 AA １ ' is AA １ The substance itself, or its reaction form, for example, an active ester, where AA １ (This has the definition described in any one of claims 13 to 14.)

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