Conjugate of protein translation inhibitor and use thereof

Abstract

Provided are a conjugate of a protein translation inhibitor and use thereof in preparing a drug for treating and / or preventing a disease, wherein the disease is a tumor or cancer.

Description

A conjugate of a protein translation inhibitor and its use

[0001] This application is based on and claims priority to CN application No. 202410063661.2, filed on January 16, 2024, CN application No. 202411574559.5, filed on November 6, 2024, and CN application No. 202510025596.9, filed on January 7, 2025. The disclosed contents of the aforementioned CN applications are hereby introduced as a whole into this application. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and particularly relates to a conjugate of a protein translation inhibitor and use thereof in preparing a drug for treating and / or preventing a disease. Background Art

[0003] Aberrant messenger RNA (mRNA) translation is a common hallmark of malignant tumors, manifested by upregulation of oncoproteins, growth factors, and signaling proteins associated with proliferation, survival, and metastasis. The expression of oncogenic drivers is under strict translational control and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex, which mediates ribosome recruitment to mRNA and initiates mRNA-to-protein translation. The eIF4F complex consists of three subunits: the mRNA 5' cap-binding protein eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A.

[0004] Overactivation of eIF4A is associated with poor prognosis in related diseases, including lymphoma, lung cancer, colorectal cancer, liver cancer, breast cancer, and ovarian cancer. The eIF4A family consists of three members: eIF4A1, eIF4A2, and eIF4A3. All of them belong to a family of helicase proteins called DEAD-box. These family proteins all have nine conserved motifs that are involved in RNA binding or ATP hydrolysis.

[0005] Natural products have been reported to inhibit eIF4A-mediated translation and exhibit antiproliferative and antitumor phenotypes in vitro and in vivo. Silvestrol and rocaglamide A, for example, have been shown to bind and stabilize untranslated RNA / eIF4A complexes. These stabilized eIF4A·RocA complexes block scanning ribosomes, thereby inhibiting the translation of target mRNAs. This inhibition of eIF4A-mediated translation can regulate the expression of oncogenic factors.

[0006] Provide a ligand-drug conjugate developed from a novel eIF4A inhibitor, which is expected to meet the huge clinical needs of tumors. Summary of the Invention

[0007] Ligand-drug conjugates

[0008] The first aspect of the present invention provides a ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the ligand-drug conjugate is composed of a ligand, a linker and a drug group, and the drug group is selected from the structure shown in formula IA, II-A', III-A', IV-A or VA

[0009] in,

[0010] M is selected from -N(R m )-, -O-, -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R m )-, the -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R m )- is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2;

[0011] n is 0 or 1;

[0012] W is absent or selected from -(C1-C6)alkylene-, -O- and -N(R w )-, said -(C1-C6)alkylene- is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2;

[0013] U is selected from -(C1-C6)alkylene-, -(C3-C6)cycloalkylene- and -(4-10 membered)heterocyclylene-, said -(C1-C6)alkylene-, -(C3-C6)cycloalkylene- and -(4-10 membered)heterocyclylene- being optionally substituted with one or more (e.g. 1, 2, 3, 4, 5, 6 or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2;

[0014] Z is absent or selected from -(C1-C6)alkylene-, -(C3-C6)cycloalkylene- and -(4-10 membered)heterocyclylene-;

[0015] Y is absent or selected from -O-, -N(R y )- and -N + (R y )2-,R y is selected from hydrogen, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C1-C6)haloalkyl and -O-(C1-C6)haloalkyl, or R y and Z form -(4-10 membered)heterocyclylene-, wherein the -(4-10 membered)heterocyclylene- is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2;

[0016] R 12 is selected from hydrogen, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C=O)-(C1-C6)alkyl, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl and -O-(4-10 membered)heterocyclyl, the -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C=O)-(C1-C6)alkyl , -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl and -O-(4-10 membered)heterocyclyl are optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2;

[0017] L is absent or selected from -C(=O)-(C1-C6)alkylene-O-, -C(=O)-(C1-C6)alkylene-N(R L )-、-C(=O)-(C1-C6)alkylene-N + (R L )2-, -C(=O)NH-(C1-C6)alkylene-O-, -C(=O)NH-(C1-C6)alkylene-N(R L )- and -C(=O)NH-(C1-C6)alkylene-N + (R L )2-,R Lis selected from hydrogen, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C1-C6)haloalkyl and -O-(C1-C6)haloalkyl, the -C(=O)-(C1-C6)alkylene-O-, -C(=O)-(C1-C6)alkylene-N(R L )-、-C(=O)-(C1-C6)alkylene-N + (R L )2-, -C(=O)NH-(C1-C6)alkylene-O-, -C(=O)NH-(C1-C6)alkylene-N(R L )- and -C(=O)NH-(C1-C6)alkylene-N + (R L )2- is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2;

[0018] Q is selected from -N(R q )-, -O-, -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R q )-, the -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R q )- is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2;

[0019] T is selected from -N(R t )-, -O-, -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R t )-, the -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R q )- is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2;

[0020] R m 、R w 、R q and R t each independently selected from hydrogen, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C1-C6)haloalkyl, and -O-(C1-C6)haloalkyl;

[0021] X 1 Selected from N and C(R 1 ), R 1 is selected from hydrogen, halogen, cyano, -OH, -(C1-C6)alkyl and -O-(C1-C6)alkyl;

[0022] X 2 Selected from N and C(R 2 ), R 2 is selected from hydrogen, halogen, cyano, -OH, -(C1-C6)alkyl and -O-(C1-C6)alkyl;

[0023] R 3 -(C3-C6)cycloalkyl, -(3-8 membered)heterocyclyl, -(C6-C 10 )aryl and -(5-12 membered)heteroaryl, the -(C3-C6)cycloalkyl, -(3-8 membered)heterocyclyl, -(C6-C 10 )aryl and -(5-12 membered)heteroaryl are optionally substituted with one or more R 31 replace;

[0024] Ring A is selected from -(C3-C6)cycloalkylene-, -(3-8 membered)heterocyclylene-, -(C6-C 10 )arylene- and -(5-12 membered)heteroarylene-, the -(C3-C6)cycloalkylene-, -(3-8 membered)heterocyclylene-, -(C6-C 10 )arylene- and -(5-12 membered)heteroarylene- are optionally substituted with one or more R 31 replace;

[0025] R 31each independently selected from oxo, hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NH[(C1-C6)alkyl], -(C1-C6)alkylene-N[(C1-C6)alkyl]2, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH (C1-C6) alkyl, -N[(C1-C6) alkyl]2, -(C3-C6) cycloalkyl, -(4-10 membered) heterocyclyl, -O-(C3-C6) cycloalkyl, -O-(4-10 membered) heterocyclyl, -C(=O)-(C1-C6) alkyl, -C(=O)-(C3-C6) cycloalkyl, -C(=O)-O-(C1-C6) alkyl, -C(=O)-O-(C3-C6) cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C6) alkyl, -C(=O)-N[(C1-C6) alkyl]2, -(C6-C 10)aryl, -(5-12 membered)heteroaryl, -S(=O)2-NH2, -S(=O)2-NH(C1-C6)alkyl, -S(=O)2-N[(C1-C6)alkyl]2, -NH-C(=O)H, -NH-C(=O)-(C1-C6)alkyl, -N[(C1-C6)alkyl]-C(=O)-(C1-C6)alkyl, N[(C1-C6)alkyl]-C(=O)H, -NH-S(=O)2-(C1-C6) -(C1-C6)alkyl]-N[(C1-C6)alkyl]-S(=O)2-(C1-C6)alkyl, -P(=O)[(C1-C6)alkyl]2, -P(=O)[(C1-C6)alkyl]-NH2, -P(=O)[(C1-C6)alkyl]-NH(C1-C6)alkyl and -P(=O)[(C1-C6)alkyl]-N[(C1-C6)alkyl]2, the -(C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkyl]- -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NH[(C1-C6)alkyl], -(C1-C6)alkylene-N[(C1-C6)alkyl]2, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -( C3-C6) cycloalkyl, -(4-10 membered) heterocyclyl, -O-(C3-C6) cycloalkyl, -O-(4-10 membered) heterocyclyl, -C(=O)-(C1-C6) alkyl, -C(=O)-(C3-C6) cycloalkyl, -C(=O)-O-(C1-C6) alkyl, -C(=O)-O-(C3-C6) cycloalkyl, -C(=O)-NH(C1-C6) alkyl, -C(=O)-N[(C1-C6) alkyl]2, -(C6-C 10) aryl, -(5-12 membered) heteroaryl, -S(=O)2-NH2, -S(=O)2-NH(C1-C6) alkyl, -S(=O)2-N[(C1-C6) alkyl]2, -NH-C(=O)H, -NH-C(=O)-(C1-C6) alkyl, -N[(C1-C6) alkyl]-C(=O)-(C1-C6) alkyl, N[(C1-C6) alkyl]-C(=O)H, -NH-S(=O)2-(C1-C6) alkyl, -N[(C1-C6) alkyl]-S(=O)2-(C1-C6) alkyl, -P(=O)[(C1-C6) alkyl]2, -P(=O)[ -(C1-C6)alkyl]-NH2, -P(=O)[(C1-C6)alkyl]-NH(C1-C6)alkyl and -P(=O)[(C1-C6)alkyl]-N[(C1-C6)alkyl]2 are optionally replaced by one or more radicals selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -(C1-C6)alkylene-OH, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NH[(C1-C6)alkyl], -(C1-C6)alkylene-N[(C1-C6)alkyl]2, -(C6-C 10 ) aryl and -(5-12 membered) heteroaryl, -(C1-C6) alkylene-O(C1-C6) alkyl and oxo groups;

[0026] R 4 is selected from hydrogen, halogen, cyano, -OH, -NH2, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(4-10 membered)heterocyclyl, -(C6 ... 10 )aryl, -O-(C6-C 10 )aryl, -(5-12 membered)heteroaryl, and -O-(5-12 membered)heteroaryl;

[0027] X is selected from O, S, NH, N[(C1-C6)alkyl], N[C(=O)-R c ]、C(R a )(R b )、C(=O)、C[=C(R a )R b ], S(=O) and S(=O)2;

[0028] R a and R b are independently selected from hydrogen, halogen, cyano, -ORc 、-SR c 、-N(R c )R c , -(C1-C6)alkyl and -(C1-C6)haloalkyl;

[0029] R c selected from hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(4-10 membered)heterocyclyl, -(C6-C 10 )aryl, -O-(C6-C 10 )aryl, -(5-12 membered)heteroaryl, and -O-(5-12 membered)heteroaryl;

[0030] Ring B is selected from -(C6-C 10 )aryl and -(5-12 membered)heteroaryl, or, Ring B is selected from -(C6-C 10 )arylene- and -(5-12 membered)heteroarylene-, the -(C6-C 10 )arylene- and -(5-12 membered)heteroarylene- are optionally substituted with one or more selected from R 5 and R 6 The group substitution;

[0031] R 5 and R 6each independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(C -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C6)alkyl, -C(=O)-N[(C1-C6)alkyl]2, -C(=O)-H and -C(=N-OH)-H, the -(C1-C6)alkyl -C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclyl, -C(=O)-(C1-C6)alkyl 6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH(C1-C6)alkyl and -C(=O)-N[(C1-C6)alkyl]2 are optionally substituted by one or more groups selected from hydrogen, halogen, oxo, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and N[(C1-C4)alkyl]2, or,

[0032] R 5 and R 6 The carbon atom to which it is attached forms a 5-membered heterocyclic group;

[0033] Ring C is selected from -(C6-C 10 )aryl and -(5-12 membered)heteroaryl, or, ring C is selected from -(C6-C 10 )arylene- and -(5-12 membered)heteroarylene-, the -(C6-C 10 )arylene- and -(5-12 membered)heteroarylene- are optionally substituted with one or more R 7 replace;

[0034] R 7each independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(C3-C6)alkyl, - )cycloalkyl, -O-(4-10 membered)heterocyclyl, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C6)alkyl, -C(=O)-N[(C1-C6)alkyl]2 and -NHC(=O)-(C1-C6)alkyl, the -(C1-C6)alkyl, -(C -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclyl, -C(=O)-(C1-C6)alkyl, -C(=O)-(C -C(═O)-O-(C1-C6)alkyl]2 and -NHC(═O)-(C1-C6)alkyl are optionally substituted by one or more groups selected from hydrogen, halogen, oxo, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2;

[0035] m is 1, 2, 3, 4 or 5;

[0036] R 8a 、R 8b 、R 9a and R 9beach independently selected from hydrogen, halogen, cyano, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -OR, -N(R)R, -[(C1-C8)alkylene]R, -[(C1-C8)alkylene]OR, -[(C1-C8)alkylene]N(R)R, -[(C1-C8)alkylene]N(R)C(=O)R, -[(C1-C8)alkylene]N( R)C(=O)N(R)R, -C(=O)R, -C(=O)N(R)R, -C(=O)[(C1-C8)alkylene]N(R)R, -C(=O)OR, -C(=S)N(R)R, -S R, -S(=O)R, -S(=O)2R, -S(=O)2N(R)R, -N(R)C(=O)R, -N(R)C(=O)N(R)R, -P(=O)(OR)(OR), -(C6-C 10 )aryl, -(5-12 membered)heteroaryl, -(C3-C6)cycloalkyl and -(4-10 membered)heterocyclyl,

[0037] R is each independently selected from hydrogen, -OH, -NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -(C1-C4)alkylene-O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -S(=O)2-(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclyl, ) heterocyclic group, -C(=O)-H, -C(=O)-(C1-C6) alkyl, -C(=O)-(C3-C6) cycloalkyl, -C(=O)-O-(C1-C6) alkyl, -C(=O)-O-(C3-C6) cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C6) alkyl, -C(=O)-N[(C1-C6) alkyl]2, -[(C1-C6) alkylene]-(C3-C6) cycloalkyl, -[(C1-C6) alkylene]-(4-10 membered) heterocyclic group, -(C6-C 10 )aryl, -[(C1-C6)alkylene]-(C6-C 10)aryl and -(5-12 membered)heteroaryl, the -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -(C1-C4)alkylene-O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -S(=O)2-(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(C3-C6)cycloalkyl , -O-(4-10 membered) heterocyclyl, -C(=O)-(C1-C6) alkyl, -C(=O)-(C3-C6) cycloalkyl, -C(=O)-O-(C1-C6) alkyl, -C(=O)-O-(C3-C6) cycloalkyl, -C(=O)-NH(C1-C6) alkyl, -C(=O)-N[(C1-C6) alkyl]2, -[(C1-C6) alkylene]-(C3-C6) cycloalkyl, -[(C1-C6) alkylene]-(4-10 membered) heterocyclyl, -(C6-C 10 )aryl, -[(C1-C6)alkylene]-(C6-C 10 )aryl and -(5-12 membered)heteroaryl are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, N[(C1-C4)alkyl]2 and (C1-C4)alkyl,

[0038] Or, R 8a and R 8b Combined to form oxo, -(C2-C6)alkenyl, -(C3-C6)cycloalkyl or -(4-10 membered)heterocyclyl,

[0039] Or, R 9a and R 9b Combined to form oxo, -(C2-C6)alkenyl, -(C3-C6)cycloalkyl or -(4-10 membered)heterocyclyl,

[0040] Or, R 8a and R 9a The carbon atoms to which it is attached together form a (C3-C6)cycloalkyl, a (4-10-membered)heterocyclyl or a (5-10-membered)heteroaryl, wherein the aforementioned groups are optionally substituted by one or more selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8-membered)heterocyclyl, -(5-6-membered)heteroaryl and -(C6-C 10 ) aryl radical substitution,

[0041] Or, R 8b and R9b The carbon atoms to which it is attached together form a (C3-C6)cycloalkyl, a (4-10-membered)heterocyclyl or a (5-10-membered)heteroaryl, wherein the aforementioned groups are optionally substituted by one or more selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8-membered)heterocyclyl, -(5-6-membered)heteroaryl and -(C6-C 10 ) aryl radical substitution;

[0042] R 10 is selected from hydrogen, cyano, -OH and -NH2, or R 10 and R 9a The atoms to which it is attached form a (5-6 membered) heterocyclic group, which is optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -(C1-C4)alkyl, -(C3-C6)cycloalkyl, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2.

[0043] The first aspect of the present invention also provides a ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the ligand-drug conjugate is composed of a ligand, a linker and a drug group, and the drug group is selected from the structure shown in formula IA, II-A, III-A, IV-A or VA

[0044] in,

[0045] M is selected from -N(R m )-, -O-, -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R m )-, the -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R m )- is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2;

[0046] W is absent or selected from -(C1-C6)alkylene-, -O- and -N(R w)-, said -(C1-C6)alkylene- is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2;

[0047] U is selected from -(C1-C6)alkylene-, -(C3-C6)cycloalkylene- and -(4-10 membered)heterocyclylene-, said -(C1-C6)alkylene-, -(C3-C6)cycloalkylene- and -(4-10 membered)heterocyclylene- being optionally substituted with one or more (e.g. 1, 2, 3, 4, 5, 6 or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2;

[0048] Z is absent or selected from -(C1-C6)alkylene-, -(C3-C6)cycloalkylene- and -(4-10 membered)heterocyclylene-;

[0049] Y is absent or selected from -O- and -N(R y )-,R y is selected from hydrogen, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C1-C6)haloalkyl and -O-(C1-C6)haloalkyl, or R y and Z form -(4-10 membered)heterocyclylene-, wherein the -(4-10 membered)heterocyclylene- is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2;

[0050] R 12 is selected from hydrogen, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C=O)-(C1-C6)alkyl, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl and -O-(4-10 membered)heterocyclyl, the -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C=O)-(C1-C6)alkyl , -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl and -O-(4-10 membered)heterocyclyl are optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2;

[0051] Q is selected from -N(Rq )-, -O-, -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R q )-, the -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R q )- is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2;

[0052] T is selected from -N(R t )-, -O-, -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R t )-, the -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R q )- is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2;

[0053] R m 、R w 、R q and R t each independently selected from hydrogen, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C1-C6)haloalkyl, and -O-(C1-C6)haloalkyl;

[0054] X 1 Selected from N and C(R 1 ), R 1 is selected from hydrogen, halogen, cyano, -OH, -(C1-C6)alkyl and -O-(C1-C6)alkyl;

[0055] X 2 Selected from N and C(R 2 ), R 2 is selected from hydrogen, halogen, cyano, -OH, -(C1-C6)alkyl and -O-(C1-C6)alkyl;

[0056] R 3 -(C3-C6)cycloalkyl, -(3-8 membered)heterocyclyl, -(C6-C 10 )aryl and -(5-12 membered)heteroaryl, said R 3 Optionally one or more R 31 replace;

[0057] Ring A is selected from -(C3-C6)cycloalkylene-, -(3-8 membered)heterocyclylene-, -(C6-C 10 )arylene- and -(5-12 membered)heteroarylene-, wherein the ring A is optionally substituted with one or more R 31 replace;

[0058] R 31each independently selected from oxo, hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NH[(C1-C6)alkyl], -(C1-C6)alkylene-N[(C1-C6)alkyl]2, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2 , -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclyl, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C6)alkyl and -C(=O)-N[(C1-C6)alkyl]2, the -(C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene -NH[(C1-C6)alkyl], -(C1-C6)alkylene-N[(C1-C6)alkyl]2, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclyl, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl , -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH(C1-C6)alkyl and -C(=O)-N[(C1-C6)alkyl]2 are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -(C1-C6)alkylene-OH, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NH[(C1-C6)alkyl] and -(C1-C6)alkylene-N[(C1-C6)alkyl]2;

[0059] R 4is selected from hydrogen, halogen, cyano, -OH, -NH2, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(4-10 membered)heterocyclyl, -(C6 ... 10 )aryl, -O-(C6-C 10 )aryl, -(5-12 membered)heteroaryl, and -O-(5-12 membered)heteroaryl;

[0060] X is selected from O, S, NH, N[(C1-C6)alkyl], N[C(=O)-R c ]、C(R a )(R b )、C(=O)、C[=C(R a )R b ], S(=O) and S(=O)2;

[0061] R a and R b are independently selected from hydrogen, halogen, cyano, -OR c 、-SR c 、-N(R c )R c , -(C1-C6)alkyl and -(C1-C6)haloalkyl;

[0062] R c selected from hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(4-10 membered)heterocyclyl, -(C6-C 10 )aryl, -O-(C6-C 10 )aryl, -(5-12 membered)heteroaryl, and -O-(5-12 membered)heteroaryl;

[0063] Ring B is selected from -(C6-C 10 )aryl and -(5-12 membered)heteroaryl, or, Ring B is selected from -(C6-C 10 )arylene- and -(5-12 membered)heteroarylene-, the -(C6-C 10 )arylene- and -(5-12 membered)heteroarylene- are optionally substituted by one or more selected from R 5 and R 6 The group substitution;

[0064] R 5 and R 6Each is independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-( -C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclyl, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C6)alkyl, -C(=O)-N[(C1-C6)alkyl]2, -C(=O)-H and -C(=N-OH)-H, the -(C -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclyl, -C(=O)-(C1 -C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH(C1-C6)alkyl and -C(=O)-N[(C1-C6)alkyl]2 are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and N[(C1-C4)alkyl]2, or,

[0065] R 5 and R 6 The carbon atom to which it is attached forms a 5-membered heterocyclic group;

[0066] Ring C is selected from -(C6-C 10 )aryl and -(5-12 membered)heteroaryl, or, ring C is selected from -(C6-C 10 )arylene- and -(5-12 membered)heteroarylene-, the -(C6-C 10 )arylene- and -(5-12 membered)heteroarylene- are optionally substituted with one or more R 7 replace;

[0067] R 7Each is independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclic -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C6)alkyl and -C(=O)-N[(C1-C6)alkyl]2, the -(C1-C6)alkyl, - (C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclyl, -C(=O)-(C1-C6) Alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH(C1-C6)alkyl and -C(=O)-N[(C1-C6)alkyl]2 are optionally substituted with one or more groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2;

[0068] m is 1, 2, 3, 4 or 5;

[0069] R 8a 、R 8b 、R 9a and R 9beach independently selected from hydrogen, halogen, cyano, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -OR, -N(R)R, -[(C1-C8)alkylene]R, -[(C1-C8)alkylene]OR, -[(C1-C8)alkylene]N(R)R, -C(=O)R, -C(=O )N(R)R, -C(=O)[(C1-C8)alkylene]N(R)R, -C(=O)OR, -C(=S)N(R)R, -SR, -S(=O)R, -S( =O)2R, -S(=O)2N(R)R, -N(R)C(=O)R, -N(R)C(=O)N(R)R, -P(=O)(OR)(OR), -(C6-C 10 )aryl, -(5-12 membered)heteroaryl, -(C3-C6)cycloalkyl and -(4-10 membered)heterocyclyl,

[0070] R is each independently selected from hydrogen, -OH, -NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclyl, -C( =O)-H, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C6)alkyl, -C(=O)-N[(C1-C6)alkyl]2, -[(C1-C6)alkylene]-(4-10 membered)heterocyclyl, -(C6-C 10 )aryl, -[(C1-C6)alkylene]-(C6-C 10) aryl and -(5-12 membered) heteroaryl, the -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, -(C1-C6) haloalkyl, -O-(C1-C6) alkyl, -O-(C1-C6) haloalkyl, -S-(C1-C6) alkyl, -(C3-C6) cycloalkyl, -(4-10 membered) heterocyclyl, -O-(C3-C6) cycloalkyl, -O-(4-10 -C(=O)-(C1-C6)alkyl]2, -[(C1-C6)alkylene]-(4-10 membered)heterocyclyl, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH(C1-C6)alkyl, -C(=O)-N[(C1-C6)alkyl]2, -[(C1-C6)alkylene]-(4-10 membered)heterocyclyl, -(C6-C 10 )aryl, -[(C1-C6)alkylene]-(C6-C 10 )aryl and -(5-12 membered)heteroaryl are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, N[(C1-C4)alkyl]2,

[0071] Or, R 8a and R 8b , and R 9a and R 9b independently combine to form oxo, -(C2-C6)alkenyl, -(C3-C6)cycloalkyl or -(4-10 membered)heterocyclyl,

[0072] Or, R 8a and R 9a , R 8b and R 9b The carbon atoms to which it is attached together form a (C3-C6)cycloalkyl, a (4-10-membered)heterocyclyl or a (5-10-membered)heteroaryl, wherein the aforementioned groups are optionally substituted by one or more selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8-membered)heterocyclyl, -(5-6-membered)heteroaryl and -(C6-C 10 ) aryl radical substitution;

[0073] R 10 is selected from hydrogen, cyano, -OH and -NH2, or R 10 and R 9aThe atoms to which it is attached form a (5-6 membered) heterocyclic group, which is optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -(C1-C4)alkyl, -(C3-C6)cycloalkyl, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2.

[0074] In certain embodiments, the drug group is selected from the structure shown in Formula IA

[0075] Among them, X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 and M are as defined in any embodiment of the present invention.

[0076] In certain embodiments, R m is selected from hydrogen, -(C1-C4)alkyl, -O-(C1-C4)alkyl, -(C1-C4)haloalkyl and -O-(C1-C4)haloalkyl.

[0077] In certain embodiments, the R m is selected from the group consisting of hydrogen, methyl, ethyl, propyl, -O-methyl, -O-ethyl and -O-propyl.

[0078] In certain embodiments, the R m For hydrogen.

[0079] In certain embodiments, the M is selected from -NH-, -O-, -(C1-C6)alkylene-O- and -(C1-C6)alkylene-NH-, and the -(C1-C6)alkylene-O- and -(C1-C6)alkylene-NH- are optionally substituted with 1, 2 or 3 groups selected from hydrogen, halogen, -OH, -O-methyl, -NH2, -NH-methyl, -N(methyl)2 and -N(ethyl)2.

[0080] In certain embodiments, the M is selected from -NH-, -O-, -(C1-C6)alkylene-O-, and -(C1-C6)alkylene-NH-.

[0081] In certain embodiments, the M is selected from -NH-, -O-, -(C1-C4)alkylene-O-, and -(C1-C4)alkylene-NH-.

[0082] In certain embodiments, the M is selected from -NH-, -O-, -CH2O-, and -CH2NH-.

[0083] In certain embodiments, the M is selected from -NH-, -O-, *-CH2O-, and *-CH2NH-, wherein the * end is connected to the ring C.

[0084] In certain embodiments, said M is selected from -NH-.

[0085] In certain embodiments, the ring C is selected from -(C6-C 10 )arylene- and -(5-10 membered)heteroarylene-, the -(C6-C 10 )arylene- and -(5-10 membered)heteroarylene- are optionally substituted with 1, 2 or 3 R 7 replace.

[0086] In certain embodiments, the ring C is selected from phenylene, naphthylene and (5-6 membered) heteroarylene, wherein the phenylene, naphthylene and (5-6 membered) heteroarylene are optionally substituted by 1 or 2 R 7 replace.

[0087] In certain embodiments, the ring C is phenylene, which is optionally substituted with 1 R 7 replace.

[0088] In certain embodiments, the R 7 Each is independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl and -O-(4-8 membered)heterocyclyl, wherein the -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl and -O-(4-8 membered)heterocyclyl are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2.

[0089] In certain embodiments, the R 7 Each is independently selected from hydrogen, halogen, cyano, -OH, -NH2, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NH(C1-C4)alkyl, -(C1-C4)alkylene-N[(C1-C4)alkyl]2 and -(C1-C4)alkylene-NH2.

[0090] In certain embodiments, the R 7 Each is independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -NH2, -CH2OH and -CH2NH2.

[0091] In certain embodiments, the R 7 are each independently selected from hydrogen.

[0092] In certain embodiments, the ring C is * is connected to M.

[0093] In certain embodiments, the drug group is selected from the structure shown in formula II-A'

[0094] Among them, X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 , m, W, U, Z and Y are as defined in any embodiment of the present invention, and n is 0 or 1.

[0095] In certain embodiments, the drug group is selected from the structure shown in Formula II-A

[0096] Among them, X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 , m, W, U, Z and Y are as defined in any embodiment of the present invention.

[0097] In certain embodiments, the R w and R y Each is independently selected from hydrogen, -(C1-C4)alkyl, -O-(C1-C4)alkyl, -(C1-C4)haloalkyl and -O-(C1-C4)haloalkyl.

[0098] In certain embodiments, the R wand R y Each is independently selected from hydrogen, methyl, ethyl, propyl, -O-methyl, -O-ethyl and -O-propyl.

[0099] In certain embodiments, the R w is selected from hydrogen and methyl.

[0100] In certain embodiments, the R y For hydrogen.

[0101] In certain embodiments, W is absent or selected from -(C1-C6)alkylene-, -NH-, -N[(C1-C6)alkyl]-, and -N[O(C1-C6)alkyl]-.

[0102] In certain embodiments, W is absent or selected from -(C1-C4)alkylene, -NH-, and -N[-(C1-C4)alkyl]-.

[0103] In certain embodiments, said W is absent or selected from methylene, ethylene, -NH-, -N(Me)-, and -N(Et)-.

[0104] In certain embodiments, said W is absent or selected from -NH- and -N(Me)-.

[0105] In certain embodiments, U is selected from -(C1-C6)alkylene-, -(C3-C6)cycloalkylene-, and -(4-10 membered)heterocyclylene-.

[0106] In certain embodiments, U is selected from -(C1-C4)alkylene-, -(C3-C6)cycloalkylene-, and -(4-6 membered)heterocyclylene-.

[0107] In certain embodiments, U is selected from the group consisting of methylene, ethylene, cyclopropylene, azetidinylene, and pyrrolidinylene.

[0108] In certain embodiments, U is selected from methylene, ethylene and

[0109] In certain embodiments, U is selected from methylene, ethylene, wherein the * end is connected to W, and when W is absent, the * end is connected to the carbonyl group. In certain embodiments, the Z is absent or selected from -(C1-C4)alkylene-, -(C3-C6)cycloalkylene-, and -(4-6 membered)heterocyclylene-.

[0110] In certain embodiments, Z is absent or selected from methylene, ethylene, cyclopropylene, azetidinylene, and pyrrolidinylene.

[0111] In certain embodiments, said Z is absent.

[0112] In certain embodiments, said Y is absent or selected from -O-, -N(R y )- and -N + (R y )2-,R y is selected from hydrogen, -(C1-C6)alkyl and -O(C1-C6)alkyl, or R y Together with Z, it forms -(4-10 membered)heterocyclylene-.

[0113] In certain embodiments, said Y is absent or selected from -O-, -N(R y )- and -N + (R y )2-,R y is selected from hydrogen, -(C1-C4)alkyl and -O(C1-C4)alkyl, or R y Together with Z, it forms -(4-6 membered)heterocyclylene-.

[0114] In certain embodiments, said Y is absent or selected from -O-, -N(R y )- and -N + (R y )2-,R y is selected from hydrogen, methyl, ethyl and -O-methyl.

[0115] In certain embodiments, Y is selected from -O-, -NH-, -N(CH3)-, and -N + (CH3)2-.

[0116] In certain embodiments, said Y is absent or selected from -O- and -N(R y )-,R y is selected from hydrogen, -(C1-C6)alkyl and -O(C1-C6)alkyl, or R y Together with Z, it forms -(4-10 membered)heterocyclylene-.

[0117] In certain embodiments, said Y is absent or selected from -O- and -N(R y )-,R y is selected from hydrogen, -(C1-C4)alkyl and -O(C1-C4)alkyl, or R y Together with Z, it forms -(4-6 membered)heterocyclylene-.

[0118] In certain embodiments, said Y is absent or selected from -O- and -N(R y )-,R y is selected from hydrogen, methyl, ethyl and -O-methyl.

[0119] In certain embodiments, said Y is selected from -O- and -NH-.

[0120] In certain embodiments, the structural unit -WUZY- is selected from -N(R w )-(C1-C6)alkylene-N(R y )-、-N(R w )-(C1-C6)alkylene-N + (R y )2-、-N(R w )-(C1-C6)alkylene-O-, -(C1-C6)alkylene-N(R y )-、-(C1-C6)alkylene-O-、-(C3-C6)cycloalkylene-N(R y )-、-(C1-C6)alkylene-N + (R y )2-, -(C3-C6)cycloalkylene-O-, -(4-6 membered)heterocyclylene-O-, -(4-6 membered)heterocyclylene-N(R y )- and -N(R w )-(4-6 membered)heterocyclylene-, said-N(R w )-(C1-C6)alkylene-N(R y )-、-N(R w )-(C1-C6)alkylene-N + (R y )2-、-N(R w )-(C1-C6)alkylene-O-, -(C1-C6)alkylene-N(R y )-、-(C1-C6)alkylene-N + (R y )2-、-(C1-C6)alkylene-O-、-(C3-C6)cycloalkylene-N(R y )-、-(C3-C6)cycloalkylene-O-、-(4-6 membered)heterocyclylene-O-、-(4-6 membered)heterocyclylene-N(R y )- and -N(R w )-(4-6 membered)heterocyclylene- is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2.

[0121] In certain embodiments, the structural unit -WUZY- is selected from -N(R w )-(C1-C6)alkylene-N(R y )-、-N(Rw )-(C1-C6)alkylene-N + (R y )2-、-N(R w )-(C1-C6)alkylene-O-, -(C1-C6)alkylene-N(R y )-、-(C1-C6)alkylene-N + (R y )2-, -(C1-C6)alkylene-O-, -(4-6 membered)heterocyclylene-O- and -(4-6 membered)heterocyclylene-N(R y )- and -N(R w )-(4-6 membered)heterocyclylene-.

[0122] In certain embodiments, the structural unit -WUZY- is selected from *-NH-CH2-CH2-NH-, *-N(CH3)-CH2-CH2-NH-, *-NH-CH2-CH2-O-, *-CH2-O-, *-CH2-NH-, *-CH2-N(CH3)-, *-CH2-N + (CH3)2-, Among them, the * end is connected to the carbonyl group.

[0123] In certain embodiments, the structural unit -WUZY- is selected from -N(R w )-(C1-C6)alkylene-N(R y )-、-N(R w )-(C1-C6)alkylene-O-, -(C1-C6)alkylene-N(R y )-、-(C1-C6)alkylene-O-、-(C3-C6)cycloalkylene-N(R y )-、-(C3-C6)cycloalkylene-O-、-(4-6 membered)heterocyclylene-O-、-(4-6 membered)heterocyclylene-N(R y )- and -N(R w )-(4-6 membered)heterocyclylene-, said-N(R w )-(C1-C6)alkylene-N(R y )-、-N(R w )-(C1-C6)alkylene-O-, -(C1-C6)alkylene-N(R y )-、-(C1-C6)alkylene-O-、-(C3-C6)cycloalkylene-N(R y )-、-(C3-C6)cycloalkylene-O-、-(4-6 membered)heterocyclylene-O-、-(4-6 membered)heterocyclylene-N(R y )- and -N(R w)-(4-6 membered)heterocyclylene- is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2.

[0124] In certain embodiments, the structural unit -WUZY- is selected from -N(R w )-(C1-C6)alkylene-N(R y )-、-N(R w )-(C1-C6)alkylene-O-, -(C1-C6)alkylene-N(R y )-, -(C1-C6)alkylene-O-, -(4-6 membered)heterocyclylene-O-, -(4-6 membered)heterocyclylene-N(R y )- and -N(R w )-(4-6 membered)heterocyclylene-.

[0125] In certain embodiments, the structural unit -WUZY- is selected from *-NH-CH2-CH2-NH-, *-N(CH3)-CH2-CH2-NH-, *-NH-CH2-CH2-O-, *-CH2-O-, *-CH2-NH-, Wherein, the * end is connected to the carbonyl group. For example, the structural unit -WUZY- is selected from *-NH-CH2-CH2-NH- and Among them, the * end is connected to the carbonyl group.

[0126] In certain embodiments, the drug group is selected from the structure shown in formula III-A'

[0127] Among them, X, X 1 、X 2 , Ring B, Ring C, L, R 3 、R 4 、R 5 、R 6 、R 7 ,m,R 8a 、R 8b and R 12 is as defined in any embodiment of the present invention.

[0128] In certain embodiments, the drug group is selected from the structure shown in formula III-A

[0129] Among them, X, X 1 、X 2 , Ring B, Ring C, R3 、R 4 、R 5 、R 6 、R 7 ,m,R 8a 、R 8b and R 12 is as defined in any embodiment of the present invention.

[0130] In certain embodiments, the R 12 Selected from hydrogen, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C=O)-(C1-C6)alkyl, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10 membered)heterocyclyl and -O-(4-10 membered)heterocyclyl.

[0131] In certain embodiments, the R 12 is selected from hydrogen, -(C1-C4)alkyl, -O-(C1-C4)alkyl, -(C=O)-(C1-C4)alkyl, -(C3-C6)cycloalkyl and -O-(C3-C6)cycloalkyl.

[0132] In certain embodiments, the R 12 is selected from hydrogen, -(C1-C4)alkyl, -O-(C1-C4)alkyl and -(C3-C6)cycloalkyl.

[0133] In certain embodiments, the R 12 is selected from hydrogen and -(C1-C4)alkyl.

[0134] In certain embodiments, the R 12 is selected from hydrogen, methyl and ethyl.

[0135] In certain embodiments, the R 12 is selected from hydrogen and methyl.

[0136] In certain embodiments, the R 12 Selected from hydrogen.

[0137] In certain embodiments, the L is absent or selected from -C(=O)-(C1-C4)alkylene-O-, -C(=O)-(C1-C4)alkylene-N(R L )-、-C(=O)-(C1-C4)alkylene-N + (R L )2-, -C(=O)NH-(C1-C4)alkylene-O-, -C(=O)NH-(C1-C4)alkylene-N(R L )- and -C(=O)NH-(C1-C4)alkylene-N + (R L)2-,R L is selected from hydrogen, -(C1-C4)alkyl and -(C1-C4)haloalkyl.

[0138] In certain embodiments, the L is absent or selected from -C(=O)-(C1-C4)alkylene-O-, -C(=O)-(C1-C4)alkylene-N(R L )- and -C(=O)-(C1-C4)alkylene-N + (R L )2-,R L is selected from hydrogen, methyl and ethyl.

[0139] In certain embodiments, L is absent or selected from -C(=O)CH2O-, -C(=O)CH2CH2O-, -C(=O)CH2N(R L )-、-C(=O)CH2CH2N(R L )-、-C(=O)CH2N + (R L )2- and -C(=O)CH2CH2N + (R L )2-,R L is selected from hydrogen, methyl and ethyl.

[0140] In certain embodiments, L is absent or selected from *-C(=O)CH2O-, *-C(=O)CH2N(CH3)-, *-C(=O)CH2N + (CH3)2-, where the * end is connected to N.

[0141] In certain embodiments, said L is absent.

[0142] In certain embodiments, the drug group is selected from the structure shown in Formula IV-A

[0143] Among them, X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 ,Q,R 7 ,m,R 8a 、R 8b 、R 9a 、R 9b and R 10 is as defined in any embodiment of the present invention.

[0144] In certain embodiments, the R qis selected from hydrogen, -(C1-C4)alkyl, -O-(C1-C4)alkyl, -(C1-C4)haloalkyl and -O-(C1-C4)haloalkyl.

[0145] In certain embodiments, the R q is selected from the group consisting of hydrogen, methyl, ethyl, propyl, -O-methyl, -O-ethyl and -O-propyl.

[0146] In certain embodiments, the R q For hydrogen.

[0147] In certain embodiments, the Q is selected from -NH-, -O-, -(C1-C6)alkylene-O-, and -(C1-C6)alkylene-NH-, wherein the -(C1-C6)alkylene-O- and -(C1-C6)alkylene-NH- are optionally substituted with 1, 2, or 3 groups selected from hydrogen, halogen, -OH, -O-methyl, -NH2, -NH-methyl, -N(methyl)2, and -N(ethyl)2.

[0148] In certain embodiments, Q is selected from -NH-, -O-, -(C1-C6)alkylene-O-, and -(C1-C6)alkylene-NH-.

[0149] In certain embodiments, Q is selected from -NH-, -O-, -(C1-C4)alkylene-O-, and -(C1-C4)alkylene-NH-.

[0150] In certain embodiments, said Q is selected from -NH-, -O-, -CH2O-, and -CH2NH-.

[0151] In certain embodiments, Q is selected from -NH-, -O-, *-CH2O-, and *-CH2NH-, wherein the * end is connected to ring B.

[0152] In certain embodiments, said Q is selected from -NH-.

[0153] In certain embodiments, the ring B is selected from -(C6-C 10 )arylene- and (5-10 membered)heteroarylene-, the -(C6-C 10 )arylene- and (5-10 membered)heteroarylene- are optionally substituted by 1, 2 or 3 groups selected from R 5 and R 6 substituted by a group.

[0154] In certain embodiments, the ring B is selected from phenylene, naphthylene and (5-6 membered) heteroarylene, wherein the phenylene, naphthylene and (5-6 membered) heteroarylene are optionally substituted by 1 or 2 groups selected from R 5 and R 6 substituted by a group.

[0155] In certain embodiments, the ring B is phenylene, which is optionally substituted with 1 R 5 or R 6 replace.

[0156] In certain embodiments, the R 5 and R 6 Each is independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl and -O-(4-8 membered)heterocyclyl, wherein the -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl and -O-(4-8 membered)heterocyclyl are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and N[(C1-C4)alkyl]2.

[0157] In certain embodiments, the R 5 and R 6 Each is independently selected from hydrogen, halogen, cyano, -OH, -NH2, -(C1-C4)alkyl, -(C1-C4)alkyl-OH, -(C1-C4)alkyl-NH2, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl and -(C3-C6)cycloalkyl.

[0158] In certain embodiments, the R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2 and -CH2NH2.

[0159] In certain embodiments, the R 5 is selected from hydrogen, -OH, -NH2 and -CH2NH2.

[0160] In certain embodiments, the R 5 Selected from hydrogen.

[0161] In certain embodiments, the R 6 is selected from hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2, -O-methyl and cyclopropyl.

[0162] In certain embodiments, the R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2 and -O-methyl.

[0163] In certain embodiments, the R 6 is selected from hydrogen, cyano and -O-methyl.

[0164] In certain embodiments, the R 6 Selected from cyano and -O-methyl.

[0165] In certain embodiments, the R 6 It is a cyano group.

[0166] In certain embodiments, the R 6 For hydrogen.

[0167] In certain embodiments, Ring B is * terminal is connected to Q.

[0168] In certain embodiments, the drug group is selected from the structure shown in formula VA

[0169] Among them, X, X 1 、X 2 , T, Ring A, Ring B, Ring C, R 4 、R 5 、R 6 、R 7 ,m,R 8a 、R 8b 、R 9a 、R 9b and R 10 is as defined in any embodiment of the present invention.

[0170] In certain embodiments, the R t is selected from hydrogen, -(C1-C4)alkyl, -O-(C1-C4)alkyl, -(C1-C4)haloalkyl and -O-(C1-C4)haloalkyl.

[0171] In certain embodiments, the R t is selected from the group consisting of hydrogen, methyl, ethyl, propyl, -O-methyl, -O-ethyl and -O-propyl.

[0172] In certain embodiments, the R t For hydrogen.

[0173] In certain embodiments, T is selected from -NH-, -O-, -(C1-C6)alkylene-O-, and -(C1-C6)alkylene-NH-, wherein -(C1-C6)alkylene-O- and -(C1-C6)alkylene-NH- are optionally substituted with 1, 2, or 3 groups selected from hydrogen, halogen, -OH, -O-methyl, -NH2, -NH-methyl, -N(methyl)2, and -N(ethyl)2.

[0174] In certain embodiments, T is selected from -NH-, -O-, -(C1-C6)alkylene-O-, and -(C1-C6)alkylene-NH-.

[0175] In certain embodiments, T is selected from -NH-, -O-, -(C1-C4)alkylene-O-, and -(C1-C4)alkylene-NH-.

[0176] In certain embodiments, T is selected from -NH-, -O-, -CH2O-, and -CH2NH-.

[0177] In certain embodiments, the T is selected from -NH-, -O-, *-CH2O-, and *-CH2NH-, wherein the * end is connected to ring A.

[0178] In certain embodiments, the T is selected from -NH-, *-CH2O-, and *-CH2NH-, wherein the * end is connected to ring A.

[0179] In certain embodiments, the T is selected from -NH- and *-CH2NH-, wherein the * end is connected to ring A.

[0180] In certain embodiments, said T is selected from -NH-.

[0181] In certain embodiments, the ring A is selected from -(C3-C6)cycloalkylene-, -(4-6 membered)heterocyclylene-, -(C6-C 10 )arylene- and -(5-12 membered)heteroarylene-, the -(C3-C6)cycloalkylene-, -(4-6 membered)heterocyclylene-, -(C6-C 10 )arylene- and -(5-12 membered)heteroarylene are optionally substituted with one or more R 31 replace.

[0182] In certain embodiments, the R 31is selected from the group consisting of oxo, hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C4)alkyl, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NH2, -(C1-C4)alkylene-NH(C1-C4)alkyl, -(C1-C4)alkylene-N[(C1-C4)alkyl]2, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH (C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-8 membered)heterocyclyl, -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C4)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C4)alkyl and -C(=O)-N[(C1-C4)alkyl]2.

[0183] In certain embodiments, the R 31 Selected from oxo, hydrogen, halogen, cyano, -OH, -SH, -NH2, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -NH-(C1-C4)alkyl, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NH2, -(C1-C4)alkylene-NH(C1-C4)alkyl and -(C1-C4)alkylene-N[(C1-C4)alkyl]2.

[0184] In certain embodiments, the R 31 is selected from the group consisting of oxo, hydrogen, fluoro, chloro, cyano, -OH, -SH, -NH2, methyl, halomethyl, -O-methyl, -CH2OH, -CH2NH2 and -CH2CH2N(CH3)2.

[0185] In certain embodiments, the R 31 is selected from the group consisting of oxo, hydrogen, fluoro, cyano, -NH2, -CH2OH, -CH2NH2, methyl, trifluoromethyl and -O-methyl.

[0186] In certain embodiments, the R 31 is selected from hydrogen, -NH2, -CH2OH and -CH2NH2.

[0187] In certain embodiments, the R 31 For hydrogen.

[0188] In certain embodiments, the ring A is selected from phenylene, naphthylene and -(5-10 membered)heteroarylene-, wherein the phenylene, naphthylene and -(5-10 membered)heteroarylene are optionally substituted by one or more R 31 Replacement, R 31 is as defined in any embodiment of the present invention.

[0189] In certain embodiments, the ring A is selected from -(5-9 membered)heteroarylene-, wherein the -(5-9 membered)heteroarylene- is optionally substituted by 1, 2, 3 or 4 R 31 Replacement, R 31 is as defined in any embodiment of the present invention.

[0190] In certain embodiments, the ring A is selected from -(5-6 membered)heteroarylene-, wherein the -(5-6 membered)heteroarylene- is optionally substituted by 1, 2, 3 or 4 R 31 Replacement, R 31 is as defined in any embodiment of the present invention.

[0191] In certain embodiments, the ring A is selected from oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, triazolylene, tetrazolylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene, pyridazinoimidazolylene, pyrazinoimidazolylene and pyrimidinonylene, for example, the ring A is selected from oxazolylene, imidazolylene or pyrimidinylene, for example, the ring A is selected from oxazolylene, the ring A is optionally substituted by 1, 2 or 3 R 31 Replacement, R 31 is as defined in any embodiment of the present invention.

[0192] In certain embodiments, the ring A is selected from The * end is connected to T. For example, ring A is

[0193] In certain embodiments, the ring A is selected from The * end is connected to T.

[0194] In certain embodiments, the ring A is selected from Wherein the * end is connected to T. For example, ring A is selected from

[0195] In certain embodiments, the R 1 is selected from hydrogen, halogen, cyano, -OH, -(C1-C4)alkyl and -O-(C1-C4)alkyl.

[0196] In certain embodiments, the R 1is selected from the group consisting of hydrogen, fluorine, chlorine, cyano, -OH, methyl, ethyl, propyl, -O-methyl, -O-ethyl and -O-propyl.

[0197] In certain embodiments, the R 1 is selected from hydrogen and -O-methyl.

[0198] In certain embodiments, the R 1 It is -O-methyl.

[0199] In certain embodiments, the X 1 Selected from N, CH and C(OCH3).

[0200] In certain embodiments, the X 1 Selected from N and C(OCH3).

[0201] In certain embodiments, the X 1 Selected from C(OCH3).

[0202] In certain embodiments, the X 1 Selected from N.

[0203] In certain embodiments, the R 2 is selected from hydrogen, halogen, cyano, -OH, -(C1-C4)alkyl and -O-(C1-C4)alkyl.

[0204] In certain embodiments, the R 2 is selected from the group consisting of hydrogen, fluorine, chlorine, cyano, -OH, methyl, ethyl, propyl, -O-methyl, -O-ethyl and -O-propyl.

[0205] In certain embodiments, the R 2 For hydrogen.

[0206] In certain embodiments, the X 2 Selected from N and CH.

[0207] In certain embodiments, the X 2 C(R 2 ).

[0208] In certain embodiments, the X 2 Selected from CH.

[0209] In certain embodiments, the R 3 -(C3-C6)cycloalkyl, -(4-6 membered)heterocyclyl, -(C6-C 10 )aryl and -(5-12 membered)heteroaryl, the -(C3-C6)cycloalkyl, -(4-6 membered)heterocyclyl, -(C6-C 10)aryl and -(5-12 membered)heteroaryl are optionally substituted with one or more R 31 replace.

[0210] In certain embodiments, the R 31 is selected from the group consisting of oxo, hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C4)alkyl, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NH2, -(C1-C4)alkylene-NH(C1-C4)alkyl, -(C1-C4)alkylene-N[(C1-C4)alkyl]2, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH (C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-8 membered)heterocyclyl, -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C4)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C4)alkyl and -C(=O)-N[(C1-C4)alkyl]2.

[0211] In certain embodiments, the R 31 Selected from oxo, hydrogen, halogen, cyano, -OH, -SH, -NH2, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -NH-(C1-C4)alkyl, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NH2, -(C1-C4)alkylene-NH(C1-C4)alkyl and -(C1-C4)alkylene-N[(C1-C4)alkyl]2.

[0212] In certain embodiments, the R 31 is selected from the group consisting of oxo, hydrogen, fluoro, chloro, cyano, -OH, -SH, -NH2, methyl, halomethyl, -O-methyl, -CH2OH, -CH2NH2 and -CH2CH2N(CH3)2.

[0213] In certain embodiments, the R 31 is selected from the group consisting of oxo, hydrogen, fluoro, cyano, -NH2, -CH2OH, -CH2NH2, methyl, trifluoromethyl and -O-methyl.

[0214] In certain embodiments, the R 31 is selected from hydrogen, -NH2, -CH2OH and -CH2NH2.

[0215] In certain embodiments, the R 31 Selected from hydrogen.

[0216] In certain embodiments, the R 3 -(C3-C6)cycloalkyl and -(4-6 membered)heterocyclyl, wherein the -(C3-C6)cycloalkyl and -(4-6 membered)heterocyclyl are optionally substituted by one or more R 31 Replacement, R 31 is as defined in any embodiment of the present invention.

[0217] In certain embodiments, the R 3 is selected from cyclopropyl, oxetanyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, morpholinyl, morpholinonyl, piperidinyl, piperazinyl and piperazinonyl, wherein the cyclopropyl, oxetanyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, morpholinyl, morpholinonyl, piperidinyl, piperazinyl and piperazinonyl are optionally substituted by 1, 2 or 3 R 31 Replacement, R 31 is as defined in any embodiment of the present invention.

[0218] In certain embodiments, the R 3 Selected from

[0219] In certain embodiments, the R 3 is selected from phenyl, naphthyl and -(5-10 membered) heteroaryl, wherein the phenyl, naphthyl and -(5-10 membered) heteroaryl are optionally substituted by one or more R 31 Replacement, R 31 is as defined in any embodiment of the present invention.

[0220] In certain embodiments, the R 3 -(5-9 membered)heteroaryl, wherein the -(5-9 membered)heteroaryl is optionally substituted by 1, 2, 3 or 4 R 31 Replacement, R 31 is as defined in any embodiment of the present invention.

[0221] In certain embodiments, the R 3 is selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridazinoimidazolyl, pyrazinoimidazolyl and pyrimidinonyl, for example, R 3 is selected from oxazolyl, imidazolyl or pyrimidinyl, for example, R 3 is selected from oxazolyl, wherein R 3 Optional 1, 2 or 3 R 31 Replacement, R 31is as defined in any embodiment of the present invention.

[0222] In certain embodiments, the R 3 Selected from described Optional 1, 2 or 3 R 31 Replacement, R 31 is as defined in any embodiment of the present invention.

[0223] In certain embodiments, the R 3 Selected from The R 3 Optional 1, 2 or 3 R 31 replace.

[0224] In certain embodiments, the R 3 Selected from

[0225] In certain embodiments, the R 3 Selected from

[0226] In certain embodiments, the R 3 Selected from

[0227] In certain embodiments, the R 3 Selected from

[0228] In certain embodiments, the R 3 Selected from

[0229] In certain embodiments, the R 3 Selected from

[0230] In certain embodiments, the R 3 Selected from

[0231] In certain embodiments, the R 4Selected from hydrogen, halogen, cyano, -OH, -NH2, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl and -O-(C1-C4)haloalkyl.

[0232] In certain embodiments, the R 4 is selected from hydrogen, fluorine, chlorine, cyano, -OH, -NH2 and methyl.

[0233] In certain embodiments, the R 4 For hydrogen.

[0234] In certain embodiments, X is selected from O, S, NH, N[(C1-C4)alkyl], N[C(=O)-R c ]、C(R a )(R b )、C(=O)、C[=C(R a )R b ], S(=O) and S(=O)2, R a and R b are independently selected from hydrogen, halogen, cyano, -OR c 、-SR c 、-N(R c )R c , -(C1-C4)alkyl and -(C1-C4)haloalkyl, R c is selected from hydrogen, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl and -(C3-C6)cycloalkyl.

[0235] In certain embodiments, the R c is selected from hydrogen, methyl, ethyl, halomethyl, -O-methyl and cyclopropyl.

[0236] In certain embodiments, the R a and R b Each is independently selected from hydrogen, fluorine, chlorine, cyano, -OH, -O-methyl, -SH, -S-methyl, -NH2, -N(methyl)2, -N(methyl)-ethyl, -N(ethyl)2, methyl, ethyl, propyl, halomethyl, haloethyl and halopropyl.

[0237] In certain embodiments, X is selected from O, S, NH, and N[(C1-C4)alkyl].

[0238] In certain embodiments, said X is selected from O, S, and NH.

[0239] In certain embodiments, said X is selected from O and S.

[0240] In certain embodiments, said X is selected from O.

[0241] In certain embodiments, the ring B is selected from -(C6-C 10 )aryl and (5-10 membered)heteroaryl.

[0242] In certain embodiments, the ring B is selected from phenyl, naphthyl, and (5-6 membered) heteroaryl.

[0243] In certain embodiments, the structural unit for

[0244] In certain embodiments, the R 5 and R 6 Each is independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl and -O-(4-8 membered)heterocyclyl, wherein the -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl and -O-(4-8 membered)heterocyclyl are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and N[(C1-C4)alkyl]2.

[0245] In certain embodiments, the R 5 and R 6 Each is independently selected from hydrogen, halogen, cyano, -OH, -NH2, -(C1-C4)alkyl, -(C1-C4)alkyl-OH, -(C1-C4)alkyl-NH2, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl and -(C3-C6)cycloalkyl.

[0246] In certain embodiments, the R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2 and -CH2NH2.

[0247] In certain embodiments, the R 5 is selected from hydrogen, -OH, -NH2 and -CH2NH2.

[0248] In certain embodiments, the R 5 Selected from hydrogen.

[0249] In certain embodiments, the R 6 is selected from hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2, -O-methyl and cyclopropyl.

[0250] In certain embodiments, the R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2 and -O-methyl.

[0251] In certain embodiments, the R 6 is selected from hydrogen, cyano and -O-methyl.

[0252] In certain embodiments, the R 6 Selected from cyano and -O-methyl.

[0253] In certain embodiments, the R 6 It is a cyano group.

[0254] In certain embodiments, the R 5 and R 6 The atoms connected to it form Where * indicates the positions of connected atoms.

[0255] In certain embodiments, the ring C is selected from -(C6-C 10 )aryl and (5-10 membered)heteroaryl.

[0256] In certain embodiments, the ring C is selected from phenyl, naphthyl, and (5-6 membered) heteroaryl.

[0257] In certain embodiments, the structural unit for

[0258] In certain embodiments, the structural unit for

[0259] In certain embodiments, the R 7each independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-8 membered)heterocyclyl and -NHC(=O)-(C1-C4)alkyl, wherein said -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-8 membered)heterocyclyl and -NHC(=O)-(C1-C4)alkyl are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2.

[0260] In certain embodiments, the R 7 Each is independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl and -O-(4-8 membered)heterocyclyl, wherein the -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl and -O-(4-8 membered)heterocyclyl are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2.

[0261] In certain embodiments, the R7 Each is independently selected from hydrogen, halogen, cyano, -OH, -NH2, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NH(C1-C4)alkyl, -(C1-C4)alkylene-N[(C1-C4)alkyl]2, -(C1-C4)alkylene-NH2 and -NHC(=O)-(C1-C4)alkylene-NH2.

[0262] In certain embodiments, the R 7 Each is independently selected from hydrogen, halogen, cyano, -OH, -NH2, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NH(C1-C4)alkyl, -(C1-C4)alkylene-N[(C1-C4)alkyl]2 and -(C1-C4)alkylene-NH2.

[0263] In certain embodiments, the R 7 Each is independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -NH2, -CH2OH, -CH2NH2, -NHC(=O)CH2NH2 and -NHC(=O)CH2CH2NH2.

[0264] In certain embodiments, the R 7 Each is independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -NH2, -CH2OH and -CH2NH2.

[0265] In certain embodiments, the R 7 are each independently selected from hydrogen.

[0266] In certain embodiments, m is 1, 2, or 3.

[0267] In certain embodiments, m is 1.

[0268] In certain embodiments, the R 8a 、R 8b 、R 9a and R 9beach independently selected from hydrogen, halogen, cyano, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -OR, -N(R)R, -[(C1-C6)alkylene]R, -[(C1-C6)alkylene]OR, -[(C1-C6)alkylene]N(R)R, -[(C1-C6)alkylene]N(R)C(=O)R, -[(C1-C6)alkylene]N(R)C(=O)N(R)R, - C(=O)R, -C(=O)N(R)R, -C(=O)[(C1-C6)alkylene]N(R)R, -C(=O)OR, -C(=S)N(R)R, -SR, -S(=O)R, -S(=O)2R, -S(=O)2N(R)R, -N(R)C(=O)R, -N(R)C(=O)N(R)R and -P(=O)(OR)(OR), R being each independently selected from hydrogen, -OH, -NH2, -(C1-C4)alkyl, -(C2- -(C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -(C1-C4)alkylene-O-(C1-C4)alkyl, -S-(C1-C4)alkyl, -S(=O)2-(C1-C4)alkyl, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-8 membered)heterocyclyl, -C(=O)-H, -C(= -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C4)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C4)alkyl, -[(C1-C4)alkylene]-(C3-C6)cycloalkyl, -C(=O)-N[(C1-C4)alkyl]2, -[(C1-C4)alkylene]-(4-8 membered)heterocyclyl, -(C6-C 10 )aryl, -[(C1-C4)alkylene]-(C6-C 10)aryl and -(5-10 membered)heteroaryl, the -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -(C1-C4)alkylene-O-(C1-C4)alkyl, -S-(C1-C4)alkyl, -S(=O)2-(C1-C4)alkyl, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl , -O-(4-8 membered) heterocyclyl, -C(=O)-(C1-C4) alkyl, -C(=O)-(C3-C6) cycloalkyl, -C(=O)-O-(C1-C4) alkyl, -C(=O)-O-(C3-C6) cycloalkyl, -C(=O)-NH(C1-C4) alkyl, -[(C1-C4) alkylene]-(C3-C6) cycloalkyl, -C(=O)-N[(C1-C4) alkyl]2, -[(C1-C4) alkylene]-(4-8 membered) heterocyclyl, -(C6-C 10 )aryl, -[(C1-C4)alkylene]-(C6-C 10 )aryl and -(5-10 membered)heteroaryl are optionally substituted with 1, 2, 3, 4, 5, 6 or 7 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, N[(C1-C4)alkyl]2 and (C1-C4)alkyl.

[0269] In certain embodiments, the R 8a 、R 8b 、R 9a and R 9beach independently selected from hydrogen, halogen, cyano, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -OR, -N(R)R, -[(C1-C6)alkylene]R, -[(C1-C6)alkylene]OR, -[(C1-C6)alkylene]N(R)R, -C(=O)R, -C(=O)N(R)R, -C(= -C(=O)OR, -C(=S)N(R)R, -SR, -S(=O)R, -S(=O)2R, -S(=O)2N(R)R, -N(R)C(=O)R, -N(R)C(=O)N(R)R and -P(=O)(OR)(OR), R being each independently selected from hydrogen, -OH, -NH2, -(C1-C4)alkane -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C3-C6)cycloalkyl, -O-(4-8 membered)heterocyclyl, -C(=O)-H, -C(=O)-(C -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C4)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C4)alkyl, -C(=O)-N[(C1-C4)alkyl]2, -[(C1-C4)alkylene]-(4-8 membered)heterocyclyl, -(C6-C 10 )aryl, -[(C1-C4)alkylene]-(C6-C 10 ) aryl and -(5-10 membered) heteroaryl, the -(C1-C4) alkyl, -(C2-C4) alkenyl, -(C2-C4) alkynyl, -(C1-C4) haloalkyl, -O-(C1-C4) alkyl, -O-(C1-C4) haloalkyl, -S-(C1-C4) alkyl, -(C3-C6) cycloalkyl, -(4-8 membered) heterocyclyl, -O-(C3-C6) cycloalkyl, -O-(4-8 -C(=O)-(C1-C4)alkyl]2, -[(C1-C4)alkylene]-(4-8 membered)heterocyclyl, -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C4)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH(C1-C4)alkyl, -C(=O)-N[(C1-C4)alkyl]2, -[(C1-C4)alkylene]-(4-8 membered)heterocyclyl, -(C6-C 10 )aryl, -[(C1-C4)alkylene]-(C6-C 10)aryl and -(5-10 membered)heteroaryl are optionally substituted with 1, 2, 3, 4, 5, 6 or 7 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, N[(C1-C4)alkyl]2.

[0270] In certain embodiments, each of the R groups is independently selected from hydrogen, -OH, -NH2, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -(C1-C4)alkylene-O-(C1-C6)alkyl, -O-(C1-C4)haloalkyl, -S(=O)2-(C1-C4)alkyl, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -C(=O)-H, -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl, -[(C1-C4)alkylene]-(C3-C6)cycloalkyl, and -[(C1-C4)alkylene]-(4-8 membered)heterocyclyl, wherein the -(C1-C4)alkyl, -(C1-C4)alkyl, - Haloalkyl, -O-(C1-C4)alkyl, -(C1-C4)alkylene-O-(C1-C6)alkyl, -O-(C1-C4)haloalkyl, -S(=O)2-(C1-C4)alkyl, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl, -[(C1-C4)alkylene]-(C3-C6)cycloalkyl and -[(C1-C4)alkylene]-(4-8 membered)heterocyclyl are optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, methyl and ethyl.

[0271] In certain embodiments, each of the R groups is independently selected from hydrogen, -OH, -NH2, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -C(=O)-H, -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl, and -[(C1-C4)alkylene]-(4-8 membered)heterocyclyl. -C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl and -[(C1-C4)alkylene]-(4-8 membered)heterocyclyl are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, N[(C1-C4)alkyl]2.

[0272] In certain embodiments, each of the R groups is independently selected from hydrogen, -OH, -NH2, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2NH2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2N(CH3)2, -CH(N(CH3)2)CH2OH, -CH2OCH2CH2OH, -OCH3, -C(=O)-H, -C(=O)CH3, -C(=O)CH2OH, -S(=O)2CH3, cyclobutyl-OH, oxetanyl, azetidinyl, azetidinyl-OH, pyrrolidinyl, piperazinyl, azetidinyl-CH3, piperazinyl-CH3, and -CH2-azetidinyl.

[0273] In certain embodiments, each of the R groups is independently selected from hydrogen, -OH, -NH2, -CH3, -CH2OH, -CH2CH2OH, -CH2NH2, -CH2CH2NH2, -OCH3, -C(=O)-H, -C(=O)CH2OH, oxetanyl, azetidinyl, and azetidinyl-OH.

[0274] In certain embodiments, each of the R groups is independently selected from hydrogen, -OH, -NH2, -(C1-C4)alkyl, -O-(C1-C4)alkyl, and -(4-8 membered)heterocyclyl, and the -(C1-C4)alkyl, -O-(C1-C4)alkyl, and -(4-8 membered)heterocyclyl groups are optionally substituted with 1, 2, 3, 4, or 5 groups selected from hydrogen, halogen, -OH, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, and -O-(C1-C4)alkyl.

[0275] In certain embodiments, the R is each independently selected from hydrogen, -OH, -(C1-C4)alkyl, -O-(C1-C4)alkyl and -(4-8 membered)heterocyclyl, and the -(C1-C4)alkyl, -O-(C1-C4)alkyl and -(4-8 membered)heterocyclyl are optionally substituted with 1, 2 or 3 groups selected from hydrogen, halogen, -OH, -NH2, -NH-methyl and -N(methyl)2.

[0276] In certain embodiments, each of the R groups is independently selected from methyl, ethyl, propyl, -O-methyl, -O-ethyl, -O-propyl, oxetanyl, and azetidinyl, each of which is independently optionally substituted with 1, 2, or 3 groups selected from -OH and -NH2.

[0277] In certain embodiments, the R 8a 、R 8b 、R 9a and R 9b Each is independently selected from hydrogen, cyano, -OR, -N(R)R, -[(C1-C4)alkylene]R, -[(C1-C4)alkylene]OR, -[(C1-C4)alkylene]N(R)R, -[(C1-C4)alkylene]N(R)C(=O)R, -[(C1-C4)alkylene]N(R)C(=O)N(R)R, -C(=O)R, -C(=O)N(R)R, -C(=O)[(C1-C4)alkylene]N(R)R, -C(=O)OR, -C(=S)N(R)R, -S(=O)R, -S(=O)2R, -S(=O)2N(R)R, -N(R)C(=O)R and -N(R)C(=O)N(R)R, and R is defined as described in any embodiment of the present invention.

[0278] In certain embodiments, the R 8a 、R 8b 、R 9a and R 9bEach is independently selected from hydrogen, -OR, -N(R)R, -[(C1-C4)alkylene]R, -[(C1-C4)alkylene]OR, -[(C1-C4)alkylene]N(R)R, -C(=O)R, -C(=O)N(R)R, -C(=O)[(C1-C4)alkylene]N(R)R, -C(=O)OR, -C(=S)N(R)R, -S(=O)R, -S(=O)2R, -S(=O)2N(R)R, -N(R)C(=O)R and -N(R)C(=O)N(R)R, and R is defined as described in any embodiment of the present invention.

[0279] In certain embodiments, the R 8a and R 8b Each is independently selected from hydrogen, -methylene-R, -ethylene-R, -propylene-R, -methylene-OR, -ethylene-OR, -propylene-OR, -methylene-N(R)R, -ethylene-N(R)R, -propylene-N(R)R, -C(=O)R, -C(=O)N(R)R and -C(=O)OR, and R is defined as described in any embodiment of the present invention.

[0280] In certain embodiments, the R 8a and R 8b Each is independently selected from hydrogen, -methylene-R, -methylene-OR, -methylene-N(R)R, -C(=O)R, -C(=O)OR and -C(=O)N(R)R, and R is defined as described in any embodiment of the present invention, for example, R is independently selected from hydrogen, -OH, -NH2, -(C1-C4)alkyl, -O-(C1-C4)alkyl, -C(=O)-(C1-C4)alkyl, -S(=O)2(C1-C4)alkyl and -(4-8 membered)heterocyclyl, and the -(C1-C4)alkyl and -(4-8 membered)heterocyclyl are optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -NH2, -NHCH3 and CH3.

[0281] In certain embodiments, the R 8a and R 8b Each is independently selected from hydrogen, -methylene-R, -methylene-OR, -methylene-N(R)R, -C(=O)R, -C(=O)OR and -C(=O)N(R)R, and R is as defined in any embodiment of the present invention.

[0282] In certain embodiments, the R 8a For hydrogen.

[0283] In certain embodiments, the R 8a for

[0284] In certain embodiments, the R 8b Selected from hydrogen,

[0285] In certain embodiments, the R 8b Selected from hydrogen,

[0286] In certain embodiments, the R 8b Selected from hydrogen,

[0287] In certain embodiments, the R 8b Selected from hydrogen,

[0288] In certain embodiments, the R 8b Each is independently selected from hydrogen, -methylene-R, -methylene-OR, -methylene-N(R)R and -C(=O)N(R)R, and each R is independently selected from hydrogen, -(C1-C4)alkyl and -O-(C1-C4)alkyl.

[0289] In certain embodiments, the R 8b Selected from hydrogen,

[0290] In certain embodiments, the R 8b Selected from hydrogen,

[0291] In certain embodiments, the R 8b Selected from hydrogen,

[0292] In certain embodiments, the R 8b Selected from hydrogen,

[0293] In certain embodiments, the R 9a and R 9b each is independently selected from hydrogen, -CN, -OR, -NHR, -N(R)R, -NHC(=O)R, -methylene-R, -ethylene-R, -propylene-R, -methylene-N(R)R, -ethylene-N(R)R, -propylene-N(R)R, -methylene-NHC(=O)R and -methylene-NHC(=O)NHR, and R is defined as described in any embodiment of the present invention.

[0294] In certain embodiments, the R9a and R 9b Each is independently selected from hydrogen, -OR, -NHR, -methylene-R, -ethylene-R, -propylene-R, -methylene-N(R)R, -ethylene-N(R)R, -propylene-N(R)R and -NHC(=O)R, and R is defined as described in any embodiment of the present invention.

[0295] In certain embodiments, the R 9a and R 9b Each is independently selected from hydrogen, -CN, -OR, -N(R)R, -NHC(=O)R, -methylene-N(R)R, -methylene-NHC(=O)R and -methylene-NHC(=O)NHR, R is defined as described in any embodiment of the present invention, for example, R is independently selected from hydrogen, -OH, -(C1-C4)alkyl, -(C1-C4)alkylene-O-(C1-C4)alkyl, -S(=O)2(C1-C4)alkyl, -(C3-C6) Cycloalkyl, -(4-8 membered)heterocyclyl, -methylene-(C3-C6)cycloalkyl and -methylene-(4-8 membered)heterocyclyl, wherein the -(C1-C4)alkyl, -(C3-C6)cycloalkyl and -(4-8 membered)heterocyclyl are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -O-(C1-C4)alkyl and -(C1-C4)alkyl.

[0296] In certain embodiments, the R 9a and R 9b Each is independently selected from hydrogen, -OR, -N(R)R, -methylene-N(R)R and -NHC(=O)R, and R is as defined in any embodiment of the present invention.

[0297] In certain embodiments, the R 9a is selected from hydrogen, -CN, -N(R)R, -NHC(=O)R, -methylene-N(R)R, -methylene-NHC(=O)R and -methylene-NHC(=O)NHR, R is defined as described in any embodiment of the present invention, for example, R is independently selected from hydrogen, -OH, methyl, ethyl, -methylene-O-ethyl, -S(=O)2-methyl, cyclobutyl, azetidinyl, -methylene-cyclobutyl and -methylene-azetidinyl, and the foregoing groups are each independently optionally substituted by 1, 2 or 3 groups selected from -OH, OCH3, NHCH3, N(CH3)2 and CH3.

[0298] In certain embodiments, the R 9a is selected from hydrogen and -methylene-N(R)R, R is as defined in any embodiment of the present invention.

[0299] In certain embodiments, the R 9a Selected from hydrogen, -CN, -NHCH3, -N(CH3)2, -NHC(=O)H, -NHC(=O)CH2OH, -NHC(=O)CH2OCH3, -NHC(=O)CH2NHCH3, -NHC(=O)CH2N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH 3)2, -CH2N(CH2CH3)2, -CH2N(CH3)(CH2CH3), -CH2NHC(=O)CH2OH, -CH2NHC(=O)CH2OCH3, -CH2NHC(=O)CH2NHCH3, -CH2NHC(=O)CH2N(CH3)2, -CH2NHC(=O )H, -CH2NHC(=O)CH3, -CH2NHC(=O)NHOH, -CH2NHC(=O)NHCH2CH2OH, -CH2NHC(=O)CH(N(CH3)2)CH2OH, -CH2NHC(=O)CH2NHCH3, -CH2NHC(=O)CH2N(CH3)2, -CH2NHC(=O)CH2N(CH2CH3)2, -CH2NHC(=O)CH2OCH2CH2OH, -CH2NHS(=O)2CH3, -CH2NHC(=O)cyclobutyl-OH, -CH2NHC(=O)-azetidinyl-CH3 and -CH2NHC(=O)CH2-azetidinyl.

[0300] In certain embodiments, the R 9a Selected from hydrogen, -CH2NH2, -CH2NHCH3, -NHC(=O)H, -NHC(=O)CH2OH and -CH2NHC(=O)CH2OH.

[0301] In certain embodiments, the R 9a Selected from hydrogen,

[0302] In certain embodiments, the R 9a Selected from hydrogen,

[0303] In certain embodiments, the R 9a Selected from hydrogen,

[0304] In certain embodiments, the R 9aSelected from hydrogen, -CN, -methylene-N(R)R and -methylene-NHC(=O)R, each independently selected from hydrogen, -(C1-C4)alkyl, -methylene-O-(C1-C4)alkyl, -methylene-NH-(C1-C4)alkyl, -methylene-N[(C1-C4)alkyl]2, -S(=O)2-(C1-C4)alkyl.

[0305] In certain embodiments, the R 9a Selected from hydrogen,

[0306] In certain embodiments, the R 9a Selected from hydrogen,

[0307] In certain embodiments, the R 9a Selected from hydrogen,

[0308] In certain embodiments, the R 9a Selected from hydrogen,

[0309] In certain embodiments, the R 9a Selected from hydrogen,

[0310] In certain embodiments, the R 9a For hydrogen.

[0311] In certain embodiments, the R 9a for

[0312] In certain embodiments, the R 9b Selected from hydrogen and

[0313] In certain embodiments, the R 9b It is -OH.

[0314] In certain embodiments, the R 9b for

[0315] In certain embodiments, the R 9b Selected from hydrogen,

[0316] In certain embodiments, the R 8a 、R 8b 、R 9a is hydrogen, R9b As described in any embodiment of the present invention.

[0317] In certain embodiments, the R 8a 、R 8b 、R 9b is hydrogen, R 9a As described in any embodiment of the present invention.

[0318] In certain embodiments, the R 8a 、R 9a is hydrogen, R 8b 、R 9b As described in any embodiment of the present invention, and R 8b 、R 9b In certain embodiments, the R 8a and R 8b , and R 9a and R 9b Independently combine to form oxo, -(C2-C4)alkenyl, -(C3-C6)cycloalkyl or -(4-8 membered)heterocyclyl.

[0319] In certain embodiments, the R 8a and R 8b The combination forms oxo, -(C2-C4)alkenyl, -(C3-C6)cycloalkyl or -(4-8 membered)heterocyclyl.

[0320] In certain embodiments, the R 9a and R 9b The combination forms oxo, -(C2-C4)alkenyl, -(C3-C6)cycloalkyl or -(4-8 membered)heterocyclyl.

[0321] In certain embodiments, the R 8a and R 8b , and R 9a and R 9b Independently combine to form oxo, vinyl, propenyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl.

[0322] In certain embodiments, the R 8a and R 9a The carbon atoms to which it is attached together form a (C3-C6)cycloalkyl, a (4-8 membered)heterocyclyl or a (5-9 membered)heteroaryl, wherein the aforementioned groups are optionally substituted by 1, 2, 3, 4, 5, 6 or 7 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl and -(C6-C 10 ) aryl group substitution.

[0323] In certain embodiments, the R 8b and R 9b The carbon atoms to which it is attached together form a (C3-C6)cycloalkyl, a (4-8 membered)heterocyclyl or a (5-9 membered)heteroaryl, wherein the aforementioned groups are optionally substituted by 1, 2, 3, 4, 5, 6 or 7 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl and -(C6-C 10 ) aryl group substitution.

[0324] In certain embodiments, the R 8a and R 9a , R 8b and R 9b The carbon atoms to which it is attached together form a (C3-C6)cycloalkyl, a (4-8 membered)heterocyclyl or a (5-9 membered)heteroaryl, wherein the aforementioned groups are optionally substituted by 1, 2, 3, 4, 5, 6 or 7 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl and -(C6-C 10 ) aryl group substitution.

[0325] In certain embodiments, the R 8a and R 9a The carbon atoms to which they are attached together form a (4-8 membered) heterocyclyl or a (5-9 membered) heteroaryl, and the aforementioned groups are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, -OH, -O-methyl, -O-ethyl, -NH2, -NH-methyl, -NH-ethyl, -N(methyl)2, -N(methyl)-ethyl, -N(ethyl)2, cyclopropyl, cyclobutyl, cyclopentyl, phenyl and naphthyl.

[0326] In certain embodiments, the R 8b and R 9b The carbon atoms to which they are attached together form a (4-8 membered) heterocyclyl or a (5-9 membered) heteroaryl, and the aforementioned groups are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, -OH, -O-methyl, -O-ethyl, -NH2, -NH-methyl, -NH-ethyl, -N(methyl)2, -N(methyl)-ethyl, -N(ethyl)2, cyclopropyl, cyclobutyl, cyclopentyl, phenyl and naphthyl.

[0327] In certain embodiments, the R 8a and R 9a , R 8b and R 9bThe carbon atoms to which they are attached together form a (4-8 membered) heterocyclyl or a (5-9 membered) heteroaryl, and the aforementioned groups are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, -OH, -O-methyl, -O-ethyl, -NH2, -NH-methyl, -NH-ethyl, -N(methyl)2, -N(methyl)-ethyl, -N(ethyl)2, cyclopropyl, cyclobutyl, cyclopentyl, phenyl and naphthyl.

[0328] In certain embodiments, the R 8a and R 9a The carbon atoms to which they are attached together form a (4-8 membered) heterocyclyl or a (5-9 membered) heteroaryl, and the aforementioned groups are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, -OH, -O-methyl, -O-ethyl, -NH2, -NH-methyl, -NH-ethyl, -N(methyl)2, -N(methyl)-ethyl, -N(ethyl)2, cyclopropyl, cyclobutyl, cyclopentyl, phenyl and naphthyl.

[0329] In certain embodiments, the R 8b and R 9b The carbon atoms to which they are attached together form a (4-8 membered) heterocyclyl or a (5-9 membered) heteroaryl, and the aforementioned groups are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, -OH, -O-methyl, -O-ethyl, -NH2, -NH-methyl, -NH-ethyl, -N(methyl)2, -N(methyl)-ethyl, -N(ethyl)2, cyclopropyl, cyclobutyl, cyclopentyl, phenyl and naphthyl.

[0330] In certain embodiments, the R 8a and R 9a Does not exist, R 8b and R 9b The atoms connected to it form Where * indicates the positions of connected atoms.

[0331] In certain embodiments, the R 10 Selected from -OH.

[0332] In certain embodiments, the R 10 and R 9a The atoms to which it is attached form a 5-membered nitrogen-containing heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2.

[0333] In certain embodiments, the R 10 and R 9aThe atoms to which it is attached form an imidazolinyl group, which is optionally substituted with 1, 2 or 3 groups selected from halogen, -OH, methyl, -NH2, -NH-methyl and -N(methyl)2.

[0334] In certain embodiments, the R 10 and R 9a The atoms connected to it form Where * indicates the positions of connected atoms.

[0335] In certain embodiments, the R 10 It is -OH.

[0336] In certain embodiments, the R 10 for

[0337] In certain embodiments, the drug group is selected from the structure represented by Formula IA-1, II-A-1', II-A-1, III-A-1', III-A-1, IV-A-1 or VA-1:

[0338] Among them, X, X 1 、X 2 , Ring A, Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 、R 12 , m, n, M, W, U, Z, Y, L, Q and T are as defined in any embodiment of the present invention.

[0339] In certain embodiments, the drug group is selected from the structures represented by Formula IA-2, II-A-2', II-A-2, III-A-2', III-A-2, IV-A-2, or VA-2:

[0340] Among them, X, X 1 、X 2 , Ring A, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 9a 、R9b 、R 10 、R 12 , m, n, M, W, U, Z, Y, L, Q and T are as defined in any embodiment of the present invention.

[0341] In certain embodiments, the drug group is selected from the structures shown in Formula IA-3, III-A-3', III-A-3, IV-A-3 or VA-3:

[0342] Among them, X, X 1 、X 2 , Ring A, R 3 、R 4 、R 5 、R 6 、R 7 、R 8b 、R 9b 、R 12 , m, M, L, Q and T are as defined in any embodiment of the present invention.

[0343] In certain embodiments, the drug group is selected from the structure represented by Formula IA-4, II-A-4', II-A-4, III-A-4', III-A-4, IV-A-4 or VA-4:

[0344] Among them, X, R 1 , Ring A, R 3 、R 4 、R 5 、R 6 、R 7 、R 8b 、R 12 , m, n, M, W, U, Z, Y, L, Q and T are as defined in any embodiment of the present invention.

[0345] In certain embodiments, the compound of the structure shown in the above general formula, wherein:

[0346] M is selected from -NH-, -O-, -(C1-C4)alkylene-O- and -(C1-C4)alkylene-NH-;

[0347] n is 0 or 1;

[0348] W is absent or selected from -(C1-C4)alkylene, -NH- and -N[-(C1-C4)alkyl]-;

[0349] U is selected from -(C1-C4)alkylene-, -(C3-C6)cycloalkylene- and -(4-6 membered)heterocyclylene-;

[0350] Z is absent or selected from -(C1-C4)alkylene-, -(C3-C6)cycloalkylene- and -(4-6 membered)heterocyclylene-;

[0351] Y is absent or selected from -O-, -N(R y )- and -N + (R y )2-,R y is selected from hydrogen, -(C1-C4)alkyl and -O(C1-C4)alkyl, or R y Forming -(4-6 membered)heterocyclylene- with Z;

[0352] R 12 is selected from hydrogen, -(C1-C4)alkyl, -O-(C1-C4)alkyl and -(C3-C6)cycloalkyl;

[0353] L is absent or selected from -C(=O)-(C1-C4)alkylene-O-, -C(=O)-(C1-C4)alkylene-N(R L )- and -C(=O)-(C1-C4)alkylene-N + (R L )2-,R L is selected from hydrogen, -(C1-C4)alkyl and -(C1-C4)haloalkyl;

[0354] Q is selected from -NH-, -O-, -(C1-C4)alkylene-O- and -(C1-C4)alkylene-NH-;

[0355] T is selected from -NH-, -O-, -(C1-C4)alkylene-O- and -(C1-C4)alkylene-NH-;

[0356] X 1 Selected from N and C(R 1 ), R 1 is selected from hydrogen, halogen, cyano, -OH, -(C1-C4)alkyl and -O-(C1-C4)alkyl;

[0357] X 2 Selected from C(R 2 ), R 2 is selected from hydrogen, halogen, cyano, -OH, -(C1-C4)alkyl and -O-(C1-C4)alkyl;

[0358] R 31is selected from the group consisting of oxo, hydrogen, fluorine, chlorine, cyano, -OH, -SH, -NH2, -(C1-C4)alkyl, -O-(C1-C4)alkyl, -(C1-C4)alkylene-OH, -(C1-C4)haloalkyl, -(C1-C4)alkylene-NH2, -(C1-C4)alkylene-NH(C1-C4)alkyl and -(C1-C4)alkylene-N[(C1-C4)alkyl]2;

[0359] R 3 is selected from -(5-9 membered)heteroaryl, -(C3-C6)cycloalkyl and -(4-6 membered)heterocyclyl, wherein R 3 Optional 1, 2, 3 or 4 R 31 replace;

[0360] Ring A is selected from -(5-9 membered)heteroarylene-, said ring A being optionally substituted by 1, 2, 3 or 4 R 31 replace,

[0361] R 4 is selected from hydrogen, fluorine, chlorine, cyano, -OH, -NH2, methyl, halomethyl, -O-methyl, -NH-methyl and cyclopropyl;

[0362] X is selected from O, S, NH and N[(C1-C4)alkyl];

[0363] Ring B is phenyl, or phenylene, the phenylene is optionally substituted by 1 R 5 or R 6 replace;

[0364] R 5 and R 6 R is each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2, -(C1-C4)alkyl, -(C1-C4)alkyl-OH, -(C1-C4)alkyl-NH2, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl and -(C3-C6)cycloalkyl; or R 5 and R 6 The atoms connected to it form Where * indicates the connected atomic positions;

[0365] Ring C is phenyl, or phenylene, the phenylene is optionally substituted by 1 R 7 replace;

[0366] R 7each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NH(C1-C4)alkyl, -(C1-C4)alkylene-N[(C1-C4)alkyl]2 and -(C1-C4)alkylene-NH2;

[0367] m is 1, 2, or 3;

[0368] R is each independently selected from hydrogen, -OH, NH2, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -C(=O)-H, -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl and -[(C1-C4)alkylene]-(4-8 membered)heterocyclyl, wherein -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4) haloalkyl, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclyl, -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl and -[(C1-C4)alkylene]-(4-8 membered)heterocyclyl are optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -O-methyl, -O-ethyl, -O-propyl, -NH2, -NH-methyl, -NH-ethyl, -NH-propyl, -N(methyl), -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl), -N(ethyl)-propyl, methyl and ethyl;

[0369] R 8a for

[0370] R 8b is selected from the group consisting of hydrogen, -methylene-R, -ethylene-R, -propylene-R, -methylene-OR, -ethylene-OR, -propylene-OR, -methylene-N(R)R, -ethylene-N(R)R, -propylene-N(R)R, -C(=O)R, -C(=O)N(R)R, and -C(=O)OR;

[0371] R 9a is selected from hydrogen, -OR, -N(R)R, -methylene-N(R)R, -methylene-NHC(=O)R, and -NHC(=O)R;

[0372] R 9b Selected from hydrogen and

[0373] R 10 for

[0374] In certain embodiments, the compound of the structure shown in the above general formula, wherein:

[0375] M is selected from -NH-, -O-, -CH2O- and -CH2NH-;

[0376] n is 0 or 1;

[0377] The structural unit -WUZY- is selected from -N(R w )-(C1-C6)alkylene-N(R y )-、-N(R w )-(C1-C6)alkylene-N + (R y )2-、-N(R w )-(C1-C6)alkylene-O-, -(C1-C6)alkylene-N(R y )-、-(C1-C6)alkylene-N + (R y )2-, -(C1-C6)alkylene-O-, -(4-6 membered)heterocyclylene-O-, and -(4-6 membered)heterocyclylene-N(R y )-;

[0378] R 12 is selected from hydrogen and -(C1-C4)alkyl;

[0379] L is absent or selected from -C(=O)CH2O-, -C(=O)CH2CH2O-, -C(=O)CH2N(R L )-、-C(=O)CH2CH2N(R L )-、-C(=O)CH2N + (R L )2- and -C(=O)CH2CH2N + (R L )2-,R L is selected from hydrogen, methyl and ethyl;

[0380] Q is selected from -NH-, -O-, -CH2O- and -CH2NH-;

[0381] T is selected from -NH-, -O-, -CH2O- and -CH2NH-;

[0382] X 1 Selected from N and C(R 1 ), R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, cyano, -OH, methyl, ethyl, propyl, -O-methyl, -O-ethyl, and -O-propyl;

[0383] X2 Selected from C(R 2 ), R 2 is selected from the group consisting of hydrogen, fluorine, chlorine, cyano, -OH, methyl, ethyl, propyl, -O-methyl, -O-ethyl, and -O-propyl;

[0384] R 31 is selected from the group consisting of oxo, hydrogen, fluoro, chloro, cyano, -OH, -SH, -NH2, methyl, halomethyl, -O-methyl, -CH2OH, -CH2NH2 and -CH2CH2N(CH3)2;

[0385] R 3 is selected from cyclopropyl, oxetanyl, morpholinyl, morpholinonyl, piperidinyl, piperazinyl, piperazinonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridazinoimidazolyl, pyrazinoimidazolyl and pyrimidonyl, wherein R 3 Optional 1, 2 or 3 R 31 replace;

[0386] Ring A is selected from the group consisting of oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, triazolylene, tetrazolylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene, pyridazinoimidazolylene, pyrazinoimidazolylene and pyrimidinonylene, and the ring A is optionally substituted by 1, 2 or 3 R 31 replace;

[0387] R 4 is selected from hydrogen, fluorine, chlorine, cyano, -OH and -NH2;

[0388] X is selected from O;

[0389] Structural unit for

[0390] R 5 is selected from hydrogen, -OH, -NH2 and -CH2NH2;

[0391] R 6 is selected from hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2, cyclopropyl and -O-methyl;

[0392] or R 5 and R 6 The atoms connected to it form Where * indicates the connected atomic positions;

[0393] Alternatively, Ring B is * terminal is connected to Q;

[0394] Structural unit for

[0395] R 7 each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NH(C1-C4)alkyl, -(C1-C4)alkylene-N[(C1-C4)alkyl]2 and -(C1-C4)alkylene-NH2;

[0396] m is 1, 2, or 3;

[0397] Alternatively, Ring C is * end is connected to M;

[0398] R 8a for

[0399] R 8b selected from hydrogen, -methylene-R, -methylene-N(R)R, -C(=O)OR, -C(=O)N(R)R and -C(=O)R, R is as defined in any embodiment of the present invention, for example, each R is independently selected from hydrogen, -OH, methyl, ethyl, -O-methyl, -C(=O)-methyl, -S(=O)2-methyl, azetidinyl, pyrrolidinyl and piperazinyl, each of the foregoing groups being independently optionally substituted with 1, 2 or 3 groups selected from -OH and -NH2;

[0400] R 9a is selected from hydrogen, -CN, -N(R)R, -NHC(=O)R, -methylene-N(R)R, -methylene-NHC(=O)R and -methylene-NHC(=O)NHR, R is as defined in any embodiment of the present invention, for example, each R is independently selected from hydrogen, -OH, methyl, ethyl, -methylene-O-ethyl, -S(=O)2-methyl, cyclobutyl, azetidinyl, -methylene-cyclobutyl and -methylene-azetidinyl, each of the foregoing groups being optionally substituted with 1, 2 or 3 groups selected from -OH, OCH3, NHCH3, N(CH3)2 and CH3;

[0401] R 9b is selected from hydrogen and

[0402] R 10 for

[0403] In certain embodiments, the compound of the structure shown in the above general formula, wherein:

[0404] M is selected from -NH-, -O-, -CH2O- and -CH2NH-;

[0405] n is 0 or 1;

[0406] W is absent or selected from methylene, ethylene, -NH-, -N(Me)-, and -N(Et)-;

[0407] U is selected from the group consisting of methylene, ethylene, cyclopropyl, azetidinyl, and pyrrolidinyl;

[0408] Z is absent or selected from methylene, ethylene, cyclopropyl, azetidinyl, and pyrrolidinyl;

[0409] Y is selected from -O-, -N(R y )- and -N + (R y )2-,R y is selected from hydrogen, methyl, ethyl and -O-methyl;

[0410] R 12 is selected from hydrogen, methyl and ethyl;

[0411] L is absent or selected from -C(=O)CH2O-, -C(=O)CH2CH2O-, -C(=O)CH2N(R L )-、-C(=O)CH2CH2N(R L )-、-C(=O)CH2N + (R L )2- and -C(=O)CH2CH2N + (R L )2-,R L is selected from hydrogen, methyl and ethyl;

[0412] Q is selected from -NH-;

[0413] T is selected from -NH-;

[0414] X 1 C(R 1 ) and N;

[0415] R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, cyano, -OH, methyl, ethyl, propyl, -O-methyl, -O-ethyl, and -O-propyl;

[0416] X 2 Selected from CH;

[0417] R 31 is selected from the group consisting of hydrogen, fluorine, chlorine, cyano, -OH, -SH, -NH2, -CH2OH, -CH2NH2, methyl, trifluoromethyl and -O-methyl;

[0418] R 3 Selected from The R 3 Optional 1, 2 or 3 R 31 replace;

[0419] Ring A selection The * end is connected to T;

[0420] R 4 is hydrogen;

[0421] X is O;

[0422] Structural unit for

[0423] R 5 selected from hydrogen and -NH2;

[0424] R 6 is selected from hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2, cyclopropyl and -O-methyl;

[0425] or R 5 and R 6 The atoms connected to it form Where * indicates the connected atomic positions;

[0426] Alternatively, Ring B is * terminal is connected to Q;

[0427] Structural unit for

[0428] Alternatively, Ring C is * end is connected to M;

[0429] R 7 are each independently selected from hydrogen, fluorine, chlorine, bromine, -OH and -NH2;

[0430] R 8a for

[0431] R 8b Selected from hydrogen,

[0432] R 9a Selected from hydrogen,

[0433] R 9b Selected from hydrogen and

[0434] R 10 for

[0435] In certain embodiments, the compound of the structure shown in the above general formula, wherein:

[0436] M is selected from -NH-, -O-, *-CH2O- and *-CH2NH-, wherein the * end is connected to the ring C;

[0437] n is 0 or 1;

[0438] W is absent or selected from -NH- and -N(Me)-;

[0439] U is selected from methylene, ethylene and

[0440] Z does not exist;

[0441] Y is selected from -O-, -NH-, -N(CH3)- and -N + (CH3)2-;

[0442] The structural unit -WUZY- is selected from *-NH-CH2-CH2-NH-, *-NH-CH2-CH2-O-, *-CH2-O-, *-CH2-NH-, *-CH2-N(CH3)-, *-CH2-N + (CH3)2-, Among them, the * end is connected to the carbonyl group;

[0443] R 12 is selected from hydrogen and methyl;

[0444] L is absent or selected from *-C(=O)CH2O-, *-C(=O)CH2N(CH3)-, *-C(=O)CH2N + (CH3)2-, where the * end is connected to N;

[0445] Q is selected from -NH-;

[0446] T is selected from -NH-;

[0447] X 1 Selected from C(R 1 ) and N;

[0448] R 1 Selected from -O-methyl;

[0449] X 2 Selected from CH;

[0450] R 3 Selected from

[0451] Ring A is selected from The * end is connected to T;

[0452] R 4 is hydrogen;

[0453] X is O;

[0454] Structural unit for

[0455] R 5 selected from hydrogen;

[0456] R 6 is selected from cyano and -O-methyl;

[0457] Or, R 5 and R 6 The atoms connected to it form Where * indicates the connected atomic positions;

[0458] Alternatively, Ring B is * terminal is connected to Q

[0459] Structural unit for

[0460] R 7 is hydrogen;

[0461] Alternatively, Ring C is * end is connected to M;

[0462] R 8a for

[0463] R 8b Selected from hydrogen,

[0464] R 9a For hydrogen,

[0465] R 9b for

[0466] R 10 for

[0467] In certain embodiments, the drug group is selected from the structures shown in Formula IA-5, II-A-5, III-A-5, IV-A-5, or VA-5:

[0468] Among them, X, R1 , Ring A, R 3 、R 5 、R 6 、R 7 、R 8b 、R 9a 、R 9b 、R 12 , n, M, W, U, Z, Y, L, Q and T are as defined in any embodiment of the present invention.

[0469] In certain embodiments, the compound of formula IA-5, II-A-5, III-A-5, IV-A-5 or VA-5, wherein:

[0470] M is selected from -NH-, -O-, *-CH2O- and *-CH2NH-, wherein the * end is connected to the ring C;

[0471] n is 0 or 1;

[0472] W is absent or selected from -NH- and -N(Me)-;

[0473] U is selected from methylene, ethylene and

[0474] Z does not exist;

[0475] Y is selected from -O-, -NH-, -N(CH3)- and -N + (CH3)2-;

[0476] The structural unit -WUZY- is selected from *-NH-CH2-CH2-NH-, *-NH-CH2-CH2-O-, *-CH2-O-, *-CH2-NH-, *-CH2-N(CH3)-, *-CH2-N + (CH3)2-, Among them, the * end is connected to the carbonyl group;

[0477] R 12 is selected from hydrogen and methyl;

[0478] L is absent or selected from *-C(=O)CH2O-, *-C(=O)CH2N(CH3)-, *-C(=O)CH2N + (CH3)2-, where the * end is connected to N;

[0479] Q is selected from -NH-;

[0480] T is selected from -NH-;

[0481] X is O;

[0482] R 1is selected from hydrogen, halogen, cyano, -OH, -(C1-C4)alkyl and -O-(C1-C4)alkyl. In certain embodiments, the R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, cyano, -OH, methyl, ethyl, propyl, -O-methyl, -O-ethyl, and -O-propyl;

[0483] R 3 is selected from oxazolyl, pyrazolyl and pyrimidinyl, in certain embodiments, said R 3 Selected from R 3 Optional 1, 2 or 3 R 31 replace;

[0484] Ring A is selected from -(5-6 membered)heteroarylene-, wherein the -(5-6 membered)heteroarylene- is optionally substituted by 1, 2, 3 or 4 R 31 replace;

[0485] R 31 are each independently selected from hydrogen, fluorine, chlorine, cyano, -OH, -SH, -NH2, -CH2OH, -CH2NH2, -CH3, -CF3 and -OCH3;

[0486] Or, R 3 Selected from

[0487] Alternatively, Ring A is selected from The * end is connected to T;

[0488] R 5 is hydrogen or -NH2;

[0489] R 6 is selected from hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2, cyclopropyl and -O-methyl;

[0490] or R 5 and R 6 The atoms connected to it form Where * indicates the connected atomic positions;

[0491] R 7 are each independently selected from hydrogen, fluorine, chlorine, bromine, -OH and -NH2;

[0492] R 8bis selected from hydrogen, -methylene-R, -methylene-OR, -methylene-N(R)R, -C(=O)R, -C(=O)OR and -C(=O)N(R)R, R is defined as described in any embodiment of the present invention, for example, R is independently selected from hydrogen, -OH, -NH2, -(C1-C4)alkyl, -O-(C1-C4)alkyl, -C(=O)-(C1-C4)alkyl, -S(=O)2(C1-C4)alkyl and -(4-8 membered)heterocyclyl, wherein the -(C1-C4)alkyl and -(4-8 membered)heterocyclyl are optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -NH2, -NHCH3 and CH3, and in certain embodiments, the R 8b Selected from hydrogen,

[0493] R 9a is selected from hydrogen, -CN, -N(R)R, -NHC(=O)R, -methylene-N(R)R, -methylene-NHC(=O)R and -methylene-NHC(=O)NHR, R is defined as described in any embodiment of the present invention, for example, each R is independently selected from hydrogen, -OH, methyl, ethyl, -methylene-O-ethyl, -S(=O)2-methyl, cyclobutyl, azetidinyl, -methylene-cyclobutyl and -methylene-azetidinyl, each of the foregoing groups is independently optionally substituted by 1, 2 or 3 groups selected from -OH, OCH3, NHCH3, N(CH3)2 and CH3, in certain embodiments, the R 9a Selected from hydrogen,

[0494] R 9b Selected from hydrogen and

[0495] In certain embodiments, the drug group is selected from the structures represented by Formula IA-6 and IA-7:

[0496] Among them, R 1 、R 31 、R 5 、R 6 、R 8b 、R 9a 、R 9b and M are as defined in any embodiment of the present invention.

[0497] In certain embodiments, the R 8b 、R 9a is hydrogen, R 9b As described in any embodiment of the present invention.

[0498] In certain embodiments, the R 8b 、R 9b is hydrogen, R 9a As described in any embodiment of the present invention.

[0499] In certain embodiments, the R 9a is hydrogen, R 8b 、R 9b As described in any embodiment of the present invention, and R 8b 、R 9b None of them are hydrogen.

[0500] In certain embodiments, the R 31 For hydrogen.

[0501] In certain embodiments, the drug group is selected from the structures shown in Table A:

[0502] Table A

[0503] In certain embodiments, the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein the linking group is -Tr-L 3 -L 2 -L 1 -,in:

[0504] Tr does not exist or Tr is any group;

[0505] L 3 Absent or selected from polypeptide fragments and peptide fragment analogs;

[0506] L 2 Not present or selected from the junction fragment;

[0507] L 1 For the connection unit.

[0508] In certain embodiments, the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein the linking group is -Tr-L 3 -L 2 -L 1 -,in:

[0509] Tr does not exist or Tr is any group;

[0510] L 3 Not present or selected from polypeptide fragments;

[0511] L 2 Not present or selected from the junction fragment;

[0512] L 1 For the connection unit.

[0513] In certain embodiments, the linker group and the drug group are connected to form a structure selected from the group consisting of:

[0514] in,

[0515] X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 , M, Tr, L 3 , L 2 and L 1 The definition of is as described in any embodiment of the present invention;

[0516] The wavy line indicates the L 1 The nitrogen atom or carbon atom on the group is connected to the ligand.

[0517] In certain embodiments, the linker group and the drug group are connected to form a structure selected from the group consisting of:

[0518] in,

[0519] X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 ,m,n,W,U,Z,Y,Tr,L 3 , L 2 and L 1 The definition of is as described in any embodiment of the present invention;

[0520] The wavy line indicates the L 1 The nitrogen atom or carbon atom on the group is connected to the ligand.

[0521] In certain embodiments, the linker group and the drug group are connected to form a structure selected from Formula II-B,

[0522] in,

[0523] X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 、m、W、U、Z、Y、Tr、L 3 、L 2 and L 1 The definition of is as described in any embodiment of the present invention;

[0524] The wavy line indicates the L 1 The nitrogen atom or carbon atom on the group is connected to the ligand.

[0525] In certain embodiments, the linker group and the drug group are connected to form a structure selected from the group consisting of:

[0526] in,

[0527] X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 12 ,L,m,Tr,L 3 、L 2 and L 1 The definition of is as described in any embodiment of the present invention;

[0528] The wavy line indicates the L 1 The nitrogen atom or carbon atom on the group is connected to the ligand.

[0529] In certain embodiments, the linker group and the drug group are connected to form a structure selected from Formula III-B,

[0530] in,

[0531] X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R5 、R 6 、R 7 、R 8a 、R 8b 、R 12 ,m,Tr,L 3 、L 2 and L 1 The definition of is as described in any embodiment of the present invention;

[0532] The wavy line indicates the L 1 The nitrogen atom or carbon atom on the group is connected to the ligand.

[0533] In certain embodiments, the linker group and the drug group are connected to form a structure selected from Formula IV-B,

[0534] in,

[0535] X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 ,m,Q,Tr,L 3 、L 2 and L 1 The definition of is as described in any embodiment of the present invention;

[0536] The wavy line indicates the L 1 The nitrogen atom or carbon atom on the group is connected to the ligand.

[0537] In certain embodiments, the linker group and the drug group are connected to form a structure selected from the group consisting of:

[0538] in,

[0539] X, X 1 、X 2 , Ring A, Ring B, Ring C, R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 、m、T、Tr、L 3 、L 2 and L 1The definition of is as described in any embodiment of the present invention;

[0540] The wavy line indicates the L 1 The nitrogen atom or carbon atom on the group is connected to the ligand.

[0541] In certain embodiments, the linker group and the drug group are connected to form a structure wherein:

[0542] L 1 is a connection unit;

[0543] L 2 -(C(R L21 )2) r -, r is a natural number from 0 to 50,

[0544] L 2 Any C(R L21 )2 units can be independently replaced by the following structural units: -Cy-, -C(=O)-, -NR L22 -, -O-, -S-, -S(=O)-, -S(=O)2-, -P(R L22 )-、-P(=O)(R L22 )-、-C(=S)-、-C(=NR L22 )-, -N=N-, -CH=N-, -N=CH-,

[0545] -Cy- is selected from -phenylene-, -(5-8 membered)heteroarylene-, -(4-10 membered)heterocyclylene- and -(C3-C 10 ) cycloalkylene-, wherein said -Cy- is unsubstituted or each independently substituted with one or more R Cx replace,

[0546] Each R L21 、R L22 and R Cx are each independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OR L2a 、-SR L2a 、-N(R L2a )2, -N + (R L2a )3, -C(=O)R L2a 、-C(=O)OR L2a 、-C(=O)-C(=O)R L2a 、-C(=O)CH2C(=O)R L2a 、-S(=O)R L2a 、-S(=O)2R L2a 、-C(=O)N(R L2a)2、-S(=O)2N(R L2a )2, -OC(=O)R L2a 、-N(R L2a )S(=O)2R L2b 、-N(R L2a )C(=O)R L2b 、-(CH2) y -C(=O)-(N(Me)CH2C(=O)) s -OR L2a 、-(CH2) y -C(=O)-(N(Me)CH2C(=O)) s -NHR L2a 、-(CH2) y -C(=O)-(N(Me)CH2C(=O)) s -N + (R L2a )3, -(CH2) y -NHC(=O)CH2(OCH2CH2)OR L2a 、-(CH2) y -NH(C(=O)CH2(N(Me)) s -R L2a 、-(CH2) y -C(=O)NH-(CH2CH2O) s -R L2a 、-(CH2) y -NHC(=O)-(CH2CH2O) s -R L2a 、-(CH2CH2O) s -R L2a 、-(C(=O)CH2N(Me)) s -R L2a 、-C(=O)CH2(OCH2CH2) s -OR L2a 、-C(=O)-(CH2CH2O) m -R L2a 、-C(=O)-(CH2) y -C(=O)NH-(CH2CH2O) s -R L2a 、-C(=O)-(CH2) y -NHC(=O)-(CH2CH2O) s -R L2a , -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C10 )aryl and -(5-10 membered)heteroaryl, the -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl are optionally substituted by one or more R L2a replace,

[0547] s and y are each independently a natural number between 0 and 50,

[0548] R L2a and R L2b Each is independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OH, -SH, -NH2, -N(Me)2, -C(=O)OH, -S(=O)2Me, -S(=O)2OH, -C(=O)NH2, -S(=O)2NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl;

[0549] L 3 does not exist, or is selected from amino acid residues, short peptides consisting of 2-10 amino acid residues, -C(=O)-(C1-C6)alkylene-NH-, and any combination of the aforementioned groups, wherein the amino acid residue is a natural amino acid residue or a non-natural amino acid residue, L 3 Optionally modified with one or more protecting groups, in certain embodiments, the protecting groups are selected from a polyethylene glycol fragment and -OtBu, wherein the polyethylene glycol fragment is linked to L via a structural unit -NH- 3 ;

[0550] Tr does not exist, or is selected from and any combination of the foregoing groups,

[0551] R Tr 、R Tr1 and R Tr2 Each is independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH2, -SH, -OC(=O)NH2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -CH2C(=O)-(N(Me)CH2C(=O)) z -OR Tra , -CH2C(=O)-(N(Me)CH2C(=O))z -NHR Tra 、-(CH2CH2O) z -R Tra 、-C(=O)NH-(CH2CH2O) z -R Tra , -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl, the -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl are optionally substituted by one or more R Tra replace;

[0552] Each R Tra are independently hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH2, -SH, -N(Me)2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2Me, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl,

[0553] Each z is independently a natural number between 0 and 50.

[0554] In certain embodiments, the linker group and the drug group are connected to form a structure wherein:

[0555] L 1 is a connection unit;

[0556] L 2 -(C(R L21 )2) r -, r is a natural number from 0 to 50,

[0557] L 2 Any C(R L21 )2 units can be independently replaced by the following structural units: -Cy-, -C(=O)-, -NR L22 -, -O-, -S-, -S(=O)-, -S(=O)2-, -P(R L22 )-、-P(=O)(R L22 )-、-C(=S)-、-C(=NR L22)-, -N=N-, -CH=N-, -N=CH-,

[0558] -Cy- is selected from -phenylene-, -(5-8 membered)heteroarylene-, -(4-10 membered)heterocyclylene- and -(C3-C 10 ) cycloalkylene-, wherein said -Cy- is unsubstituted or each independently substituted with one or more R Cx replace,

[0559] Each R L21 、R L22 and R Cx are each independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OR L2a 、-SR L2a 、-N(R L2a )2, -N + (R L2a )3, -C(=O)R L2a 、-C(=O)OR L2a 、-C(=O)-C(=O)R L2a 、-C(=O)CH2C(=O)R L2a 、-S(=O)R L2a 、-S(=O)2R L2a 、-C(=O)N(R L2a )2、-S(=O)2N(R L2a )2, -OC(=O)R L2a 、-N(R L2a )S(=O)2R L2b 、-N(R L2a )C(=O)R L2b 、-(CH2) y -C(=O)-(N(Me)CH2C(=O)) s -OR L2a 、-(CH2) y -C(=O)-(N(Me)CH2C(=O)) s -NHR L2a 、-(CH2) y -C(=O)-(N(Me)CH2C(=O)) s -N + (R L2a )3, -(CH2) y -NHC(=O)CH2(OCH2CH2)OR L2a 、-(CH2) y -NH(C(=O)CH2(N(Me)) s -R L2a 、-(CH2)y -C(=O)NH-(CH2CH2O) s -R L2a 、-(CH2) y -NHC(=O)-(CH2CH2O) s -R L2a 、-(CH2CH2O) s -R L2a 、-(C(=O)CH2N(Me)) s -R L2a 、-C(=O)CH2(OCH2CH2) s -OR L2a 、-C(=O)-(CH2CH2O) m -R L2a 、-C(=O)-(CH2) y -C(=O)NH-(CH2CH2O) s -R L2a 、-C(=O)-(CH2) y -NHC(=O)-(CH2CH2O) s -R L2a , -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl, the -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl are optionally substituted by one or more R L2a replace,

[0560] s and y are each independently a natural number between 0 and 50,

[0561] R L2a and R L2b Each is independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OH, -SH, -NH2, -N(Me)2, -C(=O)OH, -S(=O)2Me, -S(=O)2OH, -C(=O)NH2, -S(=O)2NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl;

[0562] L 3does not exist, or is selected from amino acid residues, short peptides consisting of 2-10 amino acid residues, and any combination of the aforementioned groups, wherein the amino acid residue is a natural amino acid residue or a non-natural amino acid residue, L 3 Optionally modified with one or more protecting groups, in certain embodiments, the protecting groups are selected from a polyethylene glycol fragment and -OtBu, wherein the polyethylene glycol fragment is linked to L via a structural unit -NH- 3 ;

[0563] Tr does not exist, or is selected from and any combination of the foregoing groups,

[0564] R Tr 、R Tr1 and R Tr2 Each is independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH2, -SH, -OC(=O)NH2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -CH2C(=O)-(N(Me)CH2C(=O)) z -OR Tra , -CH2C(=O)-(N(Me)CH2C(=O)) z -NHR Tra 、-(CH2CH2O) z -R Tra 、-C(=O)NH-(CH2CH2O) z -R Tra , -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl, the -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl are optionally substituted by one or more R Tra replace;

[0565] Each R Traare independently hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH2, -SH, -N(Me)2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2Me, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl,

[0566] Each z is independently a natural number between 0 and 50.

[0567] In certain embodiments, the L 1 is selected from carbonyl, -(C1-C8)alkylene-C(=O)-, -(4-8 membered)heterocyclylene-, -(5-10 membered)heteroarylene- and -(C1-C8)alkylene-(5-10 membered)heteroarylene-, said -(C1-C8)alkylene-C(=O)-, -(4-8 membered)heterocyclylene-, -(5-10 membered)heteroarylene- and -(C1-C8)alkylene-(5-10 membered)heteroarylene- being optionally substituted with 1, 2 or 3 oxo, -(C1-C4)alkylene- and -(C1-C4)alkyl.

[0568] In certain embodiments, the L 1 is selected from carbonyl, -(C1-C4)alkylene-C(=O)-, -(5-6 membered)heterocyclylene-, -(5-6 membered)heteroarylene- and -(C1-C4)alkylene-(5-6 membered)heteroarylene-, said -(C1-C4)alkylene-C(=O)-, -(5-6 membered)heterocyclylene-, -(5-6 membered)heteroarylene- and -(C1-C4)alkylene-(5-6 membered)heteroarylene- being optionally substituted with 1, 2 or 3 oxo, -(C1-C4)alkylene- and -(C1-C4)alkyl.

[0569] In certain embodiments, the L 1 Selected from

[0570] In certain embodiments, the L 1 Selected from

[0571] In certain embodiments, the L 1 Selected from Among them, * end and L 2 connected.

[0572] In certain embodiments, the L 1 Selected from Among them, * end and L 2 connected.

[0573] In certain embodiments, the L 2 -(C(R L21 )2) r -, r is a natural number from 0 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9),

[0574] L 2 Any C(R L21 )2 units can be independently replaced by the following structural units: -Cy-, -C(=O)-, -NR L22 -, -O-, -S-, -S(=O)-,

[0575] -Cy- is selected from -phenylene-, -4-6 membered heterocyclylene- and -(C3-C6)cycloalkylene-, wherein said -Cy- is unsubstituted or each independently substituted by 1, 2, 3, 4, 6 or 7 R Cx replace,

[0576] Each R L21 、R L22 and R Cx are each independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OR L2a 、-SR L2a 、-N(R L2a )2, -C(=O)R L2a 、-C(=O)OR L2a 、-C(=O)-C(=O)R L2a 、-C(=O)CH2C(=O)R L2a 、-S(=O)R L2a 、-S(=O)2R L2a 、-C(=O)N(R L2a )2、-S(=O)2N(R L2a )2, -(CH2)2-C(=O)NH-(CH2CH2O) t -R L2a , -(C1-C6)alkyl and -(C2-C6)alkenyl, wherein the -(C1-C6)alkyl and -(C2-C6)alkenyl groups are optionally substituted by 1, 2, 3, 4, 5, 6 or 7 R L2a replace,

[0577] t is a natural number between 0 and 30,

[0578] R L2aSelected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, -CN, -OH, -SH, -NH2, -N(Me)2, -C(=O)OH, -S(=O)2Me, -S(=O)2OH, -C(=O)2OH, -C(=O)NH2, -S(=O)2NH2, methyl, ethyl and vinyl.

[0579] In certain embodiments, the L 2 -(C(RL 21 )2) r -, r is a natural number from 0 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, or 8),

[0580] L 2 Any C(R L21 )2 units can be independently replaced by the following structural units: -Cy-, -C(=O)-, -NR L22 -, -O-, -S-, -S(=O)-,

[0581] -Cy- is selected from -phenylene-, -4-6 membered heterocyclylene- and -(C3-C6)cycloalkylene-, wherein said -Cy- is unsubstituted or each independently substituted by 1, 2, 3, 4, 6 or 7 R Cx replace,

[0582] Each R L21 、R L22 and R Cx are each independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OR L2a 、-SR L2a 、-N(R L2a )2, -C(=O)R L2a 、-C(=O)OR L2a 、-C(=O)-C(=O)R L2a 、-C(=O)CH2C(=O)R L2a 、-S(=O)R L2a 、-S(=O)2R L2a 、-C(=O)N(R L2a )2、-S(=O)2N(R L2a )2, -(CH2)2-C(=O)NH-(CH2CH2O) t -R L2a , -(C1-C6)alkyl and -(C2-C6)alkenyl, wherein the -(C1-C6)alkyl and -(C2-C6)alkenyl groups are optionally substituted by 1, 2, 3, 4, 5, 6 or 7 R L2a replace,

[0583] t is a natural number between 0 and 30,

[0584] R L2a Selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, -CN, -OH, -SH, -NH2, -N(Me)2, -C(=O)OH, -S(=O)2Me, -S(=O)2OH, -C(=O)2OH, -C(=O)NH2, -S(=O)2NH2, methyl, ethyl and vinyl.

[0585] In certain embodiments, the L 2 -(C(R L21 )2) r -, r is 2, 3, 4, 5, 6, 7, 8 or 9, L 2 Any C(R L21 )2 units can be independently replaced by the following structural units: -Cy-, -C(=O)-, -NR L22 -, -O-, -S-, -S(=O)-,

[0586] -Cy- is selected from cyclopropylene, cyclobutylene, cyclopentylene, azetidinylene, pyrrolidinylene, piperazinylene or piperidinylene, wherein said -Cy- is unsubstituted or each independently substituted by 1, 2, 3, 4 or 5 R Cx Substitute, for example, -Cy- for

[0587] Each R L21 、R L22 and R Cx Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, -CN, -OH, -SH, -NH2, -C(=O)OH, -C(=O)NH, -(CH2)2-C(=O)NH-(CH2CH2O) 11 -CH3, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, halogenated methyl, halogenated ethyl, methyl-OH, ethyl-OH, propyl-OH, vinyl-OH, vinyl, deuterated vinyl, halogenated vinyl.

[0588] In certain embodiments, the L 2 -(C(RL 21 )2) r -, r is 2, 3, 4, 5, 6, 7 or 8,

[0589] L 2 Any C(R L21 )2 units can be independently replaced by the following structural units: -Cy-, -C(=O)-, -NR L22 -, -O-, -S-, -S(=O)-,

[0590] -Cy- is selected from cyclopropylene, cyclobutylene, cyclopentylene, azetidinylene, pyrrolidinylene, piperazinylene or piperidinylene, wherein said -Cy- is unsubstituted or each independently substituted by 1, 2, 3, 4 or 5 R Cx Substitute, for example, -Cy- for

[0591] Each R L21 、R L22 and R Cx Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, -CN, -OH, -SH, -NH2, -C(=O)OH, -C(=O)NH, -(CH2)2-C(=O)NH-(CH2CH2O) 11 -CH3, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, halogenated methyl, halogenated ethyl, methyl-OH, ethyl-OH, propyl-OH, vinyl-OH, vinyl, deuterated vinyl, halogenated vinyl.

[0592] In certain embodiments, the L 2 Selected from

[0593] In certain embodiments, the L 2 Selected from

[0594] In certain embodiments, the L 2 Selected from Among them, the * end is connected to L3.

[0595] In certain embodiments, the L 2 Selected from *, where * end L3 is connected.

[0596] In certain embodiments, the L 2 Selected from Among them, the * end is connected to L3.

[0597] In certain embodiments, the L 2 Selected from Among them, the * end is connected to L3.

[0598] In certain embodiments, the -L 1 -L 2 -Selected from:

[0599] In certain embodiments, the -L1 -L 2 -Selected from:

[0600] In certain embodiments, the -L 1 -L 2 -Selected from: Among them, the * end is connected to L3.

[0601] In certain embodiments, the -L 1 -L 2 -Selected from: Among them, the * end is connected to L3.

[0602] In certain embodiments, the -L 1 -L 2 -Selected from: Among them, the * end is connected to L3.

[0603] In certain embodiments, the -L 1 -L 2 -Selected from: Among them, the * end is connected to L3.

[0604] In certain embodiments, the amino acid residue is selected from Val, D-Val, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, Arg, and Ser,

[0605] The short peptide consisting of 2-10 amino acid residues is selected from -Arg-Val-, -Arg-Leu-, -Val-Cit-, -Val-Ala-, -Val-Lys-, -Val-Lys(AC)-, -Phe-Lys-, -Phe-Lys(AC)-, -Leu-Lys-, -Leu-Lys(AC)-, -Ala-Ala-, -Ala-Lys-, -(D-Ala)-Ala-, -Gly-G lu-, -Gly-Asp-, -Gly-Asn-, -Val-Glu-, -Val-Asp-, -Asn-Asn-, -Asp-Asp-, -Asp-Glu-, -Ser-Val-, -S er-Ala-, -Ser-Gly-, -Ser-Glu-, -Ser-Gln-, -Ser-Asp-, -Gly-Gln-, -Asn-Gly-, -Asn-Ala-, -Ala-Ala- Glu-, -Gly-Gly-Glu-, -Gly-Gly-Asp-, -Gly-Gly-Asn-, -Gly-Ala-Ala-, -Gly-Val-Ala-, -Gly-Val-Ci t-, -Glu-Val-Cit-, -Ala-Ala-Ala-, -Ala-(D-Ala)-Ala-, -Ala-Ala-Asn-, -Ala-(D-Ala)-Asn-, -Ala-A la-Asp-, -Val-Lys-Gly-, -(D-Val)-Leu-Lys-, -Gly-Gly-Arg-, -Gly-Gly-Gly-, -Lys-Ala-Asn-, -Gly -Phe-Gly-, -Gly-Gly-Phe-, -Asn-Pro-Val-, -Ala-Lys-Gly-, -Gly-Lys-Gly-, -Gly-Gly-Gly-Gly-(SEQ ID NO:61), -Gly-Gly-Phe-Gly-(SEQ ID NO:62), -Gly-Gly-Glu-Gly-(SEQ ID NO:63), -Lys-Ala-Ala-Asn-(SEQ ID NO:64), -Lys-Ala-Ala-Asp-(SEQ ID NO:65), -Ala-Ala-Pro-Val-(SEQ ID NO:65) NO: 66), -Ala-Ala-Pro-Nva- (SEQ ID NO: 67),

[0606] The polyethylene glycol segment is selected from -(CH2CH2O) t -R L3 , R L3is -(C1-C6)alkyl, and t is an integer of 6-30.

[0607] In certain embodiments, the amino acid residue is selected from Val, D-Val, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, Arg, and Ser,

[0608] The short peptide consisting of 2-10 amino acid residues is selected from -Arg-Val-, -Arg-Leu-, -Val-Cit-, -Val-Ala-, -Val-Lys-, -Val-Lys(AC)-, -Phe-Lys-, -Phe-Lys(AC)-, -Leu-Lys-, -Leu-Lys(AC)-, -Ala-Ala-, -Ala-Lys-, -(D-Ala)-Ala-, -Gly-Glu-, -Gly-Asp-, -Gl y-Asn-, -Val-Glu-, -Val-Asp-, -Asn-Asn-, -Asp-Asp-, -Asp-Glu-, -Ser-Ala-, -Ser-Gly-, -Ser-Glu-, -Ser-As p-, -Gly-Gln-, -Ala-Ala-Glu-, -Gly-Gly-Glu-, -Gly-Gly-Asp-, -Gly-Gly-Asn-, -Gly-Ala-Ala-, -Gly-Val-Ala -, -Gly-Val-Cit-, -Glu-Val-Cit-, -Ala-Ala-Ala-, -Ala-(D-Ala)-Ala-, -Ala-Ala-Asn-, -Ala-(D-Ala)-Asn-, -Ala-Ala-Asp-, -Val-Lys-Gly-, -(D-Val)-Leu-Lys-, -Gly-Gly-Arg-, -Gly-Gly-Gly-, -Lys-Ala-Asn-, -Gly-Ph e-Gly-, -Gly-Gly-Phe-, -Asn-Pro-Val-, -Ala-Lys-Gly-, -Gly-Lys-Gly-, -Gly-Gly-Gly-Gly-, -Gly-Gly-Phe- Gly-, -Gly-Gly-Glu-Gly-, -Lys-Ala-Ala-Asn-, -Lys-Ala-Ala-Asp-, -Ala-Ala-Pro-Val-, -Ala-Ala-Pro-Nva-,

[0609] The polyethylene glycol segment is selected from -(CH2CH2O) t -R L3 , RL3 is a -(C1-C6) alkyl group, and t is an integer from 6 to 30.

[0610] In certain embodiments, the L 3 is selected from Val, D-Val, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, Arg, Ser, -Arg-Val-, -Arg-Leu-, -Val-Cit-, -Val-Ala-, -Val-Lys-, -Val-Lys(AC)-, -Phe-Lys-, -Phe-Lys(AC)-, -Leu-Lys-, -Leu-Lys(AC)-, -Ala-Ala-, -Ala-Lys-, -(D-Ala)-Ala-, -Gly-Glu-, -Gly-Asp-, -Gly-Asn-, -Val-Glu-, -Val-Asp-, -Asn-Asn-, -Asp-Asp-, -Asp-Glu-, -Ser-Val-, -Ser-Ala-, -Ser-Gly-, -Ser-Glu-, -Ser-Gln-, -Ser-Asp-, -Gly-Gln-, -Asn-Gly-, -Asn-Ala-, -Ala-Ala-Glu-, -Gly-Gly-Glu-, -Gly-Gly-Asp-, -Gly-Gly-Asn-, -Gly-Ala-Ala-, -Gly-Val-Ala-, -Gly-Val-Cit-, -Glu-Val-Cit-, -Ala-Ala-Ala-, -Ala-(D-Ala)-Ala-, -Ala-Ala-Asn-, -Ala-(D-Ala)-Asn-, -Ala-Ala-Asp-, -Val-Lys-Gly-, -(D-Val)-Leu-Lys-, -Gly-Gly-Arg-, -Gly-Gly-Gly-, -Lys-Ala-Asn-, -Gly-Phe-Gly-, -Gly-Gly-Phe-, -Asn-Pro-Val-, -Ala-Lys-Gly-, -Gly-Lys-Gly-, -Gly-Gly-Gly-Gly-, -Gly-Gly-Phe-Gly-, -Gly-Gly-Glu-Gly-, -Lys-Ala-Ala-Asn-, -Lys-Ala-Ala-Asp-, -Ala-Ala-Pro-Val-, -Ala-Ala-Pro-Nva- -C(=O)-(C1-C4)alkylene-NH- and any combination of the aforementioned groups, wherein the Asp and Glu are each independently optionally replaced by -(CH2CH2O) t -R L3 Modification, where (CH2CH2O) t -R L3 Connected to Asp or Glu through the structural unit -NH-, R L3 is -(C1-C4)alkyl, and t is an integer from 6 to 30 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 20, 21, 22, 23, 24, 25).

[0611] In certain embodiments, the L 3Selected from Val, D-Val, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, Arg, -Arg-Val-, -Arg-Leu-, -Val-Cit-, -Va l-Ala-, -Val-Lys-, -Val-Lys(AC)-, -Phe-Lys-, -Phe-Lys(AC)-, -Leu-Lys-, -Leu-Lys(AC)-, -Ala-Ala-, -Ala-Lys-, - D-Ala-Ala-, -Gly-Glu-, -Gly-Asp-, -Gly-Asn-, -Val-Glu-, -Val-Asp-, -Asn-Asn-, -Asp-Asp-, -Asp-Glu-, -Ser-Ala- , -Ser-Gly-, -Ser-Glu-, -Ser-Asp-, -Gly-Gln-, -Ala-Ala-Glu-, -Gly-Gly-Glu-, -Gly-Gly-Asp-, -Gly-Gly-Asn-, -Gl y-Ala-Ala-, -Gly-Val-Ala-, -Gly-Val-Cit-, -Glu-Val-Cit-, -Ala-Ala-Ala-, -Ala-(D-Ala)-Ala-, -Ala-Ala-Asn-, -Ala-(D-Ala)-Asn-, -Ala-Ala-Asp-, -Val-Lys-Gly-, -D-Val-Leu-Lys-, -Gly-Gly-Arg-, -Gly-Gly-Gly-, -Lys-Ala-A sn-, -Gly-Phe-Gly-, -Gly-Gly-Phe-, -Asn-Pro-Val-, -Ala-Lys-Gly-, -Gly-Lys-Gly-, -Gly-Gly-Gly-Gly-, -Gly-Gly -Phe-Gly-, -Gly-Gly-Glu-Gly-, -Lys-Ala-Ala-Asn-, -Lys-Ala-Ala-Asp-, -Ala-Ala-Pro-Val-, -Ala-Ala-Pro-Nva-, and any combination of the foregoing groups, wherein the Asp and Glu are each independently optionally replaced by -(CH2CH2O) t -R L3 Modification, where (CH2CH2O) t -R L3 Connected to Asp or Glu through the structural unit -NH-, R L3is -(C1-C4)alkyl, and t is an integer from 6 to 30 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 20, 21, 22, 23, 24, 25).

[0612] In certain embodiments, the L 3 Selected from -Val-Cit-, -Arg-Val-, -Ala-Ala-, -Val-Ala-, -Gly-Glu-, -Ser-Val-, -Ser-Ala-, -Ser-Gly-, -Ser-Glu-, -Ser-Gln-, -Ser-Asp-, -Gly-Gln-, -Gly-A sp-, -Gly-Asn-, -Asp-Asp-, -Asp-Glu-, -Asn-Gly-, -Asn-Ala-, -Ala-Ala-Ala-, -Ala-Ala-Glu-, -Gly-Ala-Ala-, -Gly-Gly-Glu-, -Gly-Gly-Phe-Gly-, and -C(=O)-(C1-C4)alkylene-NH-, wherein Asp and Glu are each independently optionally replaced by -(CH2CH2O) t -R L3 Modification, where (CH2CH2O) t -R L3 Connected to Asp or Glu through the structural unit -NH-, R L3 is -(C1-C4)alkyl, and t is an integer from 6 to 30 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 20, 21, 22, 23, 24, 25).

[0613] In certain embodiments, the L 3 Selected from -Val-Cit-, -Arg-Val-, -Ala-Ala-, -Val-Ala-, -Gly-Glu-, -Ser-Ala-, -Ser-Gly-, -Ser-Glu-, -Ser-Asp-, -Gly-Gln-, -Gly-A sp-, -Gly-Asn-, -Asp-Asp-, -Asp-Glu-, -Ala-Ala-Ala-, -Ala-Ala-Glu-, -Gly-Ala-Ala-, -Gly-Gly-Glu-, -Gly-Gly-Phe-Gly- or The Asp and Glu are each independently optionally replaced by -(CH2CH2O) t -R L3 Modification, where (CH2CH2O) t -R L3Connected to Asp or Glu through the structural unit -NH-, R L3 is -(C1-C4)alkyl, and t is an integer from 6 to 30 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 20, 21, 22, 23, 24, 25).

[0614] In certain embodiments, the L 3 Selected from -Val-Cit-, -Arg-Val-, -Ala-Ala-, -Val-Ala-, -Gly-Glu-, -Ser-Val-, -Ser-Ala-, -Ser-Gly-, -Ser-Glu-, -Ser-Gln-, -Ser-Asp-, - Gly-Gln-, -Asn-Gly-, -Asn-Ala-, -Ala-Ala-Glu-, -Gly-Ala-Ala-, -Gly-Gly-Glu-, -Gly-Gly-Phe-Gly-, -Ala-Ala-Glu(NH-(CH2CH2O) t -R L3 )- and -C(=O)-CH2CH2-NH-, R L3 is -(C1-C4)alkyl, t is an integer from 6 to 30, for example -Ala-Ala-Glu(NH-(CH2CH2O) 11 -CH3)-or -Ala-Ala-Glu(NH-(CH2CH2O) 24 -CH3)-.

[0615] In certain embodiments, the L 3 Selected from -Val-Cit-, -Arg-Val-, -Ala-Ala-, -Gly-Glu-, -Ser-Ala-, -Ser-Gly-, -Ser-Glu-, -Ser-Asp-, -Gly-G ln-, -Ala-Ala-Glu-, -Gly-Ala-Ala-, -Gly-Gly-Glu-, -Gly-Gly-Phe-Gly-, -Ala-Ala-Glu(NH-(CH2CH2O) t -R L3 )-R L3 is -(C1-C4)alkyl, t is an integer from 6 to 30, for example -Ala-Ala-Glu(NH-(CH2CH2O) 11 -CH3)-or -Ala-Ala-Glu(NH-(CH2CH2O) 24 -CH3)-.

[0616] In certain embodiments, the L 3Selected from -Val-Cit-*, *-Ala-Ala-, -Val-Ala-*, *-Gly-Glu-, *-Ser-Val-, *-Ser-Ala-, *-Ser-Gly-, *-Ser-Glu-, *-Ser-Gln-, *-Ser-Asp-, -Gl y-Gln-*, *-Gly-Gln-, *-Asn-Gly-, *-Asn-Ala-, *-Gly-Ala-Ala-, *-Gly-Gly-Glu-, -Gly-Gly-Phe-Gly-*, *-Ala-Ala-Glu(NH-(CH2CH2O) 11 -CH3)- and Among them, the * end is connected to Tr.

[0617] In certain embodiments, the L 3 Selected from -Val-Cit-*, *-Ala-Ala-, *-Gly-Glu-, *-Ser-Ala-, *-Ser-Gly-, *-Ser-Glu-, *-Ser-Asp-, -Gl y-Gln-*, *-Gly-Ala-Ala-, *-Gly-Gly-Glu-, -Gly-Gly-Phe-Gly-*, *-Ala-Ala-Glu(NH-(CH2CH2O) 11 -CH3)-, where the * end is connected to Tr.

[0618] In certain embodiments, the L 3 Selected from -Val-Cit-*, *-Ala-Ala-, -Val-Ala-*, *-Gly-Glu-, *-Ser-Val-, *-Ser-Ala-, *-Ser-Gly-, *-Ser-Glu-, *-Ser-Gln-, *-Ser-Asp-, -Gly-Gln-*, * -Gly-Gln-, *-Asn-Gly-, *-Asn-Ala-, *-Gly-Ala-Ala-, *-Gly-Gly-Glu-, -Gly-Gly-Phe-Gly-*, *Ala-Ala-C(=O)-CH[CH2CH2-C(=O)-NH-(CH2CH2O) 11 -CH3]-NH- and Among them, the * end is connected to Tr.

[0619] In certain embodiments, the L 3Selected from -Val-Cit-*, *-Ala-Ala-, *-Gly-Glu-, *-Ser-Ala-, *-Ser-Gly-, *-Ser-Glu-, *-Ser-Asp-, -Gly-Gln-*, * -Gly-Ala-Ala-, *-Gly-Gly-Glu-, -Gly-Gly-Phe-Gly-* and *-Ala-Ala-C(=O)-CH[CH2CH2-C(=O)-NH-(CH2CH2O) 11 -CH3]-NH-, where the * end is connected to Tr.

[0620] In certain embodiments, the L 3 Selected from -Glu-Ser-, -Ala-Ser-, -Gly-Ser-, -Asp-Ser-.

[0621] In certain embodiments, the L 3 Selected from *-Ala-Ala-, *-Gly-Glu- and *-Gly-Gly-Glu-, wherein the * end is connected to Tr.

[0622] In certain embodiments, the L 3 Selected from *-Ala-Ala- and Among them, the * end is connected to Tr.

[0623] In certain embodiments, the L 3 Selected from Among them, the * end is connected to Tr.

[0624] In certain embodiments, the Tr is absent or is selected from

[0625] R Tr 、R Tr1 and R Tr2 Each is independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH2, -SH, -OC(=O)NH2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -(CH2CH2O) z -R Tra 、-C(=O)NH-(CH2CH2O) z -R Tra , gluconolactone, glucuronic acid, -(C1-C4)alkyl and -(C2-C4)alkenyl, wherein the -(C1-C4)alkyl and -(C2-C4)alkenyl groups are optionally substituted by 1, 2, 3, 4 or 5 R Tra replace,

[0626] Each R Tra are independently hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH2, -SH, -N(Me)2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2Me, -(C1-C4)alkyl, -(C2-C4)alkenyl,

[0627] Each z is independently an integer from 6 to 30.

[0628] In certain embodiments, the Tr is absent or is selected from

[0629] R Tr 、R Tr1 and R Tr2 Each is independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH2, -SH, -OC(=O)NH2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -(CH2CH2O) z -R Tra 、-C(=O)NH-(CH2CH2O) z -R Tra , -(C1-C4)alkyl and -(C2-C4)alkenyl, wherein the -(C1-C4)alkyl and -(C2-C4)alkenyl groups are optionally substituted by 1, 2, 3, 4 or 5 R Tra replace,

[0630] Each R Tra are independently hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH2, -SH, -N(Me)2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2Me, -(C1-C4)alkyl, -(C2-C4)alkenyl,

[0631] Each z is independently an integer from 6 to 30.

[0632] In certain embodiments, the R Tr 、R Tr1 and R Tr2 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, -CN, -OH, -NH2, -SH, -OC(=O)NH2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -(CH2CH2O) z -R Tra 、-C(=O)NH-(CH2CH2O) z -RTra , gluconolactone, glucuronic acid, methyl, ethyl, -ethylene-OH and -CH2-COOH,

[0633] Each R Tra are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, -CN, -OH, -NH2, -SH, -N(Me)2, -C(=O)OH, -C(=O)NH2, methyl, ethyl,

[0634] Each z is independently an integer from 6 to 30 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 20, 21, 22, 23, 24, 25).

[0635] In certain embodiments, the R Tr 、R Tr1 and R Tr2 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, -CN, -OH, -NH2, -SH, -OC(=O)NH2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -(CH2CH2O) z -R Tra 、-C(=O)NH-(CH2CH2O) z -R Tra , methyl, ethyl, -ethylene-OH and -CH2-COOH,

[0636] Each R Tra are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, -CN, -OH, -NH2, -SH, -N(Me)2, -C(=O)OH, -C(=O)NH2, methyl, ethyl,

[0637] Each z is independently an integer from 6 to 30 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 20, 21, 22, 23, 24, 25).

[0638] In certain embodiments, the R Tr Selected from hydrogen, -CH2-COOH and

[0639] In certain embodiments, the R Tr Selected from hydrogen and -CH2-COOH.

[0640] In certain embodiments, the Tr is absent or is selected from

[0641] In certain embodiments, the Tr is absent or is selected from

[0642] In certain embodiments, the Tr is absent or is selected from Among them, * end and L 3 connected.

[0643] In certain embodiments, the Tr is absent or is selected from Among them, * end and L 3 connected.

[0644] In certain embodiments, the Tr is absent or is Among them, * end and L 3 connected.

[0645] In certain embodiments, the Tr is absent or is Among them, * end and L 3 connected.

[0646] In certain embodiments, the -L 3 -L 2 -L 1 -Selected from:

[0647] In certain embodiments, the -L 3 -L 2 -L 1 -Selected from:

[0648] In certain embodiments, the -L 3 -L 2 -L 1 -Selected

[0649] In certain embodiments, the -L 3 -L 2 -L 1 -Selected

[0650] In certain embodiments, the -Tr-L 3 -L 2 -L 1 -Selected

[0651] In certain embodiments, the -Tr-L 3 -L 2 -L 1 -for

[0652] In certain embodiments, the -Tr-L 3 -L 2 -L 1 -for

[0653] In certain embodiments, the -L 1 -L 2 -L 3 -Selected from:

[0654] In certain embodiments, the -L 1 -L 2 -L 3 -Selected from:

[0655] In certain embodiments, the -L 1 -L 2 -L 3 -Selected

[0656] In certain embodiments, the -L 1 -L 2 -L 3 -Selected

[0657] In certain embodiments, the linker group and the drug group are connected to form a structure selected from the group consisting of IB-1, II-B-1', II-B-1, III-B-1', III-B-1, IV-B-1 or VB-1.

[0658] Among them, X, X 1 、X 2 , Ring A, Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R10 、R 12 ,m,n,M,W,U,Z,Y,L,Q,T,Tr,L 1 , L 2 and L 3 is as defined in any embodiment of the present invention.

[0659] In certain embodiments, the linker group and the drug group are connected to form a structure selected from the group consisting of IB-2, II-B-2', II-B-2, III-B-2', III-B-2, IV-B-2 or VB-2.

[0660] Among them, X, X 1 、X 2 , Ring A, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 、R 12 ,m,n,M,W,U,Z,Y,L,Q,T,Tr,L 1 , L 2 and L 3 is as defined in any embodiment of the present invention.

[0661] In certain embodiments, the linker group and the drug group are connected to form a structure selected from the group consisting of IB-3, III-B-3', III-B-3, IV-B-3, or VB-3.

[0662] Among them, X, X 1 、X 2 , Ring A, R 3 、R 4 、R 5 、R 6 、R 7 、R 8b 、R 9b 、R 12 、m、M、L、Q、T、Tr、L 1 , L 2 and L 3 is as defined in any embodiment of the present invention.

[0663] In certain embodiments, the linker group and the drug group are connected to form a structure selected from the group consisting of IB-4, II-B-4', II-B-4, III-B-4', III-B-4, IV-B-4 or VB-4.

[0664] Among them, X, R 1 , Ring A, R 3 、R 4 、R 5 、R 6 、R 7 、R 8b 、R 12 ,m,n,M,W,U,Z,Y,L,Q,T,Tr,L 1 , L 2 and L 3 is as defined in any embodiment of the present invention.

[0665] In certain embodiments, the linker group and the drug group are connected to form a structure selected from Formula IB-5, II-B-5, III-B-5, IV-B-5 or VB-5,

[0666] Among them, X, R 1 , Ring A, R 3 、R 5 、R 6 、R 7 、R 8b 、R 9a 、R 9b 、R 12 ,n,M,W,U,Z,Y,L,Q,T,Tr,L 1 , L 2 and L 3 is as defined in any embodiment of the present invention.

[0667] In certain embodiments, the linker group and the drug group are connected to form a structure selected from the group consisting of Formula IB-6 and IB-7.

[0668] Among them, R 1 、R 31 、R 5 、R 6 、R 8b 、R 9a 、R 9b , M, Tr, L 1 , L 2 and L 3 is as defined in any embodiment of the present invention.

[0669] In certain embodiments, the linker group and the drug group are linked to form a structure selected from the group consisting of:

[0670] Table B

[0671] In certain embodiments, the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein the ligand-drug conjugate is selected from the compound represented by formula IC,

[0672] in,

[0673] X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 , M, Tr, L 1 , L 2 and L 3 The definition of is as described in any embodiment of the present invention;

[0674] Ab is the ligand that binds to the target;

[0675] k is the drug loading capacity, which is an integer or decimal between 1 and 16.

[0676] In certain embodiments, the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein the ligand-drug conjugate is selected from the compound represented by formula II-C',

[0677] in,

[0678] X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 ,m,n,W,U,Z,Y,Tr,L 1 、L 2 and L 3 The definition of is as described in any embodiment of the present invention;

[0679] Ab is the ligand that binds to the target;

[0680] k is the drug loading capacity, which is an integer or decimal between 1 and 16.

[0681] In certain embodiments, the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein the ligand-drug conjugate is selected from the compound represented by formula II-C,

[0682] in,

[0683] X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 、m、W、U、Z、Y、Tr、L 1 、L 2 and L 3 The definition of is as described in any embodiment of the present invention;

[0684] Ab is the ligand that binds to the target;

[0685] k is the drug loading capacity, which is an integer or decimal between 1 and 16.

[0686] In certain embodiments, the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein the ligand-drug conjugate is selected from the compound represented by formula III-C',

[0687] in,

[0688] X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 12 ,L,m,Tr,L 1 , L 2 and L 3 The definition of is as described in any embodiment of the present invention;

[0689] Ab is the ligand that binds to the target;

[0690] k is the drug loading capacity, which is an integer or decimal between 1 and 16.

[0691] In certain embodiments, the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein the ligand-drug conjugate is selected from the compound represented by formula III-C,

[0692] in,

[0693] X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 12 ,m,Tr,L 1 , L 2 and L 3 The definition of is as described in any embodiment of the present invention;

[0694] Ab is the ligand that binds to the target;

[0695] k is the drug loading capacity, which is an integer or decimal between 1 and 16.

[0696] In certain embodiments, the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein the ligand-drug conjugate is selected from the compound represented by formula IV-C,

[0697] in,

[0698] X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 ,m,Q,Tr,L 1 , L 2 and L 3 The definition of is as described in any embodiment of the present invention;

[0699] Ab is the ligand that binds to the target;

[0700] k is the drug loading capacity, which is an integer or decimal between 1 and 16.

[0701] In certain embodiments, the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein the ligand-drug conjugate is selected from the compound represented by formula VC,

[0702] in,

[0703] X, X 1 、X 2 , Ring A, Ring B, Ring C, R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 、m、T、Tr、L 1 , L 2 and L 3 The definition of is as described in any embodiment of the present invention;

[0704] Ab is the ligand that binds to the target;

[0705] k is the drug loading capacity, which is an integer or decimal between 1 and 16.

[0706] In certain embodiments, the Ab is bonded to L via the S atom. 1 coupling,

[0707] In certain embodiments, the Ab is a polypeptide, an antibody or an antigen-binding fragment thereof, particularly an antibody or an antigen-binding fragment thereof, that can specifically bind to a target.

[0708] In certain embodiments, the antibody is selected from one or more of the following:

[0709] (1) Fully human antibodies, humanized antibodies, mouse antibodies and chimeric antibodies,

[0710] (2) Probody,

[0711] (3) Bispecific antibodies and multispecific antibodies,

[0712] (4) Monoclonal antibodies and polyclonal antibodies,

[0713] (5)IgG antibodies.

[0714] In certain embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab', F(ab')2, Fv, scFv, Fd, dAb, VHH, and a complementarity determining region (CDR) fragment.

[0715] In certain embodiments, the Ab is a monoclonal antibody, in particular a monoclonal antibody with a thiol group as a coupling site, or a monoclonal antibody with a thiol group as a coupling site that is site-directedly mutated or modified.

[0716] In certain embodiments, the Ab targets an antigen selected from the group consisting of HER2, HER3, B7H3, B7H4, DLL3, TROP2, Claudin18.2, CD30, CD33, CD70, EGFR, GPC-3, ADAM9, BCMA, CEACAM5, and c-met.

[0717] In certain embodiments, the Ab targets an antigen selected from the group consisting of HER2, HER3, B7H3, B7H4, DLL3, TROP2, Claudin18.2, CD30, CD33, CD70, EGFR, GPC-3, ADAM9, BCMA, and CEACAM5.

[0718] In certain embodiments, the Ab targets an antigen selected from the group consisting of HER2, HER3, B7H3, B7H4, DLL3, TROP2, Claudin18.2, CD30, CD33, CD70, EGFR, GPC-3, ADAM9, and CEACAM5.

[0719] In certain embodiments, the Ab is selected from antibodies against HER2, HER3, B7H3, TROP2, Claudin18.2, CD30, CD33, CD70, GPC-3, ADAM9, BCMA, CEACAM5 and c-met, and antigen-binding fragments thereof.

[0720] In certain embodiments, the Ab is selected from antibodies against HER2, HER3, B7H3, TROP2, Claudin18.2, CD30, CD33, CD70, GPC-3, ADAM9, BCMA, and CEACAM5, and antigen-binding fragments thereof.

[0721] In certain embodiments, the Ab is selected from antibodies against HER2, HER3, B7H3, TROP2, Claudin18.2, CD30, CD33, CD70, GPC-3, ADAM9, and CEACAM5, and antigen-binding fragments thereof.

[0722] In certain embodiments, the Ab is selected from Tusamitamab, DB1001, DB1002, DB1003, DB1004, DB1005, Cetuximab, and Panitumumab, as well as biosimilars of said antibodies and antigen-binding fragments thereof.

[0723] In certain embodiments, the Ab is selected from Tusamitamab, DB1001, DB1002, DB1003, DB1004, Cetuximab, Panitumumab, biosimilars thereof, and antigen-binding fragments thereof.

[0724] In certain embodiments, the Ab is selected from Tusamitamab, DB1001, DB1002, Cetuximab, Panitumumab, biosimilars thereof, and antigen-binding fragments thereof.

[0725] In certain embodiments, the Ab is selected from Tusamitamab, DB1001, DB1002, DB1003, DB1004, and DB1005, and antigen-binding fragments thereof.

[0726] In certain embodiments, the Ab is selected from Tusamitamab, DB1001, DB1002, DB1003, or DB1004, and antigen-binding fragments thereof.

[0727] In certain embodiments, the Ab is selected from Tusamitamab, DB1001 or DB1002, and antigen-binding fragments thereof.

[0728] In certain embodiments, the Ab comprises the sequences of CDR1, CDR2, and CDR3 contained in the heavy chain as shown in SEQ ID NO: 1, and / or the sequences of CDR1, CDR2, and CDR3 contained in the light chain as shown in SEQ ID NO: 2.

[0729] In certain embodiments, the Ab comprises the sequences of CDR1, CDR2, and CDR3 contained in the heavy chain as shown in SEQ ID NO: 3, and / or the sequences of CDR1, CDR2, and CDR3 contained in the light chain as shown in SEQ ID NO: 4.

[0730] In certain embodiments, the Ab comprises the sequences of CDR1, CDR2, and CDR3 contained in the heavy chain as shown in SEQ ID NO: 5, and / or the sequences of CDR1, CDR2, and CDR3 contained in the light chain as shown in SEQ ID NO: 6.

[0731] In certain embodiments, the Ab comprises the sequences of CDR1, CDR2, and CDR3 contained in the heavy chain as shown in SEQ ID NO: 25, and / or the sequences of CDR1, CDR2, and CDR3 contained in the light chain as shown in SEQ ID NO: 26.

[0732] In certain embodiments, the Ab comprises the sequences of CDR1, CDR2, and CDR3 contained in the heavy chain as shown in SEQ ID NO: 35, and / or the sequences of CDR1, CDR2, and CDR3 contained in the light chain as shown in SEQ ID NO: 36.

[0733] In certain embodiments, the Ab comprises the sequences of CDR1, CDR2, and CDR3 contained in the heavy chain as shown in SEQ ID NO: 15, and / or the sequences of CDR1, CDR2, and CDR3 contained in the light chain as shown in SEQ ID NO: 16.

[0734] In certain embodiments, the Ab comprises a heavy chain variable region CDR1 as shown in SEQ ID NO: 7, a heavy chain variable region CDR2 as shown in SEQ ID NO: 8, a heavy chain variable region CDR3 as shown in SEQ ID NO: 9, and / or a light chain variable region CDR1 as shown in SEQ ID NO: 10, a light chain variable region CDR2 as shown in SEQ ID NO: 11, and a light chain variable region CDR3 as shown in SEQ ID NO: 12.

[0735] In certain embodiments, the Ab comprises a heavy chain variable region CDR1 as shown in SEQ ID NO: 17, a heavy chain variable region CDR2 as shown in SEQ ID NO: 18, a heavy chain variable region CDR3 as shown in SEQ ID NO: 19, and / or a light chain variable region CDR1 as shown in SEQ ID NO: 20, a light chain variable region CDR2 as shown in SEQ ID NO: 21, and a light chain variable region CDR3 as shown in SEQ ID NO: 22.

[0736] In certain embodiments, the Ab comprises a heavy chain variable region CDR1 as shown in SEQ ID NO: 27, a heavy chain variable region CDR2 as shown in SEQ ID NO: 28, a heavy chain variable region CDR3 as shown in SEQ ID NO: 29, and / or a light chain variable region CDR1 as shown in SEQ ID NO: 30, a light chain variable region CDR2 as shown in SEQ ID NO: 31, and a light chain variable region CDR3 as shown in SEQ ID NO: 32.

[0737] In certain embodiments, the Ab comprises a heavy chain variable region CDR1 as shown in SEQ ID NO: 37, a heavy chain variable region CDR2 as shown in SEQ ID NO: 38, a heavy chain variable region CDR3 as shown in SEQ ID NO: 39, and / or a light chain variable region CDR1 as shown in SEQ ID NO: 40, a light chain variable region CDR2 as shown in SEQ ID NO: 41, and a light chain variable region CDR3 as shown in SEQ ID NO: 42.

[0738] In certain embodiments, the Ab comprises a heavy chain variable region CDR1 as shown in SEQ ID NO:45, a heavy chain variable region CDR2 as shown in SEQ ID NO:46, a heavy chain variable region CDR3 as shown in SEQ ID NO:47, and / or a light chain variable region CDR1 as shown in SEQ ID NO:48, a light chain variable region CDR2 as shown in SEQ ID NO:49, and a light chain variable region CDR3 as shown in SEQ ID NO:50.

[0739] In certain embodiments, the Ab comprises a heavy chain variable region CDR1 as shown in SEQ ID NO: 53, a heavy chain variable region CDR2 as shown in SEQ ID NO: 54, a heavy chain variable region CDR3 as shown in SEQ ID NO: 55, and / or a light chain variable region CDR1 as shown in SEQ ID NO: 56, a light chain variable region CDR2 as shown in SEQ ID NO: 57, and a light chain variable region CDR3 as shown in SEQ ID NO: 58.

[0740] In certain embodiments, the Ab comprises the sequence of the heavy chain variable region contained in the heavy chain as shown in SEQ ID NO: 1, and / or the sequence of the light chain variable region contained in the light chain as shown in SEQ ID NO: 2.

[0741] In certain embodiments, the Ab comprises the sequence of the heavy chain variable region contained in the heavy chain as shown in SEQ ID NO: 3, and / or the sequence of the light chain variable region contained in the light chain as shown in SEQ ID NO: 4.

[0742] In certain embodiments, the Ab comprises the sequence of the heavy chain variable region contained in the heavy chain as shown in SEQ ID NO: 5, and / or the sequence of the light chain variable region contained in the light chain as shown in SEQ ID NO: 6.

[0743] In certain embodiments, the Ab comprises the sequence of the heavy chain variable region contained in the heavy chain as shown in SEQ ID NO: 25, and / or the sequence of the light chain variable region contained in the light chain as shown in SEQ ID NO: 26.

[0744] In certain embodiments, the Ab comprises the sequence of the heavy chain variable region contained in the heavy chain as shown in SEQ ID NO:35, and / or the sequence of the light chain variable region contained in the light chain as shown in SEQ ID NO:36.

[0745] In certain embodiments, the Ab comprises the sequence of the heavy chain variable region contained in the heavy chain as shown in SEQ ID NO:15, and / or the sequence of the light chain variable region contained in the light chain as shown in SEQ ID NO:16.

[0746] In certain embodiments, the Ab comprises the sequence of the heavy chain variable region shown in SEQ ID NO:14 and / or the sequence of the light chain variable region shown in SEQ ID NO:13.

[0747] In certain embodiments, the Ab comprises the sequence of the heavy chain variable region shown in SEQ ID NO: 24 and / or the sequence of the light chain variable region shown in SEQ ID NO: 23.

[0748] In certain embodiments, the Ab comprises the sequence of the heavy chain variable region shown in SEQ ID NO:34 and / or the sequence of the light chain variable region shown in SEQ ID NO:33.

[0749] In certain embodiments, the Ab comprises the sequence of the heavy chain variable region shown in SEQ ID NO:44 and / or the sequence of the light chain variable region shown in SEQ ID NO:43.

[0750] In certain embodiments, the Ab comprises the sequence of the heavy chain variable region shown in SEQ ID NO:52 and / or the sequence of the light chain variable region shown in SEQ ID NO:51.

[0751] In certain embodiments, the Ab comprises the sequence of the heavy chain variable region shown in SEQ ID NO:60 and / or the sequence of the light chain variable region shown in SEQ ID NO:59.

[0752] In certain embodiments, the amino acid sequence of the heavy chain of the Ab is shown in SEQ ID NO: 1, and the amino acid sequence of the light chain of the Ab is shown in SEQ ID NO: 2.

[0753] In certain embodiments, the amino acid sequence of the heavy chain of the Ab is shown in SEQ ID NO:3, and the amino acid sequence of the light chain of the Ab is shown in SEQ ID NO:4.

[0754] In certain embodiments, the amino acid sequence of the heavy chain of the Ab is shown in SEQ ID NO:5, and the amino acid sequence of the light chain of the Ab is shown in SEQ ID NO:6.

[0755] In certain embodiments, the amino acid sequence of the heavy chain of the Ab is shown in SEQ ID NO:25, and the amino acid sequence of the light chain of the Ab is shown in SEQ ID NO:26.

[0756] In certain embodiments, the amino acid sequence of the heavy chain of the Ab is shown in SEQ ID NO:35, and the amino acid sequence of the light chain of the Ab is shown in SEQ ID NO:36.

[0757] In certain embodiments, the amino acid sequence of the heavy chain of the Ab is shown in SEQ ID NO:15, and the amino acid sequence of the light chain of the Ab is shown in SEQ ID NO:16.

[0758] In certain embodiments, the Ab is an anti-CEACAM5 antibody or an antigen-binding fragment thereof, such as Tusamitamab or an antigen-binding fragment thereof or a variant thereof.

[0759] In certain embodiments, the Ab comprises a heavy chain and a light chain of an anti-CEACAM5 antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1, or as set forth in SEQ ID NO: 1, and the amino acid sequence of the light chain is a sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, or as set forth in SEQ ID NO: 2.

[0760] In certain embodiments, the Ab is an anti-HER3 antibody or an antigen-binding fragment thereof, such as DB1001 or an antigen-binding fragment thereof or a variant thereof.

[0761] In certain embodiments, the Ab comprises a heavy chain and a light chain of an anti-HER3 antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 3, or as shown in SEQ ID NO: 3, and the amino acid sequence of the light chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 4, or as shown in SEQ ID NO: 4.

[0762] In certain embodiments, the Ab is an anti-GPC-3 antibody or an antigen-binding fragment thereof, such as DB1002 or an antigen-binding fragment thereof or a variant thereof.

[0763] In certain embodiments, the Ab comprises a heavy chain and a light chain of an anti-GPC-3 antibody or antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to, or as set forth in, SEQ ID NO:5, and the amino acid sequence of the light chain is a sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to, or as set forth in, SEQ ID NO:6.

[0764] In certain embodiments, the Ab is an anti-ADAM9 antibody or an antigen-binding fragment thereof, such as DB1003 or an antigen-binding fragment thereof or a variant thereof.

[0765] In certain embodiments, the Ab comprises a heavy chain and a light chain of an anti-ADAM9 antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO: 25, or as shown in SEQ ID NO: 25, and the amino acid sequence of the light chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO: 26, or as shown in SEQ ID NO: 26.

[0766] In certain embodiments, the Ab is an anti-BCMA antibody or an antigen-binding fragment thereof, such as DB1004 or an antigen-binding fragment thereof or a variant thereof.

[0767] In certain embodiments, the Ab comprises a heavy chain and a light chain of an anti-BCMA antibody or antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to, or as set forth in, SEQ ID NO: 35, and the amino acid sequence of the light chain is a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to, or as set forth in, SEQ ID NO: 36.

[0768] In certain embodiments, the Ab is an anti-c-met antibody or an antigen-binding fragment thereof, such as DB1005 or an antigen-binding fragment thereof or a variant thereof.

[0769] In certain embodiments, the Ab comprises a heavy chain and a light chain of an anti-c-met antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 15 or as shown in SEQ ID NO: 15, and the amino acid sequence of the light chain is a sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 16 or as shown in SEQ ID NO: 16.

[0770] In certain embodiments, k is an integer or decimal selected from 1-10.

[0771] In certain embodiments, k is an integer or decimal selected from 2-9.

[0772] In certain embodiments, k is an integer or decimal selected from 2-8.

[0773] In certain embodiments, k is selected from an integer or decimal of 4-8 (e.g., about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8).

[0774] In certain embodiments, k is selected from an integer or decimal between 6 and 8 (e.g., about 6.1, about 6.3, about 6.5, about 6.7, about 6.9, about 7.1, about 7.3, about 7.5, about 7.7, about 8).

[0775] In certain embodiments, k is selected from an integer or decimal between 7 and 9 (e.g., about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5).

[0776] In certain embodiments, k is selected from an integer decimal between 7.5 and 8.1 (e.g., 7.81, 7.82, 7.83, 7.84, 7.85, 7.86, 7.87, 7.88, 7.89, 7.90, 7.91, 7.92, 7.93, 7.94, 7.95, 7.96, 7.97, 7.98, 7.99, 8.00, 8.01, 8.02, 8.03, 8.04, 8.05, 8.06, 8.07, 8.08, 8.09, 8.10).

[0777] In certain embodiments, k is selected from an integer or decimal between 7 and 8 (e.g., about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8).

[0778] In certain embodiments, k is an integer or decimal selected from 7.5-8.

[0779] In certain embodiments, said k is selected from a number of 2-8, for example, 2, 3, 4, 5, 6, 7, 8. In certain embodiments, said k is selected from 6 and 8.

[0780] In certain embodiments, the k is selected from an integer of 1 to 10. In certain embodiments, the k is selected from an integer of 2 to 8 (e.g., 2, 3, 4, 5, 6, 7, 8), such as an integer of 4 to 8 (e.g., 4, 5, 6, 7, 8), such as an integer of 6 to 8 (e.g., 6, 7, 8), such as an integer of 7 to 8.

[0781] In certain embodiments, the ligand-drug conjugate is selected from the compounds represented by formula IC-1, II-C-1', II-C-1, III-C-1', III-C-1, IV-C-1 or VC-1;

[0782] Among them, X, X 1 、X 2 , Ring A, Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 、R 12 ,m,n,M,W,U,Z,Y,L,Q,T,Tr,L 1 , L 2 , L 3 , Ab and k are as defined in any embodiment of the present invention.

[0783] In certain embodiments, the ligand-drug conjugate is selected from the compounds represented by formula IC-2, II-C-2', II-C-2, III-C-2', III-C-2, IV-C-2 or VC-2,

[0784] Among them, X, X 1 、X 2 , Ring A, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 、R 12 ,m,n,M,W,U,Z,Y,L,Q,T,Tr,L 1 , L 2 , L 3 , Ab and k are as defined in any embodiment of the present invention.

[0785] In certain embodiments, the ligand-drug conjugate is selected from the compounds represented by formula IC-3, III-C-3', III-C-3, IV-C-3 or VC-3,

[0786] Among them, X, X 1 、X 2 , Ring A, R 3 、R 4 、R 5 、R 6 、R 7 、R 8b 、R9b 、R 12 、m、M、L、Q、T、Tr、L 1 , L 2 , L 3 , Ab and k are as defined in any embodiment of the present invention.

[0787] In certain embodiments, the ligand-drug conjugate is selected from the compounds represented by formula IC-4, II-C-4', II-C-4, III-C-4', III-C-4, IV-C-4 or VC-4,

[0788] Among them, X, R 1 , Ring A, R 3 、R 4 、R 5 、R 6 、R 7 、R 8b 、R 12 ,m,n,M,W,U,Z,Y,L,Q,T,Tr,L 1 , L 2 , L 3 , Ab and k are as defined in any embodiment of the present invention.

[0789] In certain embodiments, the ligand-drug conjugate is selected from the compounds represented by formula IC-5, II-C-5, III-C-5, IV-C-5 or VC-5,

[0790] Among them, X, R 1 , Ring A, R 3 、R 5 、R 6 、R 7 、R 8b 、R 9a 、R 9b 、R 12 ,n,M,W,U,Z,Y,L,Q,T,Tr,L 1 , L 2 , L 3 , Ab and k are as defined in any embodiment of the present invention.

[0791] In certain embodiments, the ligand-drug conjugate is selected from compounds represented by formula IC-6 and IC-7,

[0792] Among them, R 1 、R 31 、R 5 、R 6、R 8b 、R 9a 、R 9b , M, Tr, L 1 , L 2 , L 3 , Ab and k are as defined in any embodiment of the present invention.

[0793] In certain embodiments, the ligand-drug conjugate is selected from the structures shown in Table C:

[0794] Table C

[0795] wherein Ab and k are as described in any embodiment of the present invention.

[0796] In certain embodiments, the ligand-drug conjugate is selected from the structures shown in Table E:

[0797] Table E

[0798] wherein k is as described in any embodiment of the present invention.

[0799] In a second aspect, the present invention provides a mixture of ligand-drug conjugates, comprising or consisting of the aforementioned ligand-drug conjugates, their tautomers, their enantiomers, their diastereomers, their pharmaceutically acceptable salts or solvates thereof, wherein the ligand-drug conjugates have one, two or more k values.

[0800] In some embodiments, the average drug to ligand ratio (DAR) of the mixture of ligand drug conjugates is an integer or decimal selected from 1 to 32. In certain embodiments, the DAR value is an integer or decimal selected from 1 to 16. In certain embodiments, the DAR value is selected from an integer or decimal of 2-9, preferably an integer or decimal of 2-8, such as 2, 3, 4, 5, 6, 7, 8, 3.01, 3.22, 3.75, 3.76, 3.87, 3.89, 3.95, 3.98, 4.05, 4.06, 4.08, 4.11, 4.16, 4.22, 4.29, 5.11, 5.58, 6.17, 6.46, 6.56, 6.82, 6.88, 6.98, 7.02, 7.06, 7.08, 7.12, 7.18, 7.22, 7.25, 7.28, 7.31, 7.32, 7.33, 7.4 1, 7.42, 7.43, 7.45, 7.48, 7.52, 7.53, 7.56, 7.57, 7.58, 7.62, 7.64, 7.65, 7.71, 7.73, 7.78, 7.81, 7.82, 7.87, 7.88 or 7.93, for example, 7.83, 7.84, 7.85, 7.86, 7.89, 7.90, 7.91, 7.92, 7.94, 7.95, 7.96, 7.97, 7.98, 7.99, 8.00, 8.01, 8.02, 8.03, 8.04, 8.05, 8.06, 8.07, 8.08, 8.09, 8.10.

[0801] Drug-Linker

[0802] The third aspect of the present invention provides a compound or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the structure shown in formula ID, II-D', III-D', IV-D or VD

[0803] in,

[0804] X, X 1 、X 2 , Ring A, Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 、R 12 ,m,n,M,W,U,Z,Y,L,Q,T,Tr,L2 and L 3 The definition is as described in any embodiment of the first aspect of the present invention;

[0805] L 1a For the connection unit.

[0806] The third aspect of the present invention also provides a compound or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the structure shown in formula ID, II-D, III-D, IV-D or VD

[0807] in,

[0808] X, X 1 、X 2 , Ring A, Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 、R 12 ,m,M,W,U,Z,Y,Q,T,Tr,L 2 and L 3 The definition is as described in any embodiment of the first aspect of the present invention;

[0809] L 1a For the connection unit.

[0810] In certain embodiments, the compound is selected from the group consisting of the structures shown in Formula ID

[0811] Among them, X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 , M, Tr, L 1a , L 2 and L 3 is as defined in any embodiment of the present invention.

[0812] In certain embodiments, the compound is selected from the group consisting of the structure shown in formula II-D'

[0813] Among them, X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 ,m,n,W,U,Z,Y,Tr,L 1a , L 2 and L 3 is as defined in any embodiment of the present invention.

[0814] In certain embodiments, the compound is selected from the group consisting of the structure shown in Formula II-D

[0815] Among them, X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 、m、W、U、Z、Y、Tr、L 1a , L 2 and L 3 is as defined in any embodiment of the present invention.

[0816] In certain embodiments, the compound is selected from the structure shown in formula III-D'

[0817] Among them, X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 12 ,L,m,Tr,L 1a , L 2 and L 3 is as defined in any embodiment of the present invention.

[0818] In certain embodiments, the compound is selected from the group consisting of the structure shown in formula III-D

[0819] Among them, X, X 1 、X 2, Ring B, Ring C, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 12 ,m,Tr,L 1a 、L 2 and L 3 is as defined in any embodiment of the present invention.

[0820] In certain embodiments, the compound is selected from the group consisting of the structure shown in Formula IV-D

[0821] Among them, X, X 1 、X 2 , Ring B, Ring C, R 3 、R 4 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 ,m,Q,Tr,L 1a 、L 2 and L 3 is as defined in any embodiment of the present invention.

[0822] In certain embodiments, the compound is selected from the group consisting of the structures shown in formula VD

[0823] Among them, X, X 1 、X 2 , Ring A, Ring B, Ring C, R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 、m、T、Tr、L 1a 、L 2 and L 3 is as defined in any embodiment of the present invention.

[0824] In certain embodiments, the L 1a -C(=O)-(C1-C8)alkyl, -C(=O)O-(4-8 membered)heterocyclyl, -C(=O)O-(C6-C 10)aryl, (4-8 membered) heterocyclyl and (5-10 membered) heteroaryl, the -C(=O)-(C1-C8) alkyl, -C(=O)O-(4-8 membered) heterocyclyl, -C(=O)O-(C6-C 10 The (4-8 membered)aryl, (4-8 membered)heterocyclyl, (5-10 membered)heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 oxo, halogen, =CH2, -(C2-C4)alkenyl, -S-CH2-phenyl, -S(=O)2-(C1-C4)alkyl, -OS(=O)2-phenyl-(C1-C4)alkyl and -(C1-C4)alkyl.

[0825] In certain embodiments, the L 1a selected from -C(=O)-(C1-C4)alkyl, -C(=O)O-(5-6-membered)heterocyclyl, -C(=O)O-phenyl, (5-6-membered)heterocyclyl and (5-6-membered)heteroaryl, wherein the -C(=O)-(C1-C4)alkyl, -C(=O)O-(5-6-membered)heterocyclyl, -C(=O)O-phenyl, (5-6-membered)heterocyclyl and (5-6-membered)heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 oxo, fluoro, bromo, =CH2, vinyl, -S-CH2-phenyl, -S(=O)2CH3, -OS(=O)2-phenyl-CH3 and methyl groups.

[0826] In certain embodiments, the L 1a Selected from

[0827] In certain embodiments, the L 1a Selected from

[0828] In certain embodiments, the L 1a Selected from

[0829] In certain embodiments, the L 1a Selected from

[0830] In certain embodiments, the L 1a -L 2 -Selected from:

[0831] In certain embodiments, the L 1a -L 2 -Selected from:

[0832] In certain embodiments, the L 1a -L2 -Selected from:

[0833] In certain embodiments, the L 1a -L 2 -Selected from:

[0834] In certain embodiments, the L 1a -L 2 -Selected from:

[0835] In certain embodiments, the L 1a -L 2 -Selected from:

[0836] In certain embodiments, the L 1a -L 2 -L 3 -Selected from:

[0837] In certain embodiments, the L 1a -L 2 -L 3 -Selected from:

[0838] In certain embodiments, the L 1a -L 2 -L 3 -Selected from:

[0839] In certain embodiments, the L 1a -L 2 -L 3 -Selected from:

[0840] In certain embodiments, the L 1a -L 2 -L 3 -Tr- is selected from:

[0841] In certain embodiments, the L 1a -L 2 -L3 -Selected from:

[0842] In certain embodiments, the L 1a -L 2 -L 3 -Selected from:

[0843] In certain embodiments, the L 1a -L 2 -L 3 -Selected from:

[0844] In certain embodiments, the L 1a -L 2 -L 3 -Selected from:

[0845] In certain embodiments, the compound is selected from the structure shown in Formula ID-3, III-D-3', III-D-3, IV-D-3 or VD-3,

[0846] Among them, X, X 1 、X 2 , Ring A, R 3 、R 4 、R 5 、R 6 、R 7 、R 8b 、R 9b 、R 12 、m、M、L、Q、T、Tr、L 1a , L 2 and L 3 is as defined in any embodiment of the present invention.

[0847] In certain embodiments, the compound is selected from the structure shown in Formula ID-4, II-D-4', II-D-4, III-D-4', III-D-4, IV-D-4 or VD-4,

[0848] Among them, X, R 1 , Ring A, R 3 、R 4 、R 5 、R6 、R 7 、R 8b 、R 12 ,m,n,M,W,U,Z,Y,Q,T,Tr,L,L 1a 、L 2 and L 3 is as defined in any embodiment of the present invention.

[0849] In certain embodiments, the compound is selected from the structure shown in Formula ID-5, II-D-5, III-D-5, IV-D-5 or VD-5,

[0850] Among them, X, R 1 , Ring A, R 3 、R 5 、R 6 、R 7 、R 8b 、R 9a 、R 9b 、R 12 ,n,M,W,U,Z,Y,Q,T,Tr,L,L 1a 、L 2 and L 3 is as defined in any embodiment of the present invention.

[0851] In certain embodiments, the compound is selected from the structures shown in formula ID-6 and ID-7,

[0852] Among them, R 1 、R 31 、R 5 、R 6 、R 8b 、R 9a 、R 9b ,M,Tr,L,L 1a 、L 2 and L 3 is as defined in any embodiment of the present invention.

[0853] In certain embodiments, the compound is selected from the structures shown in Table D:

[0854] Table D

[0855] The fourth aspect of the present invention provides the use of the compound described in any embodiment of the third aspect of the present invention or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate in the preparation of the ligand-drug conjugate described in any embodiment of the first aspect of the present invention.

[0856] Pharmaceutical composition

[0857] The fifth aspect of the present invention provides a pharmaceutical composition comprising at least one ligand-drug conjugate as described in any embodiment of the first aspect of the present invention, or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or at least one compound as described in any embodiment of the third aspect of the present invention, or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers and / or excipients.

[0858] The sixth aspect of the present invention provides a pharmaceutical composition comprising a mixture of at least one ligand-drug conjugate as described in any embodiment of the second aspect of the present invention, and one or more pharmaceutically acceptable carriers and / or excipients.

[0859] use

[0860] The seventh aspect of the present invention provides the use of the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate, as described in any embodiment of the first aspect of the present invention, or the compound or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, as described in any embodiment of the third aspect of the present invention, or the pharmaceutical composition as described in any embodiment of the fifth aspect of the present invention in the preparation of a medicament for treating and / or preventing a disease or condition or alleviating the severity of the disease or condition, wherein the disease or condition is a tumor or cancer.

[0861] The seventh aspect of the present invention further provides the use of a mixture of the ligand-drug conjugate described in any embodiment of the second aspect of the present invention, or the pharmaceutical composition described in any embodiment of the sixth aspect of the present invention in the preparation of a medicament for treating and / or preventing a disease or condition or alleviating the severity of the disease or condition, wherein the disease or condition is a tumor or cancer.

[0862] The seventh aspect of the present invention further provides the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate as described in any embodiment of the first aspect of the present invention, or the compound or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof as described in any embodiment of the third aspect of the present invention, or the pharmaceutical composition as described in any embodiment of the fifth aspect of the present invention, for treating and / or preventing a disease or condition or alleviating the severity of the disease or condition, wherein the disease or condition is a tumor or cancer.

[0863] The seventh aspect of the present invention further provides a mixture of the ligand-drug conjugate described in any embodiment of the second aspect of the present invention, or the drug combination described in any embodiment of the sixth aspect of the present invention, which is used to treat and / or prevent a disease or condition or alleviate the severity of the disease or condition, wherein the disease or condition is a tumor or cancer.

[0864] The seventh aspect of the present invention also provides a method for treating and / or preventing a disease or condition or alleviating the severity of the disease or condition, which comprises administering to an individual in need an effective amount of the ligand-drug conjugate described in any embodiment of the first aspect of the present invention, or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or the compound described in any embodiment of the third aspect of the present invention, or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or a mixture thereof, or the pharmaceutical composition described in any embodiment of the fifth aspect of the present invention, wherein the disease or condition is a tumor or cancer.

[0865] The seventh aspect of the present invention also provides a method for treating and / or preventing a disease or condition or reducing the severity of the disease or condition, which comprises administering to an individual in need thereof an effective amount of a mixture of the ligand-drug conjugate described in any embodiment of the second aspect of the present invention, or the drug combination described in any embodiment of the sixth aspect of the present invention.

[0866] In certain embodiments, the tumor or cancer is selected from leukemia, malignant lymphoma, multiple myeloma, gastric cancer, colorectal cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, liver cancer, and lung cancer.

[0867] In certain embodiments, the tumor or cancer is selected from leukemia, malignant lymphoma, multiple myeloma, gastric cancer, colorectal cancer, breast cancer, ovarian cancer, liver cancer, and lung cancer.

[0868] In certain embodiments, the tumor or cancer is selected from gastric cancer, colorectal cancer, breast cancer, ovarian cancer, and liver cancer.

[0869] In certain embodiments, the colorectal cancer is selected from colorectal adenocarcinoma and colon cancer.

[0870] In certain embodiments, the tumor or cancer is selected from leukemia, malignant lymphoma, and multiple myeloma.

[0871] In certain embodiments, the breast cancer is selected from ductal carcinoma.

[0872] Sequence information

[0873] Tusamitamab heavy chain amino acid sequence

[0874] Tusamitamab light chain amino acid sequence

[0875] The complementarity determining region and variable region sequences of Tusamitamab are shown in the table below.

[0876] The CDR region sequences in the above table are defined using the Kabat numbering system. Any other CDR region sequence determination method known in the art may also be used to identify the amino acid residues in the CDR region within the variable region.

[0877] Anti-HER3 antibody DB1001 heavy chain amino acid sequence

[0878] Anti-HER3 antibody DB1001 light chain amino acid sequence

[0879] The complementary determining region and variable region sequences of the anti-HER3 antibody DB1001 are shown in the table below.

[0880] The CDR region sequences in the above table are defined using the Kabat numbering system. Any other CDR region sequence determination method known in the art may also be used to identify the amino acid residues in the CDR region within the variable region.

[0881] Anti-GPC-3 antibody DB1002 heavy chain amino acid sequence

[0882] Anti-GPC-3 antibody DB1002 light chain amino acid sequence

[0883] The complementarity determining region and variable region sequences of the anti-anti-GPC-3 antibody DB1002 are shown in the table below.

[0884] The CDR region sequences in the above table are defined using the Kabat numbering system. Any other CDR region sequence determination method known in the art may also be used to identify the amino acid residues in the CDR region within the variable region.

[0885] Anti-ADAM9 antibody DB1003 heavy chain amino acid sequence

[0886] Anti-ADAM9 antibody DB1003 light chain amino acid sequence

[0887] The complementarity determining region and variable region sequences of the anti-ADAM9 antibody DB1003 are shown in the table below.

[0888] The CDR region sequences in the above table are defined using the Kabat numbering system. Any other CDR region sequence determination method known in the art may also be used to identify the amino acid residues in the CDR region within the variable region.

[0889] Anti-BCMA antibody DB1004 (Belantamab) heavy chain amino acid sequence

[0890] Anti-BCMA antibody DB1004 (Belantamab) light chain amino acid sequence

[0891] The complementarity determining region and variable region sequences of the anti-BCMA antibody DB1004 are shown in the table below.

[0892] The CDR region sequences in the above table are defined using the Kabat numbering system. Any other CDR region sequence determination method known in the art may also be used to identify the amino acid residues in the CDR region within the variable region.

[0893] Anti-c-met antibody DB1005 heavy chain amino acid sequence

[0894] Anti-c-met antibody DB1005 light chain amino acid sequence

[0895] The complementarity determining region and variable region sequences of the anti-c-met antibody DB1005 are shown in the table below.

[0896] The CDR region sequences in the above table are defined using the Kabat numbering system. Any other CDR region sequence determination method known in the art may also be used to identify the amino acid residues in the CDR region within the variable region.

[0897] Short peptide sequence Note: X represents norvaline (Nva).

[0898] Definition of terms

[0899] The various terms and phrases used in this application have general meanings known to those skilled in the art. Even so, this application still hopes to provide a more detailed description and explanation of these terms and phrases. If the mentioned terms and phrases are inconsistent with the known meanings, the meanings expressed in this application shall prevail.

[0900] The terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0901] When the terms “for example”, “such as” or variations thereof are used herein, these terms will not be considered as limiting terms, but will be interpreted as meaning “including but not limited to” or “not limited to”.

[0902] When the terms "comprising," "including," or variations thereof are used herein, the terms "consisting of," and "consisting essentially of" are also provided.

[0903] As used in this application, the term "and / or" should be considered as a specific disclosure of each of two or more specified features or elements, as well as any combination of two or more features or elements. Thus, the term "and / or" used in phrases such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone).

[0904] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic or organic acids, or coordination compounds formed by the substitution of acidic protons present in the parent compound with metal ions or organic bases.

[0905] As used in this application, the term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In a compound with one or more (such as 1, 2, 3 or 4) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a diastereomeric mixture and a single diastereomer. The term "stereoisomer" includes conformers and configurational isomers, wherein the configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention can exist in the form of stereoisomers, and therefore encompass all possible stereoisomeric forms, and any combination or any mixture thereof. For example, a single enantiomer, a single diastereomer or a mixture thereof. When the compounds of the present invention contain an olefin double bond, unless otherwise stated, it includes cis-isomers and trans-isomers, and any combination thereof.

[0906] As used in this application, the term "tautomer" refers to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol tautomers, imine-enamine tautomers, etc. If tautomers exist for the compounds of the present invention, they may exist in the form of a single tautomer or a mixture thereof, preferably in the form of a more stable tautomer as the main component.

[0907] As used in this application, the term "racemate" includes "racemate". The term "racemate" refers to an equimolar mixture of an optically active chiral molecule and its enantiomer; the term "enantiomer" refers to one of a pair of molecular entities that are mirror images of each other and are non-superimposable. A mixture of enantiomers can be separated under conditions such as chiral resolution; the term "diastereomer" refers to stereoisomers that are not related to each other as mirror images. Diastereomers are characterized by some differences in physical and chemical properties. A mixture of diastereomers can be separated under conditions such as chromatography or crystallization.

[0908] As used herein, the term "solvate" refers to a substance formed by the association of a compound of the present invention with solvent molecules. The solvent may be an organic solvent (e.g., methanol, ethanol, propanol, acetonitrile, etc.). For example, the compound of the present invention may form an ethanolate with ethanol. The compound of the present invention may also form a hydrate with water. The amount of the solvent may be present in a stoichiometric or non-stoichiometric ratio.

[0909] Unless otherwise defined, divalent groups have no directional restrictions, for example, ALB, when L is -C(=O)-NH-, ALB is AC(=O)-NH-B and / or A-NH-C(=O)-B.

[0910] As used herein, the term "substituted" refers to the replacement of a hydrogen atom in a group by a corresponding substituent, for example, -CH2- in A-CH2-B is replaced by one -NH2, thus obtaining A-CH(NH2)-B. It should be understood that the substituents are only in their possible chemical positions.

[0911] As used herein, the term "substituted" means that the group itself is replaced by a corresponding group, for example, -CH2- in A-CH2-B is replaced by -NH- to obtain A-NH-B.

[0912] As used in this application, "optionally substituted by..." means that the group may be unsubstituted or substituted by a substituent. For example, -(C1-C6)alkyl is optionally substituted by halogen, which means that -(C1-C6)alkyl may be unsubstituted or substituted by halogen to obtain a haloalkyl. It should be understood that when a group is composed of multiple parts, the definition that one of the parts can be substituted means that this part in the group can also be substituted. For example, "R is selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl and -NH(C1-C6)alkyl, and the -(C1-C6)alkyl is optionally substituted with halogen", which means that the (C1-C6)alkyl in -(C1-C6)alkyl, -O-(C1-C6)alkyl and -NH(C1-C6)alkyl are optionally substituted with halogen. For example, "R is selected from methyl, -O-methyl, -NH-methyl, -S-methyl, -C(=O)-methyl and -C(=O)NH-methyl, and the methyl is optionally substituted with one hydroxyl group or amino group" means that the methyl group and the methyl groups in -O-methyl, -NH-methyl, -S-methyl, -C(=O)-methyl and -C(=O)NH-methyl are optionally substituted with one hydroxyl group or amino group.

[0913] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0914] As used herein, the term "alkyl" refers to a linear or branched monovalent saturated hydrocarbon group, for example, a (C1-C6) alkyl group has 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms; a (C1-C4) alkyl group has 1 to 4 carbon atoms, such as 1, 2, 3, or 4 carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, propyl, butyl, and the like.

[0915] As used herein, the term "alkylene" refers to a straight or branched divalent saturated hydrocarbon group, for example, a (C1-C6) alkylene group has 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms; a (C1-C4) alkylene group has 1 to 4 carbon atoms, such as 1, 2, 3, or 4 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.

[0916] As used herein, the term "halo" refers to a group that is substituted with one or more halogens, such as 1, 2, 3, 4, 5, or 6 halogens. For example, "(C1-C6)haloalkyl" refers to a (C1-C6)alkyl group as defined above that is substituted with one or more halogens, non-limiting examples of which include but are not limited to CF3, CHF2, or CF2CF3.

[0917] As used herein, the term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing at least one double bond. 2- C6) alkenyl refers to a group having 2 to 6 (such as 2, 3, 4, 5 or 6) carbon atoms, including (C 2- C5) alkenyl, (C 2- C4) alkenyl, (C 2- C3) alkenyl, etc. Non-limiting examples include but are not limited to -CH=CH2, -CH=CH-CH=CH2 or -CH=C(CH)3-CH3, etc.

[0918] As used herein, the term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing at least one triple bond, such as (C 2- C6) alkynyl refers to a group having 2 to 6 (such as 2, 3, 4, 5 or 6) carbon atoms, including (C 2- C5) alkynyl, (C 2- C4) alkynyl, (C 2- C3) alkynyl, etc. Non-limiting examples include but are not limited to ethynyl or propynyl, etc.

[0919] As used herein, the term "cycloalkyl" refers to a monovalent saturated hydrocarbon group consisting of carbon atoms, for example, a (C3-C6) cycloalkyl group consisting of 3-6 (e.g., 3, 4, 5, or 6) carbon atoms. The cycloalkyl group includes a monocyclic, bicyclic, or polycyclic ring, including a spirocyclic, cyclocyclic, or bridged ring. Non-limiting examples include, but are not limited to, cyclobutyl, cyclopentyl, or cyclohexyl.

[0920] As used herein, the term "cycloalkylene" refers to a divalent saturated hydrocarbon group consisting of carbon atoms, for example, a (C3-C6) cycloalkylene group consisting of 3-6 (e.g., 3, 4, 5, or 6) carbon atoms. The cycloalkylene group includes a monocyclic, bicyclic, or polycyclic ring, including a spirocyclic, cyclocyclic, or bridged ring. Non-limiting examples include, but are not limited to, cyclobutylene, cyclopentylene, or cyclohexylene.

[0921] As used in this application, the term "heterocyclyl" refers to a saturated or partially unsaturated monovalent cyclic group consisting of ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms and the rest are carbon atoms; preferably, the heteroatoms are selected from N, O or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized; preferably, the carbon atom is optionally substituted with =O. For example, (4-10 yuan) heterocyclyl refers to being composed of 4, 5, 6, 7, 8, 9 or 10 ring atoms, and (4-10 yuan) heterocyclyl includes (4-9 yuan) heterocyclyl, (4-8 yuan) heterocyclyl, (4-7 yuan) heterocyclyl, (4-6 yuan) heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, etc. The heterocyclyl includes a monocyclic, bicyclic or polycyclic ring, including a spirocyclic, a cyclic or bridged ring. Non-limiting examples include but are not limited to oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, etc.

[0922] As used herein, the term "heterocyclylene" refers to a saturated or partially unsaturated divalent cyclic group consisting of ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms and the rest are carbon atoms; preferably, the heteroatoms are selected from N, O or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized; preferably, the carbon atom is optionally substituted with =O. For example, a (4-10 yuan) heterocyclylene refers to a group consisting of 4-10 (e.g., 4, 5, 6, 7, 8, 9 or 10) ring atoms, and a (4-10 yuan) heterocyclylene includes a (4-8 yuan) heterocyclylene, a (4-6 yuan) heterocyclylene, a 5-membered heterocyclylene, etc. The heterocyclylene includes a monocyclic, bicyclic or polycyclic ring, including a spirocyclic, a cyclic or bridged ring. Non-limiting examples include, but are not limited to, oxetane, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0923] As used herein, the term "aryl" refers to an unsaturated carbocyclic group having a conjugated π electron system, such as (C6-C 10 ) aryl consists of 6 to 10 (e.g., 6, 7, 8, 9 or 10) carbon atoms. Non-limiting examples include, but are not limited to, phenyl and the like.

[0924] As used herein, the term "arylene" refers to a divalent unsaturated carbocyclic group having a conjugated π electron system, such as (C6-C 10 ) arylene is composed of 6 to 10 (such as 6, 7, 8, 9 or 10) carbon atoms. Non-limiting examples include, but are not limited to, phenylene and the like.

[0925] As used herein, the term "heteroaryl" refers to an unsaturated group having a conjugated π electron system consisting of ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms and the rest are carbon atoms; preferably, the heteroatoms are selected from N, O or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. For example, a (5-12 membered) heteroaryl group is composed of 5 to 12 (e.g., 5, 6, 7, 8, 9, 10, 11 or 12) ring atoms, including 5-9 membered, 6-9 membered, 5-6 membered heteroaryl groups, etc. The heteroaryl group includes monocyclic and polycyclic rings, non-limiting examples of which include, but are not limited to, imidazolyl or pyridyl groups.

[0926] As used herein, the term "heteroarylene" refers to an unsaturated group having a conjugated π electron system composed of ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms and the rest are carbon atoms; preferably, the heteroatoms are selected from N, O or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. For example, a (5-10 membered) heteroarylene group is composed of (5 to 10) (e.g., 5, 6, 7, 8, 9 or 10) ring atoms, including 5-9 membered, 6-9 membered, 5-6 membered heteroarylene groups, etc. The heteroarylene group includes monocyclic and polycyclic rings, and non-limiting examples include but are not limited to imidazolylene or pyridylene groups.

[0927] As used herein, amino acid abbreviations have meanings generally known in the art. The amino acids described are generally L-amino acids, but those skilled in the art will appreciate that they can be replaced with D-amino acids having similar chemical properties. For example, Val represents valine, Ala represents alanine, Glu represents glutamic acid, Cit represents citrulline, Nva represents norvaline, and Lys (AC) represents acetylated lysine.

[0928] As used herein, the term "short peptide" refers to a chain comprising at least two consecutively linked amino acid residues. Unless otherwise indicated, the direction of linkage of the short peptide is not limited by the orientation of the representation. For example, A-short peptide-B, where the short peptide is Ala-Val, can be A-Ala-Val-B or A-Val-Ala-B.

[0929] As used herein, the term "linking unit" refers to a fragment used to link antibodies.

[0930] As used herein, the term "about" generally refers to variations within a range of 0.5%-10% above or below a specified value, such as 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below a specified value. Unless otherwise apparent from the context, all numerical values ​​provided herein are modified by the term "about."

[0931] The endpoints of the ranges and any values ​​disclosed in this application are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered to be specifically disclosed in this application.

[0932] As used herein, the term "antibody" refers to any form of antibody having the desired biological activity. Therefore, it is used in the broadest sense and specifically includes, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized antibodies, fully human antibodies, chimeric antibodies, and camelized single domain antibodies.

[0933] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in small amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically include a large number of antibodies directed against (or specific for) different epitopes. The modifier "monoclonal" indicates the characteristic of the antibody obtained from a substantially homogeneous antibody population and is not to be construed as requiring the antibody to be produced by any particular method.

[0934] As used herein, the term "antigen-binding fragment" of an antibody includes fragments or derivatives of an antibody, typically including at least one fragment of the antigen-binding region or variable region (e.g., one or more CDRs) of a parent antibody that retains at least some of the binding specificity of the parent antibody. Examples of antibody binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, such as scFv; nanobodies and multispecific antibodies formed from antibody fragments. When the binding activity to the antigen is expressed on a molar concentration basis, the binding fragment or derivative typically retains at least 10% of its antigen-binding activity. Preferably, the binding fragment or derivative retains at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more of the antigen-binding affinity of the parent antibody. It is also contemplated that antigen-binding fragments of an antibody may include conservative or non-conservative amino acid substitutions that do not significantly change its biological activity (referred to as "conservative variants" or "function-conservative variants" of the antibody).

[0935] In this application, the term "ligand-drug conjugate" generally refers to a ligand linked to a biologically active cytotoxic drug via a stable linker. In some embodiments of this application, the "ligand-drug conjugate" may be an antibody-drug conjugate (ADC), which may be a monoclonal antibody or antigen-binding fragment linked to a biologically active cytotoxic drug via a stable linker.

[0936] In this application, the term "ligand" generally refers to small molecules, polypeptides, RNA, DNA, carbohydrates and macromolecular compounds that can recognize and bind to antigens or receptors associated with target cells. The function of the ligand can be to present the drug to the target cell population bound to the ligand. These ligands include but are not limited to protein hormones, lectins, growth factors, antibodies or other molecules that can bind to cells, receptors and / or antigens. In this application, the ligand can be represented by Ab, and the ligand antigen forms a connection bond with a connecting unit (also called "linker" or "linker") through a heteroatom on the ligand. The ligand can be an antibody or an antigen-binding fragment thereof. The antibody can be selected from a chimeric antibody, a humanized antibody, a fully human antibody or a murine antibody; the antibody can be a monoclonal antibody; the antibody can be a bispecific antibody. For example, the antibody can be an antibody targeting a target selected from the following targets: HER2, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70 and EGFR. For example, the antibody can be an antibody targeting a target selected from the group consisting of 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CCR7, CD11c, CD123, CD138, CD142, CD147, CD166, CD19, CD19,CD22, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD45(PTPRC), CD46, CD47, CD49D(ITGA4), CD56, CD66e, CD70 , CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CDllb, CEA, CEACAM5, c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT 4. DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRvIII, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3, FLT3, FOLR-α, G D2, GEDA, GPC-1, GPC-3, GPNMB, GPR20, GZMB, HER2, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL-4, IL-6, IR TA2, KISS1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MPF, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PTK7, P-Cadherin, RNF 43, ROR1, ROR2, SERPINE1, SLC39A6, SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, ADAM9, epidermal growth factor, brevican, mesothelin, sodium phosphate cotransporter 2B, Claudin18.2, endotenin receptor, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin α4β7, integrin αvβ6, trophoblast glycoprotein and tissue factor.

[0937] As used herein, the terms "specific binding," "specificity," or "specific for" refer to a non-random binding reaction between two molecules, such as an antibody and its antigen. In certain embodiments, an antibody that specifically binds to an antigen (or has specificity for an antigen) means that the antibody binds to the antigen with a specificity of less than about 10 -5 M, for example, less than about 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M or 10 -10 Affinity of M or less (K D ) binds to the antigen.

[0938] The term "drug loading" generally refers to the average amount of cytotoxic drug loaded per ligand and can also be expressed as the ratio of the cytotoxic drug to the ligand, for example, the average drug / ligand ratio (DAR). The cytotoxic drug loading can range from 0 to 20, as an integer or decimal. In embodiments of the present application, the drug / ligand ratio is expressed as k, and exemplary integers or decimals may be 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, or 9-10. The drug loading per ADC molecule after the conjugation reaction can be determined using conventional methods such as UV / visible spectroscopy, mass spectrometry, HIC, ELISA assays, and HPLC characterization.

[0939] As used herein, the term "pharmaceutically acceptable carrier and / or excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient, as is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995). Pharmaceutically acceptable carriers and / or excipients include, but are not limited to, pH adjusters, surfactants, ionic strength enhancers, diluents, agents that maintain osmotic pressure, agents that delay absorption, preservatives, and stabilizers. For example, pH adjusters include, but are not limited to, phosphate buffers. Surfactants include, but are not limited to, cationic, anionic, or nonionic surfactants, such as Tween-80. Ionic strength enhancers include, but are not limited to, sodium chloride. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Agents that maintain osmotic pressure include, but are not limited to, sugars, NaCl, and their analogs. Agents that delay absorption include, but are not limited to, monostearate and gelatin. Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols and polyols (such as glycerol), etc. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, etc. Stabilizers have the meanings generally understood by those skilled in the art, and are capable of stabilizing the desired activity of the active ingredient in the drug, including, but not limited to, sodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dried whey, albumin, or casein), or degradation products thereof (such as lactalbumin hydrolysate), etc.

[0940] As used herein, the term "treatment" is intended to alleviate, mitigate, improve, or eliminate the disease state or condition being treated. If a subject receives a therapeutic amount of the ligand-conjugated drug or its racemate, enantiomer, diastereomer, pharmaceutically acceptable salt, or mixture of the foregoing forms according to the methods described herein, and the subject exhibits an observable and / or detectable reduction or improvement in one or more signs and symptoms, the subject is successfully "treated." It should also be understood that the treatment of the disease state or condition includes not only complete treatment, but also achieving some biologically or medically relevant results despite not achieving complete treatment.

[0941] As used herein, the term "prevention" is intended to avoid, reduce, prevent, or delay the onset of a disease or disease-related symptoms, provided that the disease or disease-related symptoms have not yet appeared before the administration of the relevant drug. "Prevention" does not necessarily require the complete prevention of the onset of a disease or disease-related symptoms. For example, if the administration of the relevant drug can reduce the risk of a subject developing a particular disease or disease-related symptom, or reduce the severity of related symptoms that later appear, it can be considered to have "prevented" the onset or development of the disease.

[0942] As used in this application, the DMSO solvent used to dissolve compounds in NMR structure identification is deuterated DMSO, namely DMSO-d6. BRIEF DESCRIPTION OF THE DRAWINGS

[0943] FIG1 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention on HPAF-II transplanted tumors;

[0944] FIG2 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention on Panc 08.13 transplanted tumors;

[0945] FIG3 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention (5 mg / kg) on ​​NCI-H929 transplanted tumors;

[0946] FIG4 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention (3 mg / kg) on ​​NCI-H929 transplanted tumors;

[0947] FIG5 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention on KMS11 transplanted tumors;

[0948] FIG6 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention on SNU-5 transplanted tumors;

[0949] FIG7 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention on Calu3 transplanted tumors;

[0950] FIG8 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention on NCI-H1975 transplanted tumors;

[0951] FIG9 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention on NCI-H820 transplanted tumors;

[0952] FIG10 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention on LD1-0038-361928 transplanted tumors. Beneficial effects

[0953] The linker-protein translation inhibitor conjugate provided by the present invention has one or more of the following advantages:

[0954] (1) Extremely high stability;

[0955] (2) High coupling efficiency;

[0956] (3) The coupling reaction is not sensitive to pH and has high coupling efficiency at pH values ​​of 4.0-9.0.

[0957] The ligand-drug conjugates of the present invention have one or more of the following advantages:

[0958] (1) The conjugate obtained by the coupling method of the present invention can effectively improve the stability of drug molecules in the circulation, reduce the shedding of drugs in non-target cells, and reduce off-target toxicity;

[0959] (2) The conjugate has good tumor tissue targeting ability;

[0960] (3) The conjugate has a good therapeutic effect on tumor animal models.

[0961] In addition, the coupling method of the present invention has a wide range of applications and can be widely used for coupling bioactive molecules with antibodies or targeted small molecule ligands.

[0962] In summary, the linker and ligand-drug conjugates of the present invention have significant clinical value. DETAILED DESCRIPTION

[0963] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the reactions were carried out under conventional conditions or the conditions recommended by the manufacturer. Reagents or instruments used that do not specify the manufacturer are commercially available conventional products. The salts of the compounds obtained in the present invention can be neutralized by conventional methods to obtain the corresponding free base compounds.

[0964] Table 1

[0965] General chiral column separation method

[0966] The racemic compound of the present invention is dissolved in methanol and separated using a chiral preparative chromatographic column (see the table below) to obtain the product compound. The absolute configuration of the compound can be determined by optical rotation detection, X-ray single crystal diffraction, etc.

[0967] Example 1: Synthesis of intermediates

[0968] Example 1.1 Synthesis of small molecule compounds

[0969] Compounds 1 and 1A

[0970] Compounds 1 and 1A were synthesized according to the literature Liu, Tao; Nair, Somarajan J.; Lescarbeau, André; Belani, Jitendra; Peluso, Stéphane; Conley, James et al. (2012): Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors. In Journal of medicinal chemistry 55(20), pp.8859-8878. DOI: 10.1021 / jm3011542. See Supporting information, page 7, compound S2.

[0971] Compound 2

[0972] Step 1: Compound 1 (750 mg, 1.66 mmol) and compound 2A (2752 mg, 9.93 mmol) were dissolved in CHCl₃ / TFE = 7 / 3 (15 mL). The reaction mixture was pumped at a rate of 15 mL / h via a 20 mL syringe via a syringe pump into a coil wrapped around a jacketed glass cylinder equipped with a 250 W UV lamp. The temperature of the external circulating hydrazine was adjusted to maintain an internal reaction temperature of 0-5°C. The UV lamp was simultaneously turned on and the reaction mixture was irradiated for 1 hour. The solvent was removed under reduced pressure and the excess cinnamate was removed by column chromatography (EA / PE = 1 / 3). The desired racemic crude product 2B was obtained as a yellow oil (900 mg, yield: 75%). LCMS [M+H+18] + =748.5.

[0973] Step 2: Mix the racemate of compound 2B (5.2 g, 7.96 mmol) with MeOH (50 mL), add NaOMe (1.1 g, 19.91 mmol) at 0°C, and stir at 65°C for 1.5 h. The solution was concentrated, washed sequentially with H2O, aqueous NH4Cl solution, and saturated brine, dried over Na2SO4, concentrated under reduced pressure, and purified on a silica gel column (0.2% FA, EA / PE = 1 / 3) to obtain the racemate of compound 2C (3.8 g, yield: 65%). LCMS [M+H-18] + =714.4.

[0974] Step 3: Mix the racemate of compound 2C (3.8 g, 5.21 mmol) with MeCN / CHCl3 = 1 / 1 (100 mL / 100 mL). Add NaBH(OAc)3 (5.5 g, 26.03 mmol) and AcOH (3.1 g, 52.05 mmol) at 0°C and stir at room temperature for 2 h. Extract the reaction solution with EA. The organic phase is washed sequentially with water and saturated brine, dried over anhydrous Na2SO4, and purified on a silica gel column (PE:EA = 1 / 1) to obtain the racemate of compound 2D (1.9 g, yield: 50%). LCMS [M+H] + =716.5.

[0975] Step 4: The racemate of compound 2D (1.3 g, 1.78 mmol), Pd2(dba)3 (325.0 mg, 0.36 mmol), DPPF (393.6 mg, 0.71 mmol), and Zn(CN)2 (519.5 mg, 4.44 mmol) were heated to 150°C in NMP (20 mL) for 2 h. The solution was diluted with water, extracted with EA, washed sequentially with water and brine, dried over anhydrous Na2SO4, and purified on a silica gel column (EA / PE = 1 / 1) to afford the racemate of compound 2E (1.1 g, yield: 91%).

[0976] 1 H NMR (400MHz, CDCl3) δ7.48-7.40 (m, 6H), 7.37 (dt, J = 12.4, 5.3Hz, 3H), 6.96 (t, J=7.9Hz,1H),6.85(s,1H),6.51(d,J=7.7Hz,1H),6.45(s,1H),6.36(d,J=1.9Hz ,1H),6.22(d,J=1.9Hz,1H),5.09(d,J=1.7Hz,2H),5.01(d,J=6.4Hz,1H),4.35 (d,J=14.2Hz,1H),3.95-3.81(m,4H),3.66(d,J=3.8Hz,3H),1.53-1.47(m,9H). LCMS[M+H-18] + =605.4.

[0977] Step 5: Pd(OH)2 / C (10%, 250 mg) was added to a solution of the racemate of compound 2E (500.0 mg, 0.74 mol) in EA / MeOH / THF / DCM = 20:2:2:0.2 (40 mL). The atmosphere was replaced with hydrogen three times, and the mixture was stirred at room temperature for 16 hours. The suspension was filtered, and the filter cake was washed with MeOH / DCM (1 / 10). The filtrate was concentrated and purified on a silica gel column (DCM / MeOH = 10 / 1) to obtain the racemate of compound 2F (300 mg, yield: 69%).

[0978] 1 H NMR (400MHz, CDCl3) δ7.42(d,J=8.6Hz,2H),7.33(d,J=8.6Hz,2H),6.98(dd,J=16.1 ,8.2Hz,1H),6.87(s,1H),6.51(d,J=7.7Hz,1H),6.33(s,1H),6.24(d,J=1.8Hz,1H), 6.12(d,J=1.7Hz,1H),4.98(d,J=6.3Hz,1H),4.35(d,J=14.2Hz,1H),3.90(dd,J=14 .1, 6.4Hz, 1H), 3.83 (d, J = 15.4Hz, 3H), 3.67 (d, J = 4.5Hz, 3H), 1.50 (d, J = 4.8Hz, 9H). LCMS[M+H] + =515.4.

[0979] Step 6: The racemate of compound 2F (306.0 mg, 0.52 mmol) and K2CO3 (143.6 mg, 1.04 mmol) were stirred in DMF (10 mL). Compound 2G (185.8 mg, 0.52 mmol) was added, and the reaction mixture was stirred at 60°C for 20 min. The solution was diluted with water, extracted with EA, washed sequentially with water and brine, dried over anhydrous Na2SO4, and purified on a silica gel column (EA / PE = 1 / 1) to obtain the racemate of compound 2H (300 mg, yield: 80%).

[0980] 1H NMR (400MHz, CDCl3) δ7.41(d,J=8.4Hz,2H),7.33(d,J=8.5Hz,2H),7.00-6.92(m,2H),6.69(d,J=1.7Hz,1H),6.53(d,J=7.6Hz,1H ), 6.45 (d, J = 1.7Hz, 1H), 6.39 (s, 1H), 4.99 (d, J = 5.9Hz, 1H), 4.39 (d, J = 14.2Hz, 1H), 3.99-3.91 (m, 4H), 3.68 (s, 3H), 1.50 (s, 9H). LCMS[MH] + =719.2.

[0981] Step 7: A solution of the racemate of compound 2H (30 mg, 0.042 mmol) was added to DMF (3 mL). Under nitrogen, compound 2I (60 mg, 0.167 mmol), Pd(PPh3)4 (4.8 mg, 0.0042 mmol), and CuI (1.6 mg, 0.0083 mmol) were added. The mixture was stirred at 100°C for 1 h. The suspension was filtered and purified on a silica gel column (DCM / MeOH = 10 / 1) to obtain the racemate of compound 2J (15 mg, yield: 56%). LCMS [M+H] + =640.3.

[0982] Step 8: To a solution of the racemate of compound 2J (15 mg, 0.02 mmol) was added THF / 6M HCl = 1 / 1 (4 mL) and stirred at room temperature for 1 h. The solution was concentrated and purified by silica gel chromatography (DCM / MeOH) to afford the racemate of 2 as a white solid (4.5 mg, yield: 35%). Further chiral column separation afforded compound 2.

[0983] LCMS [M+H] + =540.1.

[0984] 1H NMR (400MHz, DMSO) δ8.25(d,J=0.7Hz,1H),7.50(d,J=8.6Hz,2H),7.41(d,J=0.7Hz,1H),7. 31(d,J=8.6Hz,2H),7.19(d,J=1.1Hz,1H),7.14(d,J=1.0Hz,1H),6.67(t,J=7.7Hz,1H),6. 26(s,1H),6.19-6.10(m,2H),5.63(s,1H),5.45(d,J=5.4Hz,1H),4.83(s,2H),4.66(t,J=5 .1Hz,1H),4.27(d,J=14.0Hz,1H),3.97(dd,J=13.9,4.8Hz,1H),3.83(s,3H),3.58(s,3H).

[0985] Step 9: 60% NaH (21.87 g, 546.88 mmol) was added to THF (2.5 L) at 0°C. The mixture was stirred at 0°C for 1 h, followed by the dropwise addition of compound 2L (99.59 g, 546.88 mmol). The mixture was stirred at 0°C for 2 h, followed by the dropwise addition of a solution of compound 2K (100.00 g, 451.97 mmol) in THF (300 mL). The mixture was stirred at room temperature for 3 h, followed by the addition of 10% HCl and extraction with ethyl acetate. The combined organic phases were dried over NaSO, filtered, and concentrated to afford the crude product, which was slurried with MTBE to afford 2A (120 g, 95.73% yield) as a pale yellow solid.

[0986] 1 H NMR (400MHz, DMSO) δ9.47(s,1H),7.74(s,1H),7.58(d,J=16.0Hz,1H),7.49(d,J= 7.2Hz, 1H), 7.36-7.28 (m, 2H), 6.49 (d, J = 16.0Hz, 1H), 3.73 (s, 3H), 1.49 (s, 9H).

[0987] Compound 3

[0988] Step 1: To a solution of the racemate of compound 2H (50 mg, 0.07 mmol) in dioxane / water (2 mL / 0.5 mL) were added NaCO (48.8 mg, 0.14 mL), Pd(PPh) (4.88 mg, 0.01 mmol), and compound 3A (28.3 mg, 0.08 mmol). The mixture was reacted at 80°C under nitrogen for 2 hours. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / EA = 1 / 1) to afford the racemate of compound 3B as a light yellow solid (40 mg, yield: 76%). LCMS: [M+H] + =796.4.

[0989] Step 2: The racemate of compound 3B (20 mg, 0.025 mmol) was dissolved in 6M HCl (1 mL) / THF (0.5 mL) and stirred for 3 hours. The reaction solution was purified by preparative HPLC (ACN / H2O from 0 to 100%) to obtain the racemate of 3 as a white solid (6 mg, yield: 45%). Further chiral column separation afforded compound 3.

[0990] LCMS: [M+H] + =540.2.

[0991] 1 H NMR (400MHz, DMSO) δ8.46 (s, 1H), 7.79 (s, 1H), 7.51 (d, J = 8.4Hz, 2H), 7.32 (d, J = 8.4Hz, 2H), 7.03-6.89 (m, 3H), 6. 68(s,3H),4.68(d,J=4.8Hz,1H),4.34(d,J=13.6Hz,1H),4.09(dd,J=14.0,4.8Hz,1H),3.83(s,3H),3.59(s,3H).

[0992] Compound 4

[0993] Step 1: A solution of the racemate of compound 2J (150 mg, 0.23 mmol) and LiOH (25 mg, 0.59 mmol) in THF / H2O / MeOH (10 mL) was stirred at room temperature for 3 h. The pH was adjusted to 5 with 3 M hydrochloric acid and the mixture was concentrated and purified on a silica gel column (DCM / MeOH) to obtain the racemate of compound 4A as a white solid (130 mg, yield: 88%). LCMS [M+1] + =626.1.

[0994] Step 2: HATU (61 mg, 0.16 mmol) and DIEA (31 mg, 0.24 mmol) were added separately to a solution of the racemate of compound 4A (50 mg, 0.08 mmol) in DMF (3 mL). N,O-dimethylhydroxylamine (16 mg, 0.16 mmol) was added under N2 conditions and stirred at room temperature for 3 h. The mixture was concentrated and purified on silica gel (DCM / MeOH) to obtain the racemate of compound 4B as a white solid (20 mg, yield: 38%). LCMS [M+1] + =669.2.

[0995] Step 3: The racemate of compound 4B (12 mg, 0.02 mmol) was dissolved in a 1 / 1 THF / 6M HCl solution (4 mL) and stirred at room temperature for 1 h. The solution was concentrated and purified on silica gel (DCM / MeOH) to afford the racemate of 4 as a white solid (2.2 mg, yield: 22%). This was further resolved on a chiral column to afford 4 as a white solid.

[0996] LCMS [M+H] + =569.1.

[0997] 1H NMR (400MHz, DMSO) δ8.25(s,1H),7.53(d,J=8.5Hz,2H),7.41(s,1H),7.31(d,J=8.5Hz,2 H),7.20(d,J=0.9Hz,1H),7.15(s,1H),6.66(t,J=7.7Hz,1H),6.21(s,1H),6.16(d,J=7.9 Hz,1H),6.06(d,J=7.5Hz,1H),5.61(s,1H),5.07(d,J=4.8Hz,1H),4.83(s,2H),4.78(t,J =4.8Hz,1H),4.32(d,J=13.9Hz,1H),4.16(s,1H),3.90(s,3H),3.84(s,3H),3.09(s,3H).

[0998] Compound 5

[0999] Step 1: HATU (36.4 mg, 0.1 mmol) and DIEA (18.6 mg, 0.14 mmol) were mixed with a DMF (3 mL) solution of the racemate of compound 4A (30 mg, 0.05 mmol) under N2, followed by the addition of O-methylhydroxylamine (8 mg, 0.10 mmol) and stirring at room temperature for 3 h. The mixture was concentrated and purified by silica gel (DCM / MeOH) chromatography to afford the racemate of compound 5A as a white solid (20 mg, yield: 65%). LCMS [M+1]+ =655.2.

[1000] Step 2: The racemate of compound 5A (12 mg, 0.03 mmol) was dissolved in a 1 / 1 THF / 6M HCl solution (4 mL) and stirred at room temperature for 1 h. The solution was concentrated and purified by silica gel (DCM / MeOH) chromatography to afford the racemate of 5 as a white solid (2.6 mg, 31% yield). This was then resolved by chiral column chromatography to afford compound 5.

[1001] LCMS [M+H] + =555.1.

[1002] 1 H NMR (400MHz, DMSO) δ11.27(s,1H),8.26(s,1H),7.54(d,J=8.5Hz,2H),7.42( s,1H),7.30(d,J=8.3Hz,2H),7.20(s,1H),7.16(s,1H),7.11(t,J=7.5Hz,1H) ,6.87(d,J=18.2Hz,3H),5.65(s,1H),5.27(s,1H),4.60(d,J=4.4Hz,1H),4. 46(d,J=13.9Hz,1H),3.84(s,3H),3.74(dd,J=14.1,4.1Hz,1H),3.54(s,3H).

[1003] Compound 6

[1004] Step 1: The racemate of compound 4A (30.0 mg, 0.05 mmol), HATU (36.5 mg, 0.10 mmol), and DIEA (18.6 mg, 0.14 mmol) were stirred in DMF (3 mL) for 5 min. Dimethylamine hydrochloride (7.8 mg, 0.10 mmol) was added to the mixture and stirred for 10 min.

[1005] The solution was extracted twice with EA. The organic layer was washed with saturated brine, dried over Na2SO4, concentrated under reduced pressure, and purified on a silica gel column (DCM / MeOH = 10 / 1) to obtain the racemate of compound 6A (16.0 mg, 51% yield). LCMS [M+H] + =653.2.

[1006] Step 2: Mix the racemate of compound 6A (16.0 mg, 0.02 mmol) with THF (0.5 mL), add 6M HCl (0.5 mL) at 0°C, and stir at room temperature for 4 hours. The concentrate was purified by preparative HPLC to afford the racemate of compound 6 (5.9 mg, 46% yield) as a white solid. Further chiral column separation afforded compound 6.

[1007] LCMS [M+H] + =553.2.

[1008] 1 H NMR (400MHz, DMSO) δ8.25(s,1H),7.51(d,J=8.4Hz,2H),7.41(s,1H),7.35(d,J=8.4Hz,2H),7.18(d,J=19.6Hz,2H),6.73(d,J=7.4Hz,1H),6.40- 6.17(m,3H),5.62(s,1H),4.98(s,1H),4.73(s,1H),4.39(d,J=13.4Hz,1 H), 4.15 (dd, J = 13.3, 4.9Hz, 1H), 3.84 (s, 3H), 3.29 (s, 3H), 2.79 (s, 3H).

[1009] Compound 7

[1010] Step 1: Dissolve the racemate of compound 2H (50 mg, 2.2 mmol), pyrazole (3.7 g, 13.3 mmol), tBuXPhos-Pd-G3 (4.8 mg, 0.01 mmol), tBuXPhos (12.78 mg, 0.03 mmol), and Cs2CO3 (67 mg, 0.21 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at 100°C under nitrogen for 16 hours. After completion of the reaction, the mixture was quenched with water, extracted with EA, and the layers were separated. The organic phase was concentrated and purified on a silica gel column (DCM / EA = 1 / 1) to obtain the racemate of 7A as a light yellow solid (10 mg, yield: 20%). LCMS [M+H] + =639.2.

[1011] Step 2: The racemate of compound 7A (10 mg, 0.016 mmol) was dissolved in THF (0.5 mL), 6 M HCl (0.5 mL) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was purified by flash column chromatography (ACN-H2O = 0-100%) to give the racemate of white solid 7 (4 mg, yield: 47%), which was further resolved by chiral column to give compound 7.

[1012] LCMS [M+H] + =539.1.

[1013] 1H NMR (400MHz, DMSO) δ8.58(d,J=2.4Hz,1H),7.75(d,J=1.6Hz,1H),7.51(d,J=8.4Hz,2H),7 .31(d,J=8.4Hz,2H),7.13(d,J=1.6Hz,1H),7.05(d,J=1.6Hz,1H),6.68(t,J=7.6Hz,1H), 6.58-6.54(m,1H),6.23(s,1H),6.14(m,2H),5.54(s,1H),5.39(d,J=5.2Hz,1H),4.82(s, 2H), 4.64 (t, J = 5.2Hz, 1H), 4.26 (d, J = 14.0Hz, 1H), 3.95 (m, 1H), 3.82 (s, 3H), 3.58 (s, 3H).

[1014] Compound 8

[1015] Step 1: To a solution of the racemate of compound 2H (54 mg, 0.075 mmol) and compound 8A (215 mg, 0.6 mmol) in DMF (5 mL) were added Pd(PPh) (9 mg, 0.0075 mmol) and CuI (28.5 mg, 0.015 mmol). The atmosphere was then purged with nitrogen for 2 minutes and microwaved at 120°C for 2 hours. The crude product was concentrated and purified by preparative chromatography to afford the racemate of 8B (20 mg, 40.9%) as a white solid.

[1016] LCMS: [M+H-C4H8] + =595.2.

[1017] Step 2: To a solution of the racemate of compound 8B (20 mg, 0.0308 mmol) in THF (1 mL) was added aqueous HCl (0.5 mL, 6 M). The reaction mixture was allowed to react at room temperature for 3 hours. The crude product was concentrated and purified by preparative HPLC to afford the racemate of compound 8 as a white solid (9 mg, yield: 53.1%). Further chiral column separation afforded compound 8.

[1018] LCMS: [M+H] + =551.2.

[1019] 1H NMR (400MHz, DMSO) δ9.53(s,2H),8.94(d,J=4.9Hz,2H),7.64(d,J=2.8Hz,2H),7.55-7.43(m,3H),7.36(d,J=8.6Hz,2H),7.14(t,J=7.6Hz,1H ),7.06-6.82(m,3H),5.66(d,J=58.4Hz,2H),4.74(d,J=4.6Hz,1H),4.41(d,J=13.8Hz,1H),4.18(d,J=4.8Hz,1H),3.86(s,3H),3.60(s,3H).

[1020] Compound 9

[1021] Step 1: Compound 1 (1.00 g, 2.21 mmol) and compound 9A (3.58 g, 22.08 mmol) were dissolved in a TFE / chloroform solution (CHCl₃ / TFE = 9 / 1, 18 mL). A 20 mL syringe was mounted on a syringe pump, which was connected to FEP tubing. The FEP tubing was then wrapped around two quartz cylinders, each housing a 250 W UV lamp. Both cylinders were cooled to -5°C using a low-temperature circulating pump, and a room-temperature water bath was placed outside the entire lamp system. Once the UV lamps were stably energized, the syringe pump was turned on, and the reaction solution was injected into the FEP tubes at a rate of 30 mL / h. The reaction solution was illuminated for a stable period of 1 hour. After the reaction was completed, the reaction solution was concentrated and separated by column chromatography (ethyl acetate / petroleum ether = 3 / 1) to remove excess cinnamate starting material. The crude product was diluted with ethyl acetate and reacted at 65°C for 1 hour. After further concentration, the racemic form of the target crude product 9B (0.96 g, yield 71%) was obtained as a yellow oil.

[1022] LCMS [M+H] + =615.5.

[1023] Step 2: The racemate of compound 9B (1.4 g, 2.27 mmol) was dissolved in methanol (100 mL) and NaOMe (0.3 g, 5.7 mmol) was added at 0°C. The reaction mixture was then incubated at 65°C for 1 hour. The reaction mixture was concentrated and separated by column chromatography (0.5% formic acid in ethyl acetate / petroleum ether = 1 / 3) to afford the racemate of target product 9C (0.96 g, 68% yield) as a yellow oil.

[1024] LCMS [M+H] + =615.1.

[1025] Step 3: The racemate of compound 9C (0.60 g, 0.977 mmol) and AcOH (1.06 g, 17.586 mmol) were dissolved in MeCN (40 mL) and DCM (40 mL). The mixture was then cooled to 0°C and protected with N2. STAB (1.04 g, 4.89 mmol) was added portionwise and stirred at room temperature for 1 hour. The reaction mixture was quenched with water, and aqueous NaHCO3 was added. The mixture was extracted twice with DCM. The organic layer was dried, concentrated under reduced pressure, and purified on a silica gel column (PE:EA) to afford the racemate of compound 9D as a white solid (0.32 g, 53% yield).

[1026] LCMS: [M+H] + =617.2.

[1027] Step 4: The racemate of compound 9D (2.00 g, 3.24 mmol), Cs2CO3 (1.58 g, 4.86 mmol), and MeOH (0.21 g, 6.48 mmol) were dissolved in toluene (30 mL). tBuXPhosPdG3 (51 mg, 0.06 mmol) was added and heated to 85°C for 3 hours. The reaction mixture was concentrated, diluted with MeOH / DCM (MeOH / DCM = 1 / 1), and filtered. The filtrate was concentrated and separated by column chromatography (EA / PE = 60%) to afford the racemate of the desired product 9E (810 mg, 44% yield) as a brown oil.

[1028] LCMS: [MH] - =567.0.

[1029] Step 5: Dissolve the racemate of compound 9E (300 mg, 0.53 mmol) and Pd / C (10%, 150 mg) in MeOH (15 mL) and react under H₂ for 2 hours at room temperature. The reaction mixture was filtered, and the filtrate was concentrated and separated by column chromatography to afford the racemate of target product 9F (270 mg, crude product not included in yield) as a white solid.

[1030] LCMS: [M+H] + =479.4.

[1031] Step 6: To 5 mL of DMF was added the racemate of compound 9F (360 mg, 0.75 mmol), compound 2G (268 mg, 0.75 mmol), and KCO (207 mg, 1.5 mmol) and stirred at 60°C for 1.5 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate and water. The organic phase was separated and dried over anhydrous NaSO. After filtration and concentration, the crude product was purified on a silica gel column (EA / DCM from 0 to 50%) to afford the racemate of 9G as a yellow solid (360 mg, yield: 78%).

[1032] LCMS: [MH] - =609.2.

[1033] Step 7: The racemate of compound 9G (340 mg, 0.56 mmol) was dissolved in DMF (5 mL), and compound 2I (1600 mg, 4.46 mmol), Pd(PPh3)4 (65 mg, 0.06 mmol), and CuI (21 mg, 0.11 mmol) were added. The mixture was reacted at 110°C under nitrogen for 16 hours. After cooling to room temperature, the reaction solution was directly purified on a silica gel column (PE / EA = 1 / 1) to obtain the racemate of 9H as a white solid (180 mg, yield: 61%).

[1034] LCMS [M+H] + =530.0.

[1035] Step 8: To a mixture of the racemate of compound 9H (80 mg, 0.15 mmol) and pyridine (0.5 mL) was added MsCl (171 mL, 1.5 mmol) at 0°C and reacted at 0°C for 1 hour. The mixture was diluted with ethyl acetate (5 mL), washed with 1M HCl (5 mL), and the layers separated. The organic phase was purified on a silica gel column (DCM / EA = 1 / 1) to afford the racemate of compound 9I as a white solid (90 mg, yield: 97%).

[1036] LCMS [M+H] + =608.1.

[1037] Step 9: Dissolve the racemate of compound 9I (90 mg, 0.15 mmol) in DMF (0.5 mL) and add NaCN (36 mg, 0.75 mmol). Stir at room temperature for 16 hours. Extract with ethyl acetate, separate the organic phase, and dry over anhydrous NaSO. Filter and concentrate. The crude product is purified on a silica gel column (DCM / EA = 1 / 1) to afford the racemate of compound 9J as a white solid (70 mg, yield: 88%).

[1038] LCMS [M+H] + =539.1.

[1039] Step 10: The racemate of compound 9J (10 mg, 0.016 mmol) was dissolved in THF (0.5 mL). A 2M solution of lithium aluminum hydride in THF (0.08 mL) was added at 0°C, the mixture was slowly warmed to room temperature, and stirred for 1 hour. NaSO·10HO was added to quench the mixture. The resulting mixture was filtered, and the filtrate was purified on a medium-pressure preparative column (ACN / HO = 0%-100%, containing 0.1% formic acid) to afford the racemate of 9J as a white solid (7 mg, yield: 70%). Compound 9 was further resolved on a chiral column to afford compound 9.

[1040] LCMS [M+H] + =515.1.

[1041] 1 H NMR (400MHz, DMSO) δ8.26(s,1H),7.42(s,1H),7.22(d,J=4.8Hz,2H),7.13(d,J=8.4Hz,2H),7.09-7.04(m,3H),6.8 1-6.76(m,2H),6.71(d,J=8.8Hz,2H),3.97(s,3H),3.66(s,3H),3.23(d,J=13.6Hz,5H),3.13(m,1H),2.93(s,1H).

[1042] Compound 10

[1043] Step 1: To a solution of 10A (12.11 g, 70 mmol) in THF (120 mL) was slowly added NaH (9.06 g, 234.6 mmol) at 0°C. The mixture was stirred at room temperature for 0.5 hours. BnOH (16.2 g, 150 mmol) was then added and stirred at room temperature for 3 hours. The mixture was slowly quenched with water at 0°C and extracted with EtOAc. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 19.6 g of compound 10B, yield: 89%. LCMS [M+H] + =317.2.

[1044] Step 2: To a solution of 10B (13.16 g, 41.6 mmol) in THF (150 mL) was slowly added dropwise MeMgBr solution (124.9 mL, 124.9 mmol) at -30°C. The mixture was then stirred at room temperature for 4.3 hours. The mixture was quenched with 6N HCl and stirred for another 2 hours. The organic phase was washed with 1N NaOH and water, separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give 7.12 g of compound 10C, yield: 46%. LCMS [M+H] +=334.2.

[1045] Step 3: Dissolve compound 10C (8.5 g, 25.5 mmol) in EA (60 mL), add Pd(OH)2 (850 mg), and stir at room temperature under a hydrogen balloon for 18 h. Concentrate to give 3.9 g of 10D as a white solid (yield: 100%). LCMS [M+H] + =154.2.

[1046] Step 4: To a solution of compound 10D (3.9 g, 25.5 mmol) and K2CO3 (9.85 g, 71.4 mmol) in acetone (40 mL) was added dropwise BnBr (4.36 g, 25.5 mmol). The mixture was stirred at room temperature for 48 h, acidified with acetic acid, diluted with water, extracted with EA, and the organic layer concentrated and washed with petroleum ether to obtain 4.80 g of an off-white solid 10E (yield: 77%). LCMS [M+H] + =244.1.

[1047] Step 5: To a solution of compound 10E (4800 mg, 19.73 mmol) in MeOH (60 mL) were added NaOH (2.368 g, 59.2 mmol) and 4-bromobenzaldehyde (3.65 g, 19.73 mol). The reaction solution was stirred at 70 ° C for 18 hours. Cooled and acidified with AcOH. Extracted with dichloromethane. The organic layer was washed with water and brine, dried and concentrated. The crude product was slurried with PE / EA to obtain 5.0 g of white solid 10F, yield: 60%. LCMS [M+H] + =410.2.

[1048] Step 6: To a solution of compound 10F (1150 mg, 2.8 mmol, 1.0 eq) in MeOH / H2O (130 mL / 65 mL) was added NaOH (785 mg, 19.6 mmol, 7.0 eq) and H2O2 (12.5 mL). The reaction mixture was stirred at 50°C for 3 hours. The mixture was cooled and filtered, and the solid was washed with a small amount of dichloromethane. The solid was acidified with AcOH and extracted with DCM. The organic layer was washed with water and brine, dried, and concentrated to give 670 mg of 10G as a white solid, yield: 57%. LCMS [M+H] + =424.0.

[1049] 1H NMR (400MHz, DMSO) δ9.99 (s, 1H), 8.56 (d, J = 2.4Hz, 1H), 8.18 (d, J = 8.8Hz, 2H) ,7.94(d,J=2.4Hz,1H),7.80(d,J=8.8Hz,2H),7.60-7.37(m,5H),5.34(s,2H).

[1050] Step 7: Compound 10G (2.5 g, 5.9 mmol) and compound 2A (9.8 g, 35.38 mmol) were dissolved in CHCl3 / TFE (7 / 3, 20 mL), and the reaction mixture was injected into a coil wrapped around a jacketed glass cylinder equipped with a 250W UV lamp at a rate of 12 mL / h through a syringe pump. The temperature of the external circulating cold hydrazine was adjusted to make the internal reaction temperature 0-5°C. At the same time, the UV lamp was turned on and the reaction mixture was irradiated for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / hexane) to remove excess cinnamate to obtain a racemate of the light yellow oily product 10H (3.6 g, 75% yield). LCMS [M+H] + =700.9.

[1051] Step 8: The racemate of compound 10H (2.5 g, 3.56 mmol) was dissolved in methanol (60 mL), and NaOMe (481 mg, 8.91 mmol) was added at 0°C. The reaction solution was then stirred at 65°C for 1.5 hours. After completion of the reaction, the reaction solution was concentrated and extracted with EA, washed with water, NH4Cl solution, and saturated brine, and finally dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was performed on a silica gel column (0.2% FA, EA / PE = 1 / 3) to obtain the racemate of compound 10I (3.0 g, crude product). LCMS [M+H] + =701.0.

[1052] Step 9: The racemate of compound 10I (3.0 g, 4.28 mmol) was dissolved in a mixed solvent of ACN / CHCl3 = 1 / 1 (40 mL / 40 mL). Na(AcO)3BH (4.533 g, 21.38 mmol) and AcOH (2.566 g, 47.0 mmol) were added at 0°C, and the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated and extracted with EA, washed with water and saturated brine, and finally dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was performed on a silica gel column (0.2% FA, EA / PE = 3 / 2) to obtain 500 mg of the racemate of compound 10J. LCMS [M+H] + =703.0.

[1053] 1 H NMR (400MHz, CDCl3) δ8.06 (s, 1H), 7.86 (d, J = 1.9Hz, 1H), 7.43 (d, J = 4.4Hz, 4H), 7.40 (dd, J = 8. 2,5.0Hz,2H),7.28(s,2H),7.15(d,J=8.5Hz,1H),7.10(d,J=2.0Hz,1H),7.06(d,J=8.7Hz,2H) ,7.00(t,J=7.9Hz,1H),6.90(s,1H),6.57(d,J=7.6Hz,1H),6.35(s,1H),5.14(s,2H),5.06(d, J=6.0Hz, 1H), 4.41 (d, J=13.9Hz, 1H), 3.95 (dd, J=14.0, 6.0Hz, 1H), 3.67 (s, 3H), 1.51 (s, 9H).

[1054] Step 10: To a solution of the racemate of compound 10J (500 mg, 0.71 mmol), DPPF (155 mg, 0.28 mmol), and Zn(CN)2 (208 mg, 1.80 mmol) in NMP (25 mL) was added Pd2(dba)3 (128 mg, 0.14 mmol). The reaction mixture was heated to 150°C under N2 protection for 1.2 hours. The solution was diluted with water and extracted with EA. The organic layer was washed with water and brine, dried, concentrated, and purified on a silica gel column (EA / PE = 1 / 1) to obtain 300 mg of the racemate of 10K as a yellow solid, in a yield of 65%. LCMS: [M+H] + =650.0.

[1055] Step 11: To a solution of the racemate of compound 10K (300 mg, 0.46 mol) in EA / MeOH / THF / DCM = 20:2:2:0.2 (7 mL) was added Pd(OH)2 / C (10%, 0.1 g). The mixture was stirred at room temperature under a hydrogen balloon for 18 hours. The solid was removed by filtration, and the filter cake was washed with MeOH / DCM (1 / 10). The combined filtrates were concentrated to give 0.22 g of the racemate of 10L as a white solid, yield: 87.0%. LCMS: [M+H] + =560.2.

[1056] Step 12: To a solution of the racemate of compound 10L (220 mg, 0.39 mmol) and compound 2G (150 mg, 0.39 mmol) in DMF (3 mL) was added K2CO3 (116 mg, 0.78 mmol). The mixture was stirred at 60°C for 1 hour. Water was added to quench the mixture, and the mixture was extracted with EtOAc. The organic phase was separated, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (EA-PE / DCM=0-50%) to give 221 mg of the racemate of 10M as a yellow solid, yield: 82%. LCMS [M+H-C4H8] + =636.1.

[1057] Step 13: The racemate of compound 10M (70 mg, 0.1 mmol), compound 2I (280 mg, 0.8 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) and CuI (4 mg, 0.02 mmol) were added to DMF (3 mL), and then stirred at 135°C under N2 protection in a microwave for 5 hours. Water was added and extracted with EA. The organic layer was washed with water and saturated brine, then dried and concentrated. The crude product was dissolved in DCM, and Boc2O (2 equivalents) and DIPEA (3 equivalents) and DMAP (0.2 equivalents) were added. The mixture was stirred at 40°C for 18 hours. It was concentrated and purified by flash chromatography (DCM / EA=1:1, DCM:MeOH=20:1) to give 60 mg of the racemate of 10N as a white solid, yield: 98%. LCMS [M+H] + =611.2.

[1058] Step 14: To a solution of the racemate of compound 10N (60 mg, 0.1 mmol) in THF (2 mL) was added H2O (2 mL), MeOH (2 mL), and LiOH (12.6 mg, 0.30 mmol), followed by stirring at room temperature for 5 hours. Purification by reverse phase chromatography (MeCH / HCO2H / H2O) afforded 30 mg of the racemate of compound 10N as a white solid, yield: 51%. LCMS [M+H] + =597.2.

[1059] Step 15: The racemate of compound 10O (30 mg, 0.048 mmol), N,O-dimethylhydroxylamine (9 mg, 0.096 mmol), HATU (18 mg, 0.048 mmol), and TMP (24 mg, 0.192 mmol) were added to DMF (1 mL), and the solution was stirred at 50°C for 18 hours. Purification by reverse phase column chromatography (ACN / H2O = 0%-100%) afforded 10 mg of the racemate of compound 10P as a white solid, yield: 33%. LCMS: [M+H] + =640.3.

[1060] Step 16: To a solution of the racemate of compound 10P (10 mg, 0.016 mmol) in THF (0.5 mL) was added dropwise 6 M HCl (0.5 mL), and the solution was stirred at room temperature for 4 hours. The reaction solution was separated by reverse-phase preparative column chromatography using ACN / H2O (5%-95%, +0.1% NH4HCO3) to afford 1.1 mg of the racemate of compound 10 as a white solid, yield: 10%. Further chiral column separation afforded compound 10. LCMS: [M+H] + =540.2.

[1061] Compound 11

[1062] Step 1: A solution of the racemate of compound 4A (10 mg, 0.02 mmol), compound 11A (12.7 mg, 0.1 mmol), tert-dodecanethiol (38.4 mg, 0.2 mmol), TMP (0.4 mg, 0.04 mmol), and meso-tetraphenylporphyrin zinc (1.3 mg, 0.001 mmol) in DMF (1 mL) was transferred to a microwave tube. The microwave tube was irradiated with 25W red light and maintained at 80°C. EDCI (36.6 mg, 0.2 mmol dissolved in 1 mL DMF) was added dropwise to the reaction system. The reaction solution was stirred at 80°C under 25W red light for 30 minutes. The reaction mixtures from three parallel reactions were combined and purified by reverse phase column chromatography (H2O:ACN = 0-100%) to afford 9 mg of the racemate of 11B as a white solid in a yield of 33%. LCMS: [M+H-C4H8] + =526.2.

[1063] Step 2: To a solution of the racemate of compound 11B (25 mg, 0.04 mmol) in THF (1 mL) was added 6 M HCl (1 mL). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and purified by reverse-phase column chromatography (H₂O:ACN = 0-100%) to afford 9 mg of the racemate of compound 11 as a white solid (yield: 40%). Further chiral column separation afforded compound 11. LCMS [M+H]⁺ = 482.0.

[1064] 1 H NMR (400MHz, DMSO) δ8.25 (s, 1H), 7.53 (d, J = 8.5Hz, 2H), 7.41 (s, 1H), 7.30 (d, J=8.5Hz,2H),7.16(d,J=12.3Hz,2H),6.73(t,J=7.7Hz,1H),6.35(s,1H),6.2 2(t,J=7.7Hz,2H),5.34(s,1H),4.90-4.73(m,3H),4.47(s,1H),4.03(dd,J=1 4.3, 6.1Hz, 1H), 3.85 (s, 3H), 2.78-2.60 (m, 1H), 2.08 (dd, J = 12.8, 6.1Hz, 1H).

[1065] Compound 12

[1066] Step 1: Dissolve the racemate of compound 9H (42.3 mg, 0.08 mmol) and LiOH (16.8 mg, 0.4 mmol) in MeOH / H₂O (5 mL / 1 mL), stir at room temperature for 12 h, adjust the pH to 2-3 with 1 M aqueous hydrochloric acid, and extract with ethyl acetate (20 mL). The organic phase is dried over sodium sulfate and concentrated to afford 35 mg of the racemate of compound 12A as a white solid, yield: 84.6%. LCMS [M+H] + =516.2.

[1067] Step 2: The racemate of compound 12A (31 mg, 0.06 mmol) was mixed with Boc-ethylenediamine (19 mg, 0.12 mmol), 2,4,6-trimethylpyridine (22 mg, 0.18 mmol), and HATU (34 mg, 0.09 mmol) in DMF (3 mL) and stirred at room temperature for 12 hours. 50 mL of water was then added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, dried, and concentrated. The crude product was purified on a silica gel column (PE / EA = 1 / 2) to obtain 33 mg of the racemate of compound 12B as a white solid, in a yield of 83.7%. LCMS [M+H] + =658.2.

[1068] Step 3: To a solution of the racemate of compound 12B (33 mg, 0.05 mmol) in THF (3 mL) was added aqueous HCl (1 mL, 6 M). The reaction mixture was allowed to react at room temperature for 12 hours. The crude product was concentrated and purified by preparative chromatography to afford 20 mg of the racemate of compound 12 as a white solid (yield: 71.4%). Further chiral column separation afforded compound 12.

[1069] LCMS [M+H] + =558.2.

[1070] 1 H NMR (400MHz, DMSO) δ8.45(s,2H),8.24(d,J=0.6Hz,1H),7.40(d,J=0.6Hz,1H),7. 19(d,J=1.0Hz,1H),7.14(d,J=0.9Hz,1H),7.10-7.01(m,4H),6.97(dd,J=10.1,7. 4Hz,3H),6.59(d,J=9.0Hz,2H),5.32(s,1H),4.65(d,J=4.8Hz,1H),4.30(d,J=14 .1Hz,1H),3.90-3.86(m,1H),3.84(s,3H),3.59(s,3H),3.14(s,2H),2.65(s,2H).

[1071] Compound 13

[1072] Step 1: Dissolve the racemate of compound 12A (350 mg, 0.68 mmol) in DMF (2 mL), then add N,O-dimethylhydroxylamine hydrochloride (132.5 mg, 1.36 mmol), HATU (310 mg, 0.82 mmol), and DIEA (263.2 mg, 2.04 mmol) in that order. Stir the reaction mixture at room temperature for 2 hours, then spin dry. Purify by reverse-phase chromatography (acetonitrile / water = 5%-95%, 214 nm, 20 min) to afford 300 mg of the racemate of compound 13A as a white solid, yield: 79%. LCMS [M+Na] + =581.2.

[1073] Step 2: Iodomethyl pivalate (2000 mg, 8.26 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) solution and isopropylmagnesium chloride (2.0 M, 8.26 mL, 16.52 mmol) was added at -70 ° C. The reaction mixture was stirred at -70 ° C for 2 hours to obtain a solution of compound 13B. The racemate of compound 13A (100 mg, 0.18 mmol) was dissolved in 1 mL of anhydrous tetrahydrofuran and a solution of compound 13B (5 mL) was added at -70 ° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (15 mL), extracted with dichloromethane (15 mL × 2), washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative chromatography to obtain 5.5 mg of the racemate of white solid 13, with a yield of 5.8%. Further chiral column separation gave compound 13. LCMS [M+H] + =530.0.

[1074] 1 H NMR (400MHz, DMSO-d6) δ8.25 (d, J = 0.8Hz, 1H), 7.43-7.41 (m, 3H), 7.37-7. 35(m,2H),7.31-7.27(m,2H),7.22-7.24(m,1H),7.17(d,J=1.2Hz,1H),7.1 2(d,J=1.2Hz,1H),6.93-6.91(m,2H),5.40(s,1H),4.83(d,J=4.8Hz,1H), 4.40-4.36(m,1H),3.80(s,3H),3.76-3.73(m,4H),3.10(t,J=12.0Hz,2H).

[1075] Compound 14

[1076] Step 1: A solution of the racemate of compound 9D (2.30 g, 3.7 mmol), Zn(CN)2 (1.09 g, 9.3 mmol), Pd(dba)3 (0.68 g, 0.75 mmol) and DPPF (0.83 g, 1.49 mmol) in NMP (160 mL) was stirred at 150°C for 4 hours. The mixture was extracted with H2O and EA, and the combined organic layers were washed with brine (2 x 10 mL). The mixture was purified by flash column chromatography (PE / EA = 1 / 1) to afford the racemate of 14A as a yellow solid (1.9 g, 90% yield).

[1077] LCMS: [M+H] + =564.2.

[1078] Step 2: Pd(OH)2 / C (10%, 1.4 g) was added to a solution of the racemate of compound 14A (2.8 g, 4.97 mmol) in EA / MeOH / THF / DCM (EA / MeOH / THF / DCM=20:2:0.2:0.2, 120 mL) under N2 protection. The suspension was stirred at room temperature under H2 for 4 hours. The reaction mixture was filtered and the filter cake was washed with MeOH / DCM solution (MeOH / DCM=1 / 10). The combined filtrate was concentrated and purified by flash column chromatography (DCM / MeOH=10 / 1) to give the racemate of 14B (1.6 g, 68% yield) as a yellow solid.

[1079] LCMS: [MH] + =474.2.

[1080] Step 3: At 0 ° C, trifluoromethanesulfonic anhydride (1.1 g, 4.06 mmol, 1.2 equivalents) was slowly added dropwise to a 150 mL DCM solution of compound 14B (1.6 g, 3.38 mmol) and diisopropylethylamine (0.7 g, 5.75 mmol), and the mixture was stirred for 45 minutes. Washed with 25 mL saturated sodium bicarbonate, the organic layer was collected, and the aqueous layer was extracted with DCM (20 mL). The combined organic layers were washed with 10% citric acid (20 mL) and water (20 mL) and dried. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (DCM / EA=10 / 1) to give the racemate of compound 14C (1.7 g, 83% yield) in the form of a white powder. LCMS: [M+H] + =606.2.

[1081] Step 4: The racemate of compound 14C (50 mg, 2.2 mmol), compound 14D (30.26 mg, 0.16 mmol), tBuXPhos-Pd-G3 (4.8 mg, 0.01 mmol), tBuXPhos (12.78 mg, 0.03 mmol), and Cs2CO3 (67 mg, 0.21 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction mixture was stirred at 100°C under nitrogen for 16 hours. After the reaction, the mixture was extracted with EA and concentrated to obtain 50 mg of the racemate of compound 14E. The crude product was not included in the yield. LCMS [M+H] + =639.2.

[1082] Step 5: A solution of the racemate of compound 14E (50 mg) in THF (0.5 mL) was added with 6 M HCl (0.5 mL), and the mixture was stirred at room temperature for 4 h. The reaction solution was purified by flash column chromatography (ACN-H2O = 0-100%) to give 6 mg of the racemate of white solid 14, yield: 12%. Further chiral column separation gave compound 14.

[1083] LCMS [M+H] + =539.2.

[1084] 1 H NMR (400MHz, DMSO) δ7.78(s,1H),7.47(d,J=8.6Hz,2H),7.31(d,J=8.6Hz,2 H),7.26(s,1H),7.09-7.03(m,2H),7.02-6.94(m,4H),6.92(d,J=1.6Hz,1H) ,5.51(s,1H),5.39(d,J=5.3Hz,1H),4.67(t,J=5.1Hz,1H),4.39(d,J=13.9H z, 1H), 4.18 (d, J = 18.8Hz, 2H), 4.15-4.07 (m, 1H), 3.80 (s, 3H), 3.58 (s, 3H).

[1085] Compound 15

[1086] Step 1: HBF4 (0.85 mL, 4.79 mmol) was added dropwise to a solution of the racemate of compound 2 (170 mg, 0.32 mmol) in ethanol (5 mL) at room temperature. After stirring for 15 minutes, the reaction mixture became clear and was cooled to 0°C. Tert-butyl nitrite (65.0 mg, 0.63 mmol) was added. After 30 minutes, the reaction mixture was diluted with ether (8 mL). Filtering afforded a solid, which was washed twice with ether (5 mL) and dried. The solid was added to water (500 mL) containing copper nitrate (17.7 g, 94.5 mmol) and cuprous oxide (45.0 mg, 0.32 mmol) and stirred at room temperature for 1 hour. The aqueous solution was filtered to afford a brown solid, which was purified by flash column chromatography (ACN / H2O) to afford 20 mg of the racemate of 15A as a yellow solid in a yield of 12.3%. LCMS [M+H] + =541.0.

[1087] Step 2: The racemate of compound 15A (20.0 mg, 0.04 mmol) and LiOH (34.8 mg, 0.40 mmol) were dissolved in THF / H2O (5 mL / 1 mL) and stirred at room temperature for 6 h. Purification by flash column chromatography (ACN / H2O) afforded 17.0 mg of 15B as a white solid (yield: 85.3%). LCMS [M+H] + =527.0.

[1088] Step 3: Compound 15B (15.0 mg, 0.03 mmol), N,O-dimethylhydroxylamine hydrochloride (2.92 mg, 0.03 mmol), HATU (13.0 mg, 0.03 mmol), HOAT (2.25 mg, 0.03 mmol), and TMP (10.3 mg, 0.09 mmol) were added to DMF (1.0 mL) and stirred at room temperature for 16 h. The mixture was purified by flash column chromatography (ACN / H2O) to give 9.0 mg of the racemate of 15 as a white solid, in a yield of 55.4%. Compound 15 was further resolved by chiral column.

[1089] LCMS [M+H] + =570.0.

[1090] 1 H NMR: (400MHz, CDCl3) δ9.09 (s, 1H), 8.25 (s, 1H), 7.53 (d, J = 8.4Hz, 2H), 7.41 (s, 1 H),7.30(d,J=8.4Hz,2H),7.21(s,1H),7.15(s,1H),6.85(s,1H),6.83(d,J=8.4Hz ,1H),6.56-6.36(m,3H),5.63(s,1H),5.11(d,J=4.8Hz,1H),4.79(t,J=4.8Hz,1H) ,4.38(d,J=7.2Hz,1H),4.18-4.13(m,1H),3.90(s,3H),3.84(s,3H),3.09(s,3H).

[1091] Compound 16

[1092] Step 1: To a solution of the racemate of compound 14C (2.00 g, 3.30 mmol) in DMF (10 mL) were added compound 2I (8.04 g, 22.46 mmol), Pd(PPh3)4 (763.35 mg, 0.6 mmol), and CuI (629.03 mg, 3.30 mmol). The mixture was stirred in a microwave oven at 115°C under nitrogen for 2 h. The mixture was purified on a silica gel column (PE / EA = 1 / 1) to afford 1.5 g of the racemate of compound 16A as a white solid, in a yield of 86%. LCMS [M+H] + =525.0.

[1093] Steps 2 and 3: Dissolve the racemate of compound 16A (100.00 mg, 0.19 mmol) and LiOH (20.00 mg, 0.25 mmol) in MeOH / H₂O (5 mL / 1 mL), stir at room temperature for 12 h, adjust the pH to 2-3 with 1 M aqueous hydrochloric acid, and extract with ethyl acetate (20 mL). The organic phase is dried over sodium sulfate and concentrated to afford the crude racemate of compound 16B.

[1094] The crude racemate of product 16B was dissolved in DMF (3 mL), and HATU (144.50 mg, 0.38 mmol), compound 16C (27.78 mg, 0.38 mmol), and DIEA (73.67 mg, 0.57 mmol) were added. The mixture was stirred at room temperature for 12 hours. 50 mL of water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated brine, dried, and concentrated. The crude product was purified on a silica gel column (PE / EA = 1 / 2) to obtain 20 mg of the racemate of 16 as a white solid, in a yield of 17%. Compound 16 was further resolved on a chiral column.

[1095] LCMS [M+H] + =566.2.

[1096] 1H NMR (400MHz, DMSO) δ8.25(s,1H),7.47(d,J=7.3Hz,2H),7.41(s,1H),7.32(dd,J=8.0,5.0Hz,2H),7.23(s,1H),7 .15(s,1H),7.04(t,J=6.8Hz,2H),6.96(s,3H),5.77(dd,J=15.3,5.4Hz,1H),5.62(d,J=7.0Hz,1H),5.06(dd,J=1 1.7,5.0Hz,1H),4.77(t,J=7.8Hz,1H),4.67(s,1H),4.62-4.50(m,2H),4.47(d,J=13.8Hz,1H),4.34-4.06(m,1H) ,4.01(dd,J=16.6,9.9Hz,1H), 3.93(dd,J=12.8,6.8Hz,1H), 3.85(d,J=3.9Hz,3H), 3.59(dd,J=17.2,7.4Hz,1H).

[1097] Compound 17

[1098] Step 1: Dissolve compound 17A (5.0 g, 30.10 mmol) in chloroform (50 mL) under an ice-water bath, and add N,N-dimethylformamide (0.5 mL) and thionyl chloride (5.37 g, 45.14 mmol) in sequence. Stir the mixture at 75°C for 12 hours. Concentrate the reaction mixture to obtain 6.0 g of 17B as a yellow solid. LCMS [M+H] + =185.2.

[1099] Step 2: Compound 1A (4.0 g, 13.87 mmol) was dissolved in dichloromethane (30 mL) under an ice-water bath, and triethylamine (4.2 g, 41.61 mmol) and DMAP (1.69 g, 13.8 mmol) and compound 17B (5.63 g, 30.52 mmol) were added. The mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with water (30 mL) and extracted with dichloromethane (30 mL×2). The organic phase was washed with brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel chromatography (PE / EA=1 / 1) to obtain 6.92 g of 17C as a white solid, yield: 85%. LCMS [M+H] + =585.0.

[1100] Step 3: Compound 17C (3.5 g, 5.99 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and a solution of LiHMDS in THF (1 M, 17.96 mL, 17.96 mmol) was added dropwise at -78°C, and the reaction was stirred at -78°C for 1 hour. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 2), washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and stirred with diethyl ether to obtain 2.67 g of 17D as a white solid, yield: 78%. LCMS [M+H] + =585.0.

[1101] Step 4: Compound 17D (900 mg, 1.54 mmol) was dissolved in AcOH (15 mL), sodium acetate (316 mg, 3.85 mmol) was added, and the reaction was stirred at 100° C. overnight. The reaction mixture was concentrated and extracted with dichloromethane (20 mL), washed with water (20 mL×2), brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and stirred with diethyl ether to obtain 800 mg of yellow solid 17E, yield: 92%.

[1102] Step 5: Compound 17E (100 mg, 0.24 mmol) and compound 2A (397 mg, 1.44 mmol) were dissolved in CHCl3 / TFE (7 / 3, 5 mL). The reaction mixture was injected via a syringe pump at a rate of 12 mL / h into a coil wrapped around a jacketed glass cylinder equipped with a 250W UV lamp. The temperature of the external circulating hydrazine was adjusted to maintain an internal reaction temperature of 0-5°C, while the UV lamp was turned on. The reaction mixture was irradiated for 1 hour, the solvent was removed under reduced pressure, and the residue was purified using a silica gel column (EtOAc / hexane) to remove excess compound 2A, yielding 190 mg of the racemate of 17F as a pale yellow solid, yield: 75%. LCMS [M+H] + =696.1.

[1103] Step 6: The racemate of compound 17F (4.8 g, 6.91 mmol) was dissolved in MeOH (40 mL). NaOMe (932.4 mg, 17.27 mmol) was added at 0°C and stirred at 65°C for 1.5 h. The solution was concentrated, washed with H2O, NH4Cl(aq), and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified on a silica gel column (0.2% FA, EA / PE = 1 / 3) to afford 2.8 g of the racemate of compound 17G, yield: 58%. LCMS [M+H-H2O] + =677.9.

[1104] Step 7: The racemate of compound 17G (2.85 g, 4.10 mmol) was dissolved in ACN / CHCl₃ (1 / 1, 30 mL / 30 mL). Na(AcO)₃BH (4.3 g, 20.50 mmol) and AcOH (2.5 g, 41.01 mmol) were added at 0°C and stirred at room temperature for 2 h. The mixture was concentrated, extracted with EA, washed with water and brine, dried over anhydrous Na₂SO₄, and purified on a silica gel column (A:PE, B:0.2% FA, EA) to give 1.6 g of the racemate of compound 17H, in a 56% yield. LCMS [M+H-H₂O] + =680.0.

[1105] Step 8: Dissolve the racemate of compound 17H (400 mg, 0.57 mmol) in MeOH (10 mL). Add palladium hydroxide (40 mg) to the solution and stir overnight at room temperature under a hydrogen balloon. Filter the reaction mixture, wash with methanol (10 mL), and concentrate the filtrate to obtain 320 mg of the racemate of compound 17I as a yellow solid (yield: 91%). LCMS [M+H-H2O] + =590.0.

[1106] Step 9: The racemate of compound 17I (320 mg, 0.53 mmol) was dissolved in DMF (5 mL), and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (189.3 mg, 0.53 mmol) and potassium carbonate (146.3 mg, 1.06 mmol) were added to the mixture. The reaction solution was stirred at 60 ° C for 1 hour. The reaction solution was purified by reverse phase (acetonitrile / water = 5%-95%, 214 nm, 20 minutes) to obtain 320 mg of the racemate of white solid 17J, yield: 82%. LCMS [M+H] + =740.2.

[1107] Step 10: The racemate of compound 17J (50 mg, 0.07 mmol) was dissolved in DMF (1.5 mL), and 2-(tributyltin)oxazole (190 mg, 0.54 mmol), tetrakistriphenylphosphine palladium (8 mg, 0.007 mmol) and CuI (2.6 mg, 0.014 mmol) were added to the solution in sequence. The solution was stirred at 100 ° C for 1.5 hours under microwave. The reaction mixture was filtered, washed with MeOH (5 mL) and shrunk. The residue was purified by reverse phase (acetonitrile / water = 5%-95%, 214 nm, 20 minutes) to give 30 mg of the racemate of yellow solid 17K, yield: 34%. LCMS [M+H] + =659.2.

[1108] Step 11: The racemate of compound 17K (35 mg, 0.05 mmol) was dissolved in tetrahydrofuran / water (3 mL / 1 mL) and lithium hydroxide (4.20 mg, 0.1 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by reverse phase chromatography (acetonitrile / water = 5%-95%, 214 nm, 20 minutes) to give 30 mg of the racemate of 17L as a yellow solid, yield: 88%. LCMS [M+H] + =645.2.

[1109] Step 12: In DMF (1.5 mL), the racemate of compound 17L (30 mg, 0.05 mmol), N,O-dimethylhydroxylamine (10 mg, 0.1 mmol), HATU (22.8 mg, 0.06 mmol) and DIEA (19.35 mg, 0.15 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. The racemate of compound 17M (15 mg, 47% yield) was obtained by reverse phase purification (acetonitrile / water = 5%-95%, 214 nm, 20 minutes). LCMS [M+H] + = 688.2

[1110] Step 13: To a solution of the racemate of compound 17M (15 mg, 0.02 mmol) in tetrahydrofuran (0.5 mL) was added 6N / HCl (0.3 mL). The mixture was stirred at room temperature for 12 hours. The mixture was purified by preparative chromatography to afford 3.8 mg of the racemate of 17M as a white solid (yield: 30%). Further chiral column separation afforded compound 17.

[1111] LCMS [M+H] + =588.2.

[1112] 1 H NMR (400MHz, DMSO-d6) δ8.36(s,1H),8.24(s,1H),7.41(s,1H),7.15(d,J=12.4Hz,2H),6.72-6.60(m,4H),6.23-6.18(m,3H),6.04(d,J=7.6Hz, 1H),5.86(d,J=3.2Hz,2H),5.37(s,1H),4.92(s,1H),4.83-4.73(m,3H) ,4.16(d,J=14.0Hz,1H),4.08(brs,1H),3.88-3.85(m,6H),3.06(s,3H).

[1113] Compound 18

[1114] Step 1: To a solution of the racemate of compound 2H (50 mg, 0.07 mmol) in dioxane (5 mL) were added bisborane (35.2 mg, 0.14 mmol), potassium acetate (20.4 mg, 0.21 mmol), and Pd(dppf)Cl2 (5.62 mg, 0.01 mmol). The mixture was degassed under reduced pressure and replaced with nitrogen three times. The mixture was stirred at 85°C for 10 h. The reaction solution was concentrated, and the residue was purified on a silica gel column using PE / EA = 5 / 1 to obtain the racemate of compound 18A (40.0 mg, 83% yield) as a yellow solid. LC-MS: (M+H) + =699.3. 1 H NMR: (400MHz, CDCl3) δ7.36(dd,J=8.4,28.4Hz,4H),7.22(s,1H),7.14(d,J=7.2Hz,1H),6.99-6.95(m,2H),6.86(s,1H),6.53(d,J=7.6 Hz,1H),6.30(s,1H),5.01(d,J=6.0Hz,1H),4.36(d,J=14.4Hz,1H),3.95(s,3H),3.66(s,3H),3.53(s,1H),1.51(s,9H),1.37(s,12H).

[1115] Step 2: To the racemate of compound 18A (40 mg, 0.06 mmol) in dioxane / H₂O (5 mL / 1 mL), 2-bromopyrimidine (9.1 mg, 0.09 mmol), Na₂CO₃ (18.2 mg, 0.17 mmol), and Pd(dppf)Cl₂ (4.62 mg, 0.01 mmol) were added. The mixture was stirred at 100°C under a nitrogen atmosphere in a microwave oven for 1 h. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (ACN / H₂O) to afford the racemate of compound 18B (30.0 mg, 80.5% yield) as a white solid. LC-MS: (M+H) + =651.0. 1H NMR: (400MHz, CDCl3) δ8.92 (d, J = 4.8Hz, 2H), 7.92 (s, 1H), 7.86 (s, 1H), 7.40 (dd,J=8.4,22.0Hz,5H),7.14(d,J=7.6Hz,1H),7.01-6.96(m,1H),6.91(s,1H ),6.57(d,J=7.6Hz,1H),6.31(s,1H),5.05(d,J=6.0Hz,1H),4.45(d,J=14.0 Hz, 1H), 4.07 (s, 3H), 3.97 (dd, J = 6.0, 14.0Hz, 1H), 3.69 (s, 1H), 1.52 (s, 9H).

[1116] Step 3: Dissolve the racemate of compound 18B (30 mg, 0.05 mmol) and LiOH (20.2 mg, 0.23 mmol) in THF / H₂O (1 mL / 1 mL) and stir at room temperature for 6 h. Purify by flash column chromatography (ACN / H₂O) to obtain the racemate of compound 18C (21.0 mg, 69.0% yield) as a white solid. LC-MS: [M+H-C₄H₂] + =581.0.

[1117] Step 4: The racemate of compound 18C (20.0 mg, 0.03 mmol), N,O-dimethylhydroxylamine hydrochloride (3.22 mg, 0.03 mmol), HATU (14.3 mg, 0.04 mmol), HOAT (2.25 mg, 0.03 mmol), and TMP (11.4 mg, 0.09 mmol) were added to DMF (5.0 mL) and stirred for 16 h. The mixture was purified by flash column chromatography (ACN / H2O) to afford the racemate of compound 18D (20.0 mg, 93.6% yield) as a white solid. LCMS [M+1] + =680.1.

[1118] Step 5: To a solution of the racemate of compound 18D (43.0 mg, 0.08 mmol) in THF (1 mL) was added HCl (6N, 1 mL) and stirred at room temperature overnight. Purification by flash column chromatography (ACN / H2O) afforded the racemate of compound 18 (70 mg, yield: 41%). Further chiral column separation afforded compound 18 as a white solid. LCMS [M+H] + =580.0.

[1119] Compound 19

[1120] Step 1: Compound 1A (3.5 g, 12.1 mmol), DMAP (148 mg, 1.21 mmol), and TEA (3667 mg, 36.3 mmol) were dissolved in DCM (40 mL), cooled to 0°C, and compound 19A (5860 mg, 26.7 mmol) was added portionwise. The mixture was stirred at 25°C for 1 hour. The solution was concentrated and extracted with EA, washed with water and brine, dried over anhydrous Na2SO4, and purified on a silica gel column (PE:EA = 3 / 1) to obtain 19B (5 g, 63% yield) as a yellow solid. LCMS: [M+H] + =655.0.

[1121] Step 2: Compound 19B (5 g, 7.64 mmol) was dissolved in THF (50 mL), cooled to -78°C, and under N2 protection, LiHMDS (23 mL, 23 mmol) was added dropwise to the stirred solution. The mixture was stirred at -78°C for 2 hours. The reaction solution was quenched with saturated aqueous NH4Cl solution, extracted with EA, washed with water and saturated brine, and the organic layer was dried over anhydrous Na2SO4, dried by spin drying, and purified on a silica gel column (PE:EA = 3 / 1) to obtain a yellow solid 19C (4.1 g, yield 82%). LCMS: [M+H] + =654.9.

[1122] Step 3: Compound 19C (6.1 g, 9.32 mmol) and AcONa (1912 mg, 23.31 mmol) were dissolved in AcOH (183 mL) and stirred at 100°C overnight. TLC showed no starting material, but new spots were generated. The solution was spin-dried and extracted with EA, washed with water and brine, dried over anhydrous Na2SO4, concentrated, and purified on a silica gel column (PE:EA = 1 / 1) to give 19D (4 g, 67% yield) as a yellow solid. LCMS: [M+H] + =636.9.

[1123] Step 4: Compound 19D (4 g, 6.29 mmol) was dissolved in CHCl₃ (120 mL), cooled to 0°C, and MeONa (3396 mg, 18.86 mmol) was added. The mixture was stirred at 25°C for 1 hour. TLC showed the absence of starting material, with the formation of new spots. The reaction mixture was adjusted to pH 5 with acetic acid, dried, extracted with EA, and washed with MeOH to afford a filter cake as a gray solid, 19E (2.5 g, 88% yield).

[1124] LCMS: [M+H] + =453.0.

[1125] 1H NMR (400MHz, CDCl3) δ8.33(s,1H),8.17(d,J=7.9Hz,1H),7.55(d,J=7.9Hz,1H), 7.48-7.34(m,6H),6.66(d,J=1.4Hz,1H),6.44(s,1H),5.17(s,2H),3.97(s,3H).

[1126] Step 5: Compound 19E (1 g, 2.2 mmol) and compound 9A (2.1 g, 13.25 mmol) were dissolved in CHCl3 / TFE (7 / 3, 15 mL). The reaction mixture was injected into a coil wrapped around a jacketed glass cylinder equipped with a 250W UV lamp via a syringe at a rate of 12 mL / h via a syringe pump. The temperature of the external circulating hydrazine was adjusted to keep the internal reaction temperature at 0-5°C. The UV lamp was turned on and the reaction mixture was irradiated for 1 hour. The solvent was removed under reduced pressure, and the residue was purified on a silica gel column (EtOAc / hexane) to remove excess cinnamate to obtain the racemate of compound 19F (2.9 g, 64% yield) as a light yellow solid. LCMS [M+H+H2O] + =633.1.

[1127] Step 6: A mixture of the racemate of compound 19F (2.96 g, 4.81 mmol) in MeOH (50 mL) was added to MeONa (649.76 g, 12.03 mmol), stirred at 65°C for 2 h, concentrated and extracted with EA, washed with saturated NH4Cl solution and brine, dried over anhydrous Na2SO4, and separated and purified on a silica gel column (0.5% FA, EA / PE = 31 / 69) to obtain the racemate of compound 19G (1.2 g, 75% yield) as a light yellow solid. LCMS [M+H] + =597.1.

[1128] Step 7: The racemate of compound 19G (1.7 g, 2.76 mmol) was added with Na(AcO)BH (2.9 g, 13.82 mmol) and AcOH (1.7 g, 27.64 mmol) in MeCN / CHCl = 1 / 1 (50 mL / 50 mL) at 0°C and stirred at room temperature for 2 h. The solution was concentrated and extracted with EA, washed with water and brine, dried over anhydrous NaSO, and purified on a silica gel column (A:PE, B:DCM / EA = 1 / 1) to obtain the racemate of compound 19H (919 mg, 54% yield).

[1129] LCMS [M+H-H2O] + =599.0.

[1130] 1H NMR (400MHz, CDCl3) δ7.49-7.32 (m, 6H), 7.24 (ddd, J = 7.9, 2.0, 1.0Hz, 1H), 7.15-7 .11(m,1H),7.10-7.05(m,3H),7.00(dd,J=9.1,6.7Hz,1H),6.89(dd,J=7.0,2.2Hz ,2H),6.38(d,J=1.9Hz,1H),6.23(d,J=1.9Hz,1H),5.09(s,2H),5.02(d,J=6.5Hz, 1H), 4.36 (d, J = 14.2Hz, 1H), 3.95-3.88 (m, 1H), 3.86 (s, 3H), 3.66 (d, J = 3.6Hz, 3H).

[1131] Step 8: The racemate of compound 19H (300.0 mg, 0.49 mmol), NH2Boc (170.7 mg, 1.46 mmol), Pd2(dba)3 (44.5 mg, 0.05 mmol), Xantphos (56.2 mg, 0.10 mmol), and Cs2CO3 (316.0 mg, 0.97 mmol) were mixed in 1,4-dioxane (20 mL) and stirred at 100°C under N2 for 16 h. The mixture was concentrated and purified on a silica gel column (PE / EA) to obtain the racemate of compound 19I (219 mg, 69% yield).

[1132] LCMS[MH] - =652.2.

[1133] 1 H NMR (400MHz, CDCl3) δ7.48-7.35(m,6H),7.10-7.03(m,4H),6.96(t,J=1.8Hz,1H),6.92-6.83(m,3H),6.36(d,J=1.9Hz,1H),6.22(d,J=1.9Hz, 1H), 5.09 (s, 2H), 5.03 (d, J = 6.7Hz, 1H), 4.33 (d, J = 14.2Hz, 1H), 3.95 (dd, J = 14.2, 6.7Hz, 1H), 3.86 (s, 3H), 3.65 (d, J = 3.7Hz, 3H), 1.49 (s, 9H).

[1134] Step 9: Pd(OH)2 / C (10%, 200 mg) was added to a solution of the racemate of compound 19I (219.0 mg, 0.34 mmol) in EA / MeOH / THF / DCM = 20:2:2:0.2 (10 mL). The reaction mixture was replaced with H2 several times. The mixture was stirred at room temperature for 16 hours. The suspension was filtered, and the filter cake was washed with MeOH / DCM (1 / 10). The combined filtrate was concentrated to dryness to afford the racemate of compound 19J (180 mg, 95% yield).

[1135] 1 H NMR (400MHz, CDCl3) δ7.23-7.02(m,7H),6.95-6.86(m,3H),6.47(s,1H),6.11(d,J=1.5Hz,1H),5.91(s,1H),4.9 9(d,J=7.1Hz,1H),4.31(d,J=14.1Hz,1H),3.97(dd,J=14.1,7.1Hz,1H),3.74(s,3H),3.66(s,3H),1.50(s,9H).

[1136] LCMS[M+Na] + =586.1.

[1137] Step 10: The racemate of compound 19J (180 mg, 0.32 mmol) and K2CO3 (88 mg, 0.64 mmol) were stirred in DMF (10 mL). N-phenylbis(trifluoromethanesulfonimide) (114 mg, 0.32 mmol) was added and stirred at 60°C for 20 min. The solution was concentrated and extracted with EA, washed with water and brine, dried over anhydrous Na2SO4, and purified on a silica gel column (DCM / MeOH = 10 / 1) to obtain the racemate of compound 19K (190 mg, 86% yield). LCMS: [M+Na] + =718.0.

[1138] Step 11: To a solution of the racemate of compound 19K (70 mg, 0.1 mmol) in DMF (3 mL) were added compound 2I (288.55 mg, 0.8 mmol), Pd(PPh3)4 (11.6 mg, 0.01 mmol), and CuI (3.84 mg, 0.02 mmol). The reaction mixture was purged with nitrogen three times and then reacted in a microwave reactor at 100°C for 1.5 hours. The reaction mixture was purified by reverse-phase column chromatography (H2O:ACN = 0-100%) to afford the racemate of compound 19 (2.3 mg, yield: 5%). Further chiral column separation afforded compound 19 as a white solid.

[1139] LCMS [M+H]+ =515.0.

[1140] 1 H NMR(400MHz,DMSO)δ8.25(s,1H),7.41(s,1H),7.21-7.10(m,2H),7.10-6.8 9(m,5H),6.64(t,J=7.9Hz,1H),6.48(s,1H),6.26(d,J=8.0Hz,1H),6.17(d, J=6.4Hz,1H),5.31(d,J=5.2Hz,1H),5.25(s,1H),4.70(t,J=5.2Hz,2H),4.2 0(d,J=14.1Hz,1H), 4.01(dd,J=14.0,5.2Hz,1H), 3.85(s,3H), 3.55(s,3H).

[1141] Compound 20

[1142] Step 1: Compound 1 (1000 mg, 2.21 mmol) and Cs2CO3 (1.08 g, 3.32 mmol) were dissolved in anhydrous methanol (10 mL) and anhydrous toluene (30 mL). t-BuXPhosPdG3 (35.13 mg, 0.04 mmol) was added and stirred at 85°C for 13 hours. The solution was concentrated and diluted with MeOH / DCM = 1 / 1. After filtration, the concentrated filtrate was purified on a silica gel column (DCM / MeOH = 10 / 1) to afford 0.65 g of 20A as a yellow solid in a 73% yield.

[1143] Step 2: Compound 20A (1 g, 2.2 mmol) and compound 2B (4.1 g, 13.3 mmol) were dissolved in CHCl3 / TFE (9 / 1, 15 mL). The reaction mixture was pumped via a 20 mL syringe at a rate of 12 mL / h via a syringe pump into a coil wrapped around a jacketed glass cylinder equipped with a 250 W UV lamp. The temperature of the external circulating hydrazine was adjusted to maintain an internal reaction temperature of 0-5°C. The UV lamp was simultaneously turned on and the reaction mixture was irradiated for 1 hour. The solvent was removed under reduced pressure and the excess cinnamate was removed by column chromatography (EA / PE = 1 / 3). The desired racemic product 20B (3.9 g, 80% yield) was obtained as a crude yellow oil. LCMS [M+H] + =682.3.

[1144] Step 3: The racemate of compound 20B (3.7 g, 5.43 mmol) was mixed with MeOH (50 mL), and NaOMe (733.5 mg, 13.58 mmol) was added at 0°C. The mixture was stirred at 65°C for 1.5 h. The solution was concentrated, washed with H2O, NH4Cl(aq), and brine, dried over Na2SO4, concentrated under reduced pressure, and purified on a silica gel column (0.2% FA, EA / PE = 1 / 3) to obtain 2.5 g of the racemate of compound 20C, in a yield of 67%. LCMS [M+H-H2O] + =664.2.

[1145] Step 4: The racemate of compound 20C (2.5 g, 3.67 mmol) was dissolved in MeCN / CHCl₃ (1 / 1, 50 mL / 50 mL). Na(AcO)₃BH (3.9 g, 18.36 mmol) and AcOH (2.2 g, 36.71 mmol) were added at 0°C and stirred at room temperature for 2 h. The reaction solution was extracted with EA, washed with water and brine, dried over anhydrous Na₂SO₄, and purified on a silica gel column (A:PE, B:EA = 1 / 1) to obtain 1.5 g of the racemate of compound 20D (yield: 60%). LCMS [M+H-H₂O] + =666.3.

[1146] Step 5: Pd(OH)2 / C (10%, 100 mg) was added to a solution of the racemate of compound 20D (200 mg, 0.29 mmol) in EA / MeOH / THF / DCM (20:2:2:2:0.2, 10 mL). The reaction mixture was replaced with H2 three times, and the mixture was stirred at room temperature for 16 hours. The suspension was filtered, and the filter cake was washed with MeOH / DCM (1 / 10). The filtrate was concentrated and purified on a silica gel column (DCM / MeOH = 10 / 1) to obtain 155 mg of the racemate of compound 20E, yield: 89%. LCMS [M+Na] + =616.1.

[1147] Step 6: The racemate of compound 20E (155.0 mg, 0.26 mmol) and K2CO3 (72.1 mg, 0.52 mmol) were stirred in DMF (2 mL). Compound 2G (93.3 mg, 0.26 mmol) was added, and the reaction mixture was stirred at 60°C for 20 min. The solution was diluted with water, extracted with EA, washed with water and brine, dried over anhydrous Na2SO4, and purified on a silica gel column (EA / PE = 1 / 1) to obtain 160 mg of the racemate of compound 20F, in an 84% yield. LCMS: [M+Na] + =748.1.

[1148] Step 7: The racemate of compound 20F (50 mg, 0.07 mmol) was dissolved in DMF (1.5 ml), and 2-(tributyltin)oxazole (190 mg, 0.54 mmol), tetrakistriphenylphosphine palladium (8 mg, 0.007 mmol) and CuI (2.6 mg, 0.014 mmol) were added to the solution in sequence. The solution was stirred at 100 ° C under microwave for 1.5 hours. The reaction mixture was filtered, washed with MeOH (5 mL) and concentrated. The residue was purified by reverse phase (acetonitrile / water = 5%-95%, 214 nm, 20 minutes) to give 17 mg of the racemate of 20G as a yellow solid, yield: 38%. LCMS: [M+Na] + =667.2.

[1149] Step 8: The racemate of compound 20G (35 mg, 0.05 mmol) was dissolved in tetrahydrofuran / water (3 ml / 1 ml), and lithium hydroxide (4.56 mg, 0.1 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by reverse phase purification (acetonitrile / water = 5%-95%, 214 nm, 20 minutes) to give 21 mg of the racemate of 20H as a yellow solid, yield: 61%. LCMS: [M+Na] + =653.2.

[1150] Step 9: In DMF (1.5 ml), the racemate of compound 20H (21 mg, 0.03 mmol), N,O-dimethylhydroxylamine (3.25 mg, 0.06 mmol), HATU (17.1 mg, 0.05 mmol), and DIEA (11.61 mg, 0.09 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Purification by reverse phase (acetonitrile / water = 5%-95%, 214 nm, 20 minutes) gave 12 mg of the racemate of 20I as a yellow solid, yield: 54%. LCMS: [M+Na] + =696.3.

[1151] Step 10: To a solution of the racemate of compound 20I (12 mg, 0.02 mmol) in tetrahydrofuran (0.5 mL) was added 6N / HCl (0.3 mL). The mixture was stirred at room temperature for 12 hours. The mixture was purified by preparative chromatography to afford 3.2 mg of the racemate of compound 20 as a white solid in a yield of 22%. Further chiral column separation afforded compound 20. LCMS: [M+H] + =574.2.

[1152] 1H NMR (400MHz, DMSO-d6) δ8.24(d,J=0.8Hz,1H),7.40(d,J=0.8Hz,1H),7.17(d,J=1.2H z,1H),7.14(d,J=1.2Hz,1H),7.08-7.05(m,2H),6.67-6.63(m,3H),6.23(brs,1H),6 .16(d,J=9.2Hz,1H),6.01(d,J=7.6Hz,1H),5.30(s,1H),4.86(d,J=4.4Hz,1H),4.80 -4.79(m,3H),4.15-4.08(m,2H),3.87(s,3H),3.85(s,3H),3.63(s,3H),3.06(s,3H).

[1153] Compound 21

[1154] Step 1: To a solution of the racemate of compound 14E (60 mg, 0.1 mol) in THF (2 mL) was added aqueous LiOH (12 mg, 0.3 mmol, 0.5 mL H₂O). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by reverse-phase column chromatography (H₂O:ACN = 0-100%) to afford 45 mg of the racemate of compound 21A as a white solid, yield: 77.5%. LCMS: [M+H] + =625.2.

[1155] Step 2: To a solution of the racemate of compound 21A (45 mg, 0.07 mmol), N,O-dimethylhydroxylamine (14 mg, 0.14 mmol), HATU (54.72 mg, 0.14 mmol), and HOAT (19.58 mg, 0.14 mmol) in DMF (4 mL) was added TMP (35 mg, 0.28 mmol). The reaction mixture was stirred at 50°C for 18 hours. The reaction mixture was purified by normal phase column chromatography (DCM / MeOH = 10 / 1) to give 24 mg of the racemate of compound 21B as a white solid, yield: 50%. LCMS: [M+H] + =668.2.

[1156] Step 3: To a solution of the racemate of compound 21B (24 mg, 0.03 mmol) in THF (1 mL) was added 6 M HCl (2 mL). The reaction was stirred at room temperature for 18 hours. The reaction was purified by reverse-phase column chromatography (H2O:ACN = 0-100%) to afford 14 mg of the racemate of 21 as a white solid (yield: 70%). Further chiral column separation afforded compound 21.

[1157] LCMS [M+H] +=568.2.

[1158] 1 H NMR (400MHz, DMSO) δ7.78(s,1H),7.52(d,J=8.6Hz,2H),7.34-7.24(m,3H),7.06(t,J=7.4Hz,2H),6.99(t,J=4.4Hz,2H),6.91(dd,J=18.8,4.5 Hz,3H),5.50(s,1H),5.01(d,J=4.8Hz,1H),4.80(t,J=5.1Hz,1H),4.43 (d,J=13.8Hz,1H),4.19(s,3H),3.91(s,3H),3.81(s,2H),3.09(s,3H).

[1159] Compound 22

[1160] Step 1: The racemate of compound 9G (50.0 mg, 0.08 mmol), compound 22A (24.8 mg, 0.25 mmol), t-BuXphos PdG3 (13.0 mg, 0.02 mmol), t-Bune phos (7.7 mg, 0.02 mmol), and Na2CO3 (26.1 mg, 0.25 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was stirred at 100°C under N2 protection for 16 hours. The concentrate was purified by preparative HPLC to afford 1.2 mg of the racemate of 22 as a white solid (yield: 6.7%). Compound 22 was then separated by chiral column chromatography.

[1161] LCMS [M+H] + =562.2.

[1162] 1 H NMR (400MHz, DMSO) δ7.11-6.94(m,5H),6.89(d,J=7.4Hz,2H),6.68(d,J=1.5Hz,1H),6.62-6.54(m,3H),5.29(s,1H),5.26(d,J=5.0Hz, 1H), 4.71 (t, J = 5.2Hz, 1H), 4.23-4.15 (m, 3H), 4.00-3.92 (m, 3H), 3.78 (dd, J = 11.2, 6.2Hz, 1H), 3.74 (s, 3H), 3.60 (s, 3H), 3.55 (s, 3H).

[1163] Compound 23

[1164] Step 1: To a solution of the racemate of compound 9J (200 mg, 0.37 mol) in THF (5 mL) was added a solution of LiOH (47 mg, 1.12 mmol) in water (0.5 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by reverse phase column chromatography (H2O:ACN = 0-100%) to afford the racemate of compound 23A as a white solid (180 mg, yield: 92%). LCMS [M+H] + =525.3.

[1165] Step 2: Add a solution of the racemate of compound 23A (10 mg, 0.02 mmol), compound 11A (24.3 mg, 0.2 mmol), tert-dodecylmercaptan (38.4 mg, 0.2 mmol), and meso-tetraphenylporphyrin zinc (1.3 mg, 0.001 mmol) in DMF (1 mL) to a microwave tube. Place the microwave tube in an 80°C water bath and illuminate with a 25W red light lamp. Add EDCI (36.6 mg, 0.2 mmol, dissolved in DMF) dropwise to the reaction system. Stirring is continued for 30 minutes. Three reactions were performed in parallel, and the reaction solutions were combined and purified by reverse phase column chromatography (H2O:ACN = 0-100%) to obtain the racemate of 23B as a white solid (10 mg, yield: 30%). LCMS [M+H] + =481.2.

[1166] Step 3: A THF (2 mL) solution of the racemate of compound 23B (30 mg, 0.06 mmol) was cooled to 0°C. LiAlH4 (30 μL, 0.12 mmol) was added dropwise to the reaction system, and the reaction was continued at 0°C for 1 hour. Na2SO4·10H2O was added to the reaction system and stirred at room temperature for half an hour. The suspension was filtered and the filter cake was washed three times with MeOH / DCM (1 / 10). The filtrate was dried and purified by thin layer chromatography (DCM / MeOH=7 / 1) to give the racemate of 23C as a white solid (5 mg, yield: 16.7%). LCMS [M+H] + =485.2.

[1167] Step 4: To a solution of the racemate of compound 23C (4 mg, 0.008 mmol), glycolic acid (1.2 mg, 0.008 mmol), HATU (6.4 mg, 0.016 mmol), and HOAT (2.4 mg, 0.016 mmol) in DMF (1 mL) was added TMP (4 mg, 0.032 mmol) and allowed to react at room temperature for 1 hour. The reaction solution was purified by reverse-phase column chromatography (HO:ACN = 0-100%) to afford the racemate of compound 23 as a white solid (2.2 mg, 50% yield). Compound 23 was then separated by chiral column chromatography.

[1168] LCMS [M+H-H2O] + =525.0.

[1169] 1 H NMR (400MHz, DMSO) δ8.26(d,J=0.6Hz,1H),7.79(t,J=5.7Hz,1H),7.41(d,J=0.7Hz,1H),7.22(d d,J=8.9,1.1Hz,2H),7.14(d,J=8.9Hz,2H),7.11-7.00(m,3H),6.91(d,J=6.8Hz,2H),6.69(d,J =9.0Hz,2H),5.64(t,J=5.5Hz,1H),5.42(s,1H),3.96(s,3H),3.91(d,J=5.3Hz,2H),3.70(t,J= 5.3Hz,2H),3.65(s,3H),3.39(d,J=6.2Hz,1H),2.90(td,J=14.0,6.8Hz,1H),2.24-2.01(m,2H).

[1170] Compound 24

[1171] Step 1: Dissolve the racemate of compound 2E (3200 mg, 4.715 mmol) in THF (30 mL), MeOH (10 mL), and H₂O (10 mL). Add LiOH (594 mg, 14.14 mmol) and stir at room temperature under nitrogen for 8 hours. The reaction mixture is adjusted to pH 5 with 3M HCl and concentrated to obtain the crude product. Silica gel column chromatography (DCM / MeOH = 10 / 1) afforded the racemate of compound 24A as a white solid (2.8 g, yield: 89%). LCMS [M+H] + =665.2.

[1172] Step 2: Dissolve the racemate of compound 24A (2800 mg, 4.2124 mmol) in DMF (120 mL). Add dimethylhydroxylamine hydrochloride (1233 mg, 12.6371 mmol), HATU (4802 mg, 12.6371 mmol), HOAT (1719 mg, 12.6371 mmol), and TMP (1539 mg, 12.6371 mmol). Heat to 50°C and stir under nitrogen for 16 hours. Add water (100 mL) to the reaction solution, extract twice with ethyl acetate (150 mL), combine the organic phases, wash with saturated brine (150 mL), and dry over anhydrous sodium sulfate. Filter and concentrate to obtain the crude product, which is purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain the racemate of 24B as a yellow solid (2.9 g, yield: 97%). LCMS [M+H-C4H8] + =652.2.

[1173] Step 3: Dissolve the racemate of compound 24B (2900 mg, 4.10 mmol) in a mixture of EA / MeOH / THF / DCM = 20:2:2:0.2 (40 mL). Add Pd(OH)2 (870 mg) and stir at room temperature under hydrogen for 16 hours. The reaction mixture was filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give the racemate of compound 24C as a yellow solid (1.8 g, yield: 71%). LCMS [M+H-C4H8] + =562.2.

[1174] Step 4: Dissolve the racemate of compound 24C (1800 mg, 2.9142 mmol) in DMF (50 mL), add compound 2G (1041 mg, 2.9142 mmol) and K2CO3 (804 mg, 5.8284 mmol), and stir at 60°C under nitrogen for 40 minutes. Filter the reaction mixture, add water (100 mL), and extract twice with ethyl acetate (150 mL). Combine the organic phases, wash with saturated brine (150 mL), and dry over anhydrous sodium sulfate. Filter and concentrate to obtain the crude product, which is then purified by silica gel column chromatography (EA / PE = 1 / 1) to afford the racemate of 24D as a yellow oil (1.6 g, yield: 74%). LCMS [M+H-C4H8] + =694.1.

[1175] Step 5: Dissolve the racemate of compound 24D (860 mg, 1.15 mmol) in dioxane (12 mL) and add bis-pinacol boronate (876 mg, 3.45 mmol), Pd(dppf)Cl2 (188 mg, 0.23 mmol), and KOAc (432 mg, 4.60 mmol). Stir at 85°C under nitrogen for 4 hours. The reaction mixture was filtered and concentrated to obtain the crude product, which was then purified by silica gel column chromatography (EA / PE = 1 / 1) to afford the racemate of compound 24E as a yellow oil (700 mg, yield: 84%). LCMS [M+H-C4H8] + =672.2.

[1176] Step 6: Dissolve the racemate of compound 24E (20 mg, 0.0300 mmol) in dioxane (1.5 mL) and water (0.3 mL). Add 2-bromopyrazine (8.74 mg, 0.0500 mmol), Pd(dppf)Cl2 (2.24 mg, 0.0030 mmol), and Na2CO3 (11.65 mg, 0.1099 mmol). Microwave the mixture at 100°C under nitrogen for 1 hour. The reaction mixture was filtered and concentrated to afford the racemate of compound 24F as a yellow solid (17 g, yield: 84%). LCMS [M+H] + =680.4.

[1177] Step 7: Dissolve the racemate of compound 24F (17 mg, 0.250 mmol) in THF (1 mL) and add 6M HCl (1 mL). Stir at room temperature under nitrogen for 16 hours. The reaction mixture is filtered and concentrated to obtain the crude product, which is then purified on a reverse-phase column (H2O / ACN) to afford the racemate of 24F as a white solid (1.4 mg, 9.6% yield). Further chiral column separation affords compound 24.

[1178] LCMS [M+H] + =580.2.

[1179] 1H NMR (400MHz, DMSO) δ9.38 (d, J = 0.7Hz, 2H), 7.70 (d, J = 1.1Hz, 1H), 7.66 (d, J = 1.0Hz, 1H), 7. 54(d,J=8.6Hz,2H),7.33(d,J=8.6Hz,2H),6.66(t,J=7.8Hz,1H),6.23(s,1H),6.16(d,J=7 .8Hz,1H),6.05(d,J=7.4Hz,1H),5.65(s,1H),5.09(d,J=4.9Hz,1H),4.84-4.78(m,2H),4. 33(d,J=13.9Hz,1H),4.13(dd,J=15.2,9.8Hz,1H),3.91(s,3H),3.87(s,3H),3.09(s,3H).

[1180] Compound 25

[1181] Step 1: Dissolve the racemate of compound 24E (10 mg, 0.01 mmol) in dioxane / water (5 mL / 1 mL), add compound 25A (2.19 mg, 0.02 mmol), Na2CO3 (4.37 mg, 0.04 mmol), and Pd(dppf)Cl2 (1.11 mg, 0.001 mmol). Heat to 100°C in a microwave oven under nitrogen for 1 hour. Filter the reaction mixture, wash the filter cake with ethyl acetate (2 mL x 3), and concentrate to obtain the racemate of 25B (12 mg) as a yellow solid, which is used directly in the next step. LCMS [M+H-C4H8] + =624.3.

[1182] Step 2: To a solution of the racemate of compound 25B (12 mg, 0.02 mmol) in tetrahydrofuran (0.5 mL) was added 6N HCl (0.3 mL) and stirred at room temperature for 12 hours. The reaction solution was directly purified by preparative HPLC to afford the racemate of compound 25 as a white solid (6.3 mg, yield: 73%), which was further resolved by chiral column to afford compound 25.

[1183] LCMS [M+H] + =580.0.

[1184] 1H NMR(400MHz,DMSO-d6)δ9.25-9.23(m,1H),8.33-8.31(m,1H),7.83-7.80(m,1H),7 .55(d,J=8.4Hz,2H),7.40(d,J=4.8Hz,2H),7.34(d,J=8.8Hz,2H),6.68(t,J=7.6Hz ,1H),6.22-6.17(m,2H),6.08(d,J=6.0Hz,1H),5.59(s,1H),4.80(d,J=4.8Hz,1H) ,4.33(d,J=14.0Hz,1H),4.17-4.13(m,1H),3.91(s,3H),3.88(s,3H),3.09(s,3H).

[1185] Compound 26

[1186] Step 1: Dissolve the racemate of compound 24E (20 mg, 0.03 mmol) in dioxane / water (5 mL / 1 mL), add compound 26A (8.17 mg, 0.04 mmol), Na2CO3 (8.74 mg, 0.08 mmol), and Pd(dppf)Cl2 (2.23 mg, 0.001 mmol). Heat to 100°C in a microwave oven under nitrogen protection for 1 hour. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (2 mL x 3). After concentration, the racemate of 26B was obtained as a yellow solid (19 mg), which was used directly in the next reaction. LCMS [M+H] + =719.3.

[1187] Step 2: To a solution of the racemate of compound 26B (19 mg, 0.02 mmol) in tetrahydrofuran (0.5 mL) was added 6N HCl (0.3 mL) and stirred at room temperature for 12 hours. The reaction solution was directly purified by preparative HPLC to afford the racemate of compound 26 as a white solid (2.3 mg, yield: 17%), which was further resolved on a chiral column to afford compound 26.

[1188] LCMS [M+H] + =619.2.

[1189] 1H NMR (400MHz, DMSO-d6) δ9.32(d,J=1.6Hz,1H),9.19(s,1H),8.14(s,1H),7.88(d,J=0.8H z,1H),7.55(d,J=8.4Hz,2H),7.33(d,J=8.4Hz,3H),7.28(s,1H),6.67(t,J=7.8Hz,1H),6 .20-6.16(m,2H),6.05(d,J=7.6Hz,1H),5.53(s,1H),4.98(d,J=4.4Hz,1H),4.82-4.80( m,3H),4.30(d,J=14.0Hz,1H),4.15-4.11(m,1H),3.90(s,3H),3.87(s,3H),3.09(s,3H).

[1190] Compound 27

[1191] Step 1: Dissolve the racemate of compound 24E (20 mg, 0.03 mmol) in dioxane / water (5 mL / 1 mL), add compound 27A (8.17 mg, 0.04 mmol), Na2CO3 (8.74 mg, 0.08 mmol), and Pd(dppf)Cl2 (2.23 mg, 0.001 mmol). Heat to 100°C in a microwave oven under nitrogen protection for 1 hour. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (2 mL x 3). After concentration, the racemate of 27B was obtained as a yellow solid (18 mg), which was used directly in the next reaction. LCMS [M+H] + =719.3.

[1192] Step 2: To a solution of the racemate of compound 27B (18 mg, 0.03 mmol) in tetrahydrofuran (0.5 mL) was added 6N HCl (0.3 mL) and stirred at room temperature for 12 hours. The reaction solution was directly purified by preparative HPLC to afford the racemate of compound 27 as a white solid (1.5 mg, yield: 9.7%), which was further resolved on a chiral column to afford compound 27.

[1193] LCMS [M+H] + =619.2.

[1194] 1H NMR (400MHz, DMSO-d6) δ8.38(s,1H),8.24(d,J=9.6Hz,1H),7.91(d,J=9.6Hz,1H),7.84(s,1H ),7.55(d,J=8.4Hz,2H),7.35(s,2H),7.32(s,1H),7.23(s,1H),6.67(t,J=7.8Hz,1H),6.21(s ,1H),6.17(d,J=7.6Hz,1H),6.07(d,J=7.6Hz,1H),5.60(s,1H),5.05(d,J=4.8Hz,1H),4.82-4 .79(m,3H),4.33(d,J=14.0Hz,1H),4.17-4.09(m,1H),3.91(s,3H),3.88(s,3H),3.09(s,3H).

[1195] Compound 28

[1196] Step 1: Dissolve the racemate of compound 24E (20 mg, 0.03 mmol) in dioxane / water (3 mL / 1 mL), add compound 28A (7.13 mg, 0.04 mmol), Na2CO3 (8.74 mg, 0.08 mmol), and Pd(dppf)Cl2 (2.23 mg, 0.001 mmol). Heat to 100°C in a microwave under nitrogen protection for 1 hour. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (2 mL x 3). After concentration, the racemate of crude compound 28B (20 mg) was obtained as a yellow solid, which was used directly in the next reaction. LCMS [M+H-C4H8] + =638.2.

[1197] Step 2: To a solution of the racemate of compound 28B (20 mg, 0.03 mmol) in tetrahydrofuran (0.5 mL) was added 6N HCl (0.5 mL) and stirred at room temperature for 12 hours. The reaction solution was directly purified by preparative HPLC to afford the racemate of compound 28 as a white solid (3.8 mg, yield: 22%), which was further resolved on a chiral column to afford compound 28.

[1198] LCMS [M+H] + =594.0.

[1199] 1H NMR (400MHz, DMSO-d6) δ9.25 (s, 1H), 7.53 (d, J = 8.4Hz, 2H), 7.30 (d, J = 8.4Hz, 2H), 7.2 4(d,J=1.2Hz,1H),7.16(d,J=1.2Hz,1H),6.66(t,J=15.2Hz,1H),6.20(s,1H),6.16(d, J=8.0Hz,1H),6.06(d,J=7.6Hz,1H),5.67(s,1H),5.13(d,J=4.8Hz,1H),4.83-4.76(m, 3H), 4.34 (d, J = 14.0Hz, 1H), 4.17-4.10 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.09 (s, 3H).

[1200] Compound 29

[1201] Step 1: Dissolve the racemate of compound 24E (20 mg, 0.03 mmol) in dioxane / water (3 mL / 1 mL), add compound 29A (7.30 mg, 0.04 mmol), Na2CO3 (8.74 mg, 0.08 mmol), and Pd(dppf)Cl2 (2.23 mg, 0.001 mmol). Heat to 100°C in a microwave oven under nitrogen for 1 hour. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (2 mL x 3). After concentration, the racemate of compound 29B (20 mg) was obtained as a yellow solid, which was used directly in the next step. LCMS [M+H-C4H8] + =642.2.

[1202] Step 2: To a solution of the racemate of compound 29B (20 mg, 0.03 mmol) in tetrahydrofuran (0.5 mL) was added 6N HCl (0.3 mL) and stirred at room temperature for 12 hours. The reaction solution was directly purified by preparative HPLC to afford the racemate of compound 29 as a white solid (1.5 mg, 9% yield). Further chiral column separation afforded compound 29.

[1203] LCMS [M+H] + =598.2.

[1204] 1H NMR (400MHz, DMSO-d6) δ9.01 (s, 2H), 7.57-7.53 (m, 4H), 7.32 (d, J = 8.8Hz, 2H),6.66(t,J=7.6Hz,1H),6.23(s,1H),6.17(d,J=12.0Hz,1H),6.04(d,J= 7.6Hz,1H),5.59(s,1H),5.03(d,J=4.8Hz,1H),4.87-4.79(m,3H),4.30(d ,J=14.0Hz,1H),4.16-4.09(m,1H),3.90(s,3H),3.85(s,3H),3.09(s,3H).

[1205] Compound 30

[1206] Step 1: Dissolve the racemate of compound 24E (20 mg, 0.03 mmol) in dioxane / water (3 mL / 1 mL), add compound 30A (7.59 mg, 0.04 mmol), Na2CO3 (8.74 mg, 0.08 mmol), and Pd(dppf)Cl2 (2.23 mg, 0.001 mmol). Heat to 100°C in a microwave oven under nitrogen for 1 hour. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (2 mL x 3). After concentration, the racemate of compound 30B (20 mg) was obtained as a yellow solid, which was used directly in the next step. LCMS [M+H-C4H8] + =649.2.

[1207] Step 2: To a solution of the racemate of compound 30B (20 mg, 0.03 mmol) in tetrahydrofuran (0.5 mL) was added 6N HCl (0.3 mL) and stirred at room temperature for 12 hours. The reaction solution was directly purified by preparative HPLC to afford the racemate of compound 30 as a white solid (1.1 mg, yield: 6.4%), which was further resolved on a chiral column to afford compound 30.

[1208] LCMS [M+H] + =605.2.

[1209] 1H NMR(400MHz,DMSO-d6)δ8.68(s,2H),7.55-7.53(m,4H),7.33(d,J=8.8Hz,2H ),6.66(t,J=7.6Hz,1H),6.22(s,1H),6.17-6.15(m,1H),6.03(d,J=8.0Hz,1 H),5.54(s,1H),4.98(d,J=4.8Hz,1H),4.83-4.79(m,3H),4.29(d,J=14.0Hz ,1H),4.16-4.10(m,1H),3.98(s,3H),3.90(s,3H),3.85(s,3H),3.08(s,3H).

[1210] Compound 31

[1211] Step 1: Dissolve the racemate of compound 24E (20 mg, 0.03 mmol) in dioxane / water (3 mL / 1 mL), and add compound 31A (7.80 mg, 0.04 mmol), Na2CO3 (8.74 mg, 0.08 mmol), and Pd(dppf)Cl2 (2.23 mg, 0.001 mmol). Heat to 100°C in a microwave oven under nitrogen for 1 hour. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (2 mL x 3). After concentration, the racemate of compound 31B (20 mg) was obtained as a yellow solid, which was used directly in the next step. LCMS [M+H-C4H8] + =654.2.

[1212] Step 2: To a solution of the racemate of compound 31B (20 mg, 0.03 mmol) in tetrahydrofuran (0.5 mL) was added 6N HCl (0.3 mL) and stirred at room temperature for 12 hours. The reaction solution was directly purified by preparative HPLC to afford the racemate of 31 as a white solid (3.3 mg, yield: 19%), which was further resolved on a chiral column to afford compound 31.

[1213] LCMS [M+H] + =610.2.

[1214] 1H NMR(400MHz,DMSO-d6)δ8.68(s,2H),7.55-7.53(m,4H),7.33(d,J=8.8Hz,2H ),6.66(t,J=7.6Hz,1H),6.22(s,1H),6.17-6.15(m,1H),6.03(d,J=8.0Hz,1 H),5.54(s,1H),4.98(d,J=4.8Hz,1H),4.83-4.79(m,3H),4.29(d,J=14.0Hz ,1H),4.16-4.10(m,1H),3.98(s,3H),3.90(s,3H),3.85(s,3H),3.08(s,3H).

[1215] Compound 32

[1216] Step 1: Dissolve the racemate of compound 24E (20 mg, 0.0300 mmol) in dioxane (2.0 mL) and water (0.5 mL). Add compound 32A (9.00 mg, 0.0550 mmol), Pd(dppf)Cl2 (2.24 mg, 0.0027 mmol), and Na2CO3 (12.00 mg, 0.1099 mmol). Heat to 100°C in a microwave oven under nitrogen for 1 hour. The reaction mixture was filtered and concentrated to afford the racemate of 32B as a yellow solid (17 mg, yield: 84%). LCMS [M+H-C4H8] + =692.2.

[1217] Step 2: Dissolve the racemate of compound 32B (17 mg, 0269 mmol) in THF (1 mL) and add 6M HCl (1 mL). Stir at room temperature for 16 hours. The reaction mixture was filtered and concentrated to obtain a crude product, which was purified using a reverse-phase preparative column [H2O (containing 0.1% FA) / ACN] to afford the racemate of 32 as a white solid (1.1 mg, yield: 7.5%). Further chiral column separation afforded compound 32.

[1218] LCMS [M+H] + =648.2.

[1219] 1H NMR (400MHz, DMSO) δ9.38 (d, J = 0.7Hz, 2H), 7.70 (d, J = 1.1Hz, 1H), 7.66 (d, J = 1.0Hz, 1H), 7. 54(d,J=8.6Hz,2H),7.33(d,J=8.6Hz,2H),6.66(t,J=7.8Hz,1H),6.23(s,1H),6.16(d,J=7 .8Hz,1H),6.05(d,J=7.4Hz,1H),5.65(s,1H),5.09(d,J=4.9Hz,1H),4.84-4.78(m,2H),4. 33(d,J=13.9Hz,1H),4.13(dd,J=15.2,9.8Hz,1H),3.91(s,3H),3.87(s,3H),3.09(s,3H).

[1220] Compound 33

[1221] Step 1: Dissolve the racemate of compound 24E (20 mg, 0.03 mmol) in dioxane / water (3 mL / 1 mL), and add compound 33A (11.26 mg, 0.04 mmol), Na2CO3 (8.74 mg, 0.08 mmol), and Pd(dppf)Cl2 (2.23 mg, 0.001 mmol). Heat the mixture to 100°C in a microwave oven under nitrogen for 1 hour. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (2 mL x 3). After concentration, the racemate of compound 33B (23 mg) was obtained as a yellow solid, which was used directly in the next step. LCMS [M+H-C4H8] + =739.3.

[1222] Step 2: To a solution of the racemate of compound 33B (23 mg, 0.03 mmol) in tetrahydrofuran (0.5 mL) was added 6N HCl (0.5 mL) and stirred at room temperature for 12 hours. The reaction solution was directly purified by preparative HPLC to afford the racemate of compound 33 as a white solid (1.1 mg, yield: 6.4%), which was further resolved on a chiral column to afford compound 33.

[1223] LCMS [M+H] + =595.2.

[1224] 1H NMR (400MHz, DMSO-d6) δ8.22(s,2H),7.54(d,J=8.8Hz,2H),7.44(d,J=4.8Hz,2 H),7.32(d,J=8.8Hz,2H),6.65(t,J=7.8Hz,1H),6.22(s,1H),6.16(d,J=8.0Hz, 1H),6.01(d,J=7.6Hz,1H),5.75(s,2H),5.47(s,1H),4.89(d,J=4.4Hz,1H),4. 84-4.77(m,3H),4.26(d,J=13.6Hz,1H),3.89(s,3H),3.83(s,3H),3.08(s,3H).

[1225] Compound 34

[1226] Step 1: Dissolve the racemate of compound 24E (20 mg, 0.03 mmol) in dioxane / water (3 mL / 1 mL), and add compound 34A (6.51 mg, 0.04 mmol), Na2CO3 (5.83 mg, 0.08 mmol), and Pd(dppf)Cl2 (4.89 mg, 0.001 mmol). Heat to 100°C in a microwave oven under nitrogen for 1 hour. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (2 mL x 3). After concentration, the racemate of 34B was obtained as a yellow solid (20 mg), which was used directly in the next step. LCMS [M+H-C4H8] + =649.2.

[1227] Step 2: To a solution of the racemate of compound 34B (20 mg, 0.03 mmol) in tetrahydrofuran (0.5 mL) was added 6N HCl (0.5 mL) and stirred at room temperature for 12 hours. The reaction solution was directly purified by preparative HPLC to afford the racemate of compound 34 as a white solid (4.6 mg, yield: 27%), which was further resolved on a chiral column to afford compound 34.

[1228] LCMS [M+H] + =605.2.

[1229] 1H NMR (400MHz, DMSO-d6) δ9.26(d,J=4.8Hz,1H),8.10(d,J=4.8Hz,1H),7.62(d,J=1.0Hz ,1H),7.58-7.52(m,3H),7.33(d,J=8.4Hz,2H),6.66(t,J=7.6Hz,1H),6.23(s,1H),6.1 6(d,J=8.0Hz,1H),6.04(d,J=7.6Hz,1H),5.64(s,1H),5.08(d,J=4.8Hz,1H),4.93-4. 76(m,3H),4.31(d,J=14.0Hz,1H),4.17(s,1H),3.91(S,3H),3.89(s,3H),3.09(s,3H).

[1230] Compound 35

[1231] Step 1: Dissolve the racemate of compound 24E (20 mg, 0.0275 mmol) in dioxane (2.0 mL) and water (0.4 mL). Add compound 35A (9.00 mg, 0.0550 mmol), Pd(dppf)Cl2 (2.24 mg, 0.0027 mmol), and Na2CO3 (12.00 mg, 0.1099 mmol). Heat to 100°C in a microwave oven under nitrogen for 1 hour. The reaction mixture was filtered and concentrated to obtain the crude product, which was then purified on a reverse phase column (H2O / ACN) to afford the racemate of compound 35B as a yellow solid (12 mg, yield: 63%). LCMS [M+H-C4H8] + =638.2.

[1232] Step 2: Compound 35B (12 mg, 0.0173 mmol) was dissolved in THF (1 mL) and 6 M HCl (1 mL) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and concentrated to obtain the crude product, which was purified using a reverse-phase column [H₂O (containing 0.1% FA) / ACN] to afford 35 as a white solid (2.6 mg, 25% yield). Further chiral column separation afforded compound 35.

[1233] LCMS [M+H] + =594.2.

[1234] 1H NMR (400MHz, DMSO) δ9.38 (d, J = 0.7Hz, 2H), 7.70 (d, J = 1.1Hz, 1H), 7.66 (d, J = 1.0Hz, 1H), 7. 54(d,J=8.6Hz,2H),7.33(d,J=8.6Hz,2H),6.66(t,J=7.8Hz,1H),6.23(s,1H),6.16(d,J=7 .8Hz,1H),6.05(d,J=7.4Hz,1H),5.65(s,1H),5.09(d,J=4.9Hz,1H),4.84-4.78(m,2H),4. 33(d,J=13.9Hz,1H),4.13(dd,J=15.2,9.8Hz,1H),3.91(s,3H),3.87(s,3H),3.09(s,3H).

[1235] Compound 36

[1236] Step 1: Compound 24E racemate (20 mg, 0.03 mmol) was dissolved in dioxane / H2O (2.5 mL / 0.5 mL) and added to compound 36A (9.8 mg, 0.05 mmol), Na2CO3 (8.8 mg, 0.08 mmol), and Pd(dppf)Cl2 (2.5 mg, 0.00 mmol). The mixture was heated to 100°C in a microwave oven under nitrogen for 1 hour. The reaction solution was concentrated and the crude product was purified by reverse phase column chromatography (ACN / H2O) to obtain the racemate 36B as a white solid (10.0 mg, yield: 52.1%). LCMS [M+H-C4H8] + =643.2.

[1237] Step 2: Add HCl (6N, 2 mL) to a solution of the racemate of compound 36B (10.0 mg, 0.01 mmol) in THF (2 mL) and stir at room temperature overnight. The reaction solution was directly purified using a reverse phase column (ACN / H2O) to obtain the racemate of compound 36 as a white solid (6.4 mg, yield: 74.7%). Further chiral column separation afforded compound 36. LCMS [M+H] + =599.3.

[1238] Compound 37

[1239] Step 1: The racemate of compound 10O (20 mg, 0.03 mmol), compound 11A (42.6 mg, 0.3 mmol), HOAT (6.12 mg, 0.045 mmol), tert-dodecylmercaptan (60.6 mg, 0.3 mmol), TMP (5.48 mg, 0.045 mmol), meso-tetraphenylporphyrin zinc (2.03 mg, 0.003 mmol), and DMF (2 mL) were added to a microwave vial. After nitrogen was replaced in the reaction system, the microwave vial was stirred in an 80°C hot water bath while irradiated with 25W red light. A solution of EDCI (57.3 mg, 0.3 mmol) in DMF (2 mL) was slowly added dropwise to the reaction mixture, followed by stirring for 30 minutes. After completion of the reaction, the reaction mixture was purified on a silica gel column (HO / ACN = 40%:60%) to obtain the racemate of compound 37A (8.6 mg, yield: 46%). LCMS [M+H] + =553.2.

[1240] Step 2: Dissolve the racemate of compound 37A (8.6 mg, 0.015 mmol) in THF (1 mL) and add 6 M HCl (2 mL). Stir the reaction mixture at room temperature (20°C) for 2 hours. The reaction mixture is spin-dried and purified on a silica gel column (H2O / ACN = 55:45) to obtain the racemate of compound 37 (3.7 mg, yield: 52%). Further chiral column separation affords compound 37.

[1241] LCMS [M+H] + =453.2.

[1242] 1 H NMR(400MHz,DMSO)δ8.80(d,J=1.7Hz,1H),8.33(s,1H),7.87(d,J=1.7Hz,1H),7.54 (d,J=8.6Hz,2H),7.47(d,J=0.6Hz,1H),7.30(d,J=8.6Hz,2H),6.88(s,1H),6.55(s ,1H),6.47(d,J=23.6Hz,2H),6.03(s,1H),5.21(s,1H),4.51(d,J=3.9Hz,1H),4.24 (dd,J=14.0,6.0Hz,1H),2.80(td,J=13.4,4.3Hz,1H),2.16(dd,J=12.6,6.3Hz,1H).

[1243] Compound 38

[1244] Step 1: To a solution of the racemate of compound 10O (24 mg, 0.04 mmol) in DMF (2 mL) were added dimethylamine solution (0.1 mL, 0.2 mmol), H...

Claims

1. A ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the ligand-drug conjugate is composed of a ligand, a linker group, and a drug group, and the drug group is selected from the structures represented by Formula I-A, II-A’, III-A’, IV-A or V-A Wherein, M is selected from -N(R m )-, -O-, -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R m )-, wherein the -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R m )- are optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6 or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2; n is 0 or 1; W is absent or is selected from -(C1-C6)alkylene-, -O-, and -N(R w )-, said -(C1-C6)alkylene- being optionally substituted by one or more (such as 1, 2, 3, 4, 5, 6 or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2; U is selected from -(C1-C6)alkylene-, -(C3-C6)cycloalkylene- and -(4-10 membered)heteroalkylene-, and the -(C1-C6)alkylene-, -(C3-C6)cycloalkylene- and -(4-10 membered)heteroalkylene- are optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6 or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2; Z is absent, or is selected from -(C1-C6)alkylene-, -(C3-C6)cycloalkylene- and -(4-10 membered)heteroalkylene-; Y is absent or selected from -O-, -N(R y )-, and -N + (R y )2-, R y is selected from hydrogen, -(C1-C6)alkyl, -O(C1-C6)alkyl, -(C1-C6)haloalkyl, and -O-(C1-C6)haloalkyl, or R y forms with Z a -(4-10-membered) heteroalkylene-, said -(4-10-membered) heteroalkylene- being optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2; R 12 selected from hydrogen, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C=O)-(C1-C6)alkyl, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10-membered)heterocyclic group and -O-(4-10-membered)heterocyclic group, wherein the -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C=O)-(C1-C6)alkyl, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10-membered)heterocyclic group and -O-(4-10-membered)heterocyclic group are optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6 or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2; L is absent or is selected from -C(=O)-(C1-C6)alkylene-O-, -C(=O)-(C1-C6)alkylene-N(R L )-, -C(=O)-(C1-C6)alkylene-N + (R L )2-, -C(=O)NH-(C1-C6)alkylene-O-, -C(=O)NH-(C1-C6)alkylene-N(R L )- and -C(=O)NH-(C1-C6)alkylene-N + (R L )2-, R L is selected from hydrogen, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C1-C6)haloalkyl and -O-(C1-C6)haloalkyl, and the -C(=O)-(C1-C6)alkylene-O-, -C(=O)-(C1-C6)alkylene-N(R L )-, -C(=O)-(C1-C6)alkylene-N + (R L )2-, -C(=O)NH-(C1-C6)alkylene-O-, -C(=O)NH-(C1-C6)alkylene-N(R L )- and -C(=O)NH-(C1-C6)alkylene-N + (R L )2- are optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6 or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2; Q is selected from -N(R q )-, -O-, -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R q )-, wherein the -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R q )- are optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6 or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2; T is selected from -N(R t )-, -O-, -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R t )-, wherein the -(C1-C6)alkylene-O- and -(C1-C6)alkylene-N(R q )- are optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6 or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2; R m 、R w 、R q and R t are each independently selected from hydrogen, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C1-C6)haloalkyl, and -O-(C1-C6)haloalkyl; X 1 selected from N and C(R 1 ), where R 1 is selected from hydrogen, halogen, cyano, -OH, -(C1-C6)alkyl, and -O-(C1-C6)alkyl; X 2 selected from N and C(R 2 ), R 2 is selected from hydrogen, halogen, cyano, -OH, -(C1-C6)alkyl, and -O-(C1-C6)alkyl; R 3 Selected from -(C3-C6) cycloalkyl, -(3-8 membered) heterocyclic group, -(C6-C 10 ) aryl and -(5-12 membered) heteroaryl, the -(C3-C6) cycloalkyl, -(3-8 membered) heterocyclic group, -(C6-C 10 ) aryl and -(5-12 membered) heteroaryl are optionally substituted by one or more R 31 substituents; Ring A is selected from -(C3-C6) cycloalkylidene-, -(3- to 8-membered) heterocyclidene-, -(C6-C 10 ) arylene- and -(5- to 12-membered) heteroarylene-, and the -(C3-C6) cycloalkylidene-, -(3- to 8-membered) heterocyclidene-, -(C6-C 10 ) arylene- and -(5- to 12-membered) heteroarylene- are optionally substituted by one or more R 31 substituents; R 31 Each independently selected from oxo, hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NH[(C1-C6)alkyl], -(C1-C6)alkylene-N[(C1-C6)alkyl]2, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclic group, -O-(C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclic group, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C6)alkyl, -C(=O)-N[(C1-C6)alkyl]2, -(C6-C 10 aryl, -(5-12 membered) heteroaryl, -S(=O)2-NH2, -S(=O)2-NH(C1-C6)alkyl, -S(=O)2-N[(C1-C6)alkyl]2, -NH-C(=O)H, -NH-C(=O)-(C1-C6)alkyl, -N[(C1-C6)alkyl]-C(=O)-(C1-C6)alkyl, N[(C1-C6)alkyl]-C(=O)H, -NH-S(=O)2-(C1-C6)alkyl, -N[(C1-C6)alkyl]-S(=O)2-(C1-C6)alkyl, -P(=O)[(C1-C6)alkyl]2, -P(=O)[(C1-C6)alkyl]-NH2, -P(=O)[(C1-C6)alkyl]-NH(C1-C6)alkyl and -P(=O)[(C1-C6)alkyl]-N[(C1-C6)alkyl]2, said -(C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NH[(C1-C6)alkyl], -(C1-C6)alkylene-N[(C1-C6)alkyl]2, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered) heterocyclic group, -O-(C3-C6)cycloalkyl, -O-(4-10 membered) heterocyclic group, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH(C1-C6)alkyl, -C(=O)-N[(C1-C6)alkyl]2, -(C6-C 10 )aryl, -(5- to 12-membered) heteroaryl, -S(=O)2-NH2, -S(=O)2-NH(C1-C6)alkyl, -S(=O)2-N[(C1-C6)alkyl]2, -NH-C(=O)H, -NH-C(=O)-(C1-C6)alkyl, -N[(C1-C6)alkyl]-C(=O)-(C1-C6)alkyl, N[(C1-C6)alkyl]-C(=O)H, -NH-S(=O)2-(C1-C6)alkyl, -N[(C1-C6)alkyl]-S(=O)2-(C1-C6)alkyl, -P(=O)[(C1-C6)alkyl]2, -P(=O)[(C1-C6)alkyl]-NH2, -P(=O)[(C1-C6)alkyl]-NH(C1-C6)alkyl and -P(=O)[(C1-C6)alkyl]-N[(C1-C6)alkyl]2 are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -(C1-C6)alkylene-OH, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NH[(C1-C6)alkyl], -(C1-C6)alkylene-N[(C1-C6)alkyl]2, -(C6-C 10 )aryl and -(5- to 12-membered) heteroaryl, -(C1-C6)alkylene-O(C1-C6)alkyl and oxo; R 4 selected from hydrogen, halogen, cyano, -OH, -NH2, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10-membered)heterocyclic group, -O-(4-10-membered)heterocyclic group, -(C6-C 10 )aryl, -O-(C6-C 10 )aryl, -(5-12-membered)heteroaryl and -O-(5-12-membered)heteroaryl; X is selected from O, S, NH, N[(C1-C6)alkyl], N[C(=O)-R c , C(R a )(R b ), C(=O), C[=C(R a )R b , S(=O) and S(=O)2; R a and R b are each independently selected from hydrogen, halogen, cyano, -OR c , -SR c , -N(R c )R c , -(C1-C6)alkyl, and -(C1-C6)haloalkyl; R c selected from hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10 membered)heterocyclic group, -O-(4-10 membered)heterocyclic group, -(C6-C 10 )aryl, -O-(C6-C 10 )aryl, -(5-12 membered)heteroaryl and -O-(5-12 membered)heteroaryl; Ring B is selected from -(C6-C 10 ) aryl and -(5-12 membered) heteroaryl, or Ring B is selected from -(C6-C 10 ) arylene- and -(5-12 membered) heteroarylene-, said -(C6-C 10 ) arylene- and -(5-12 membered) heteroarylene- being optionally substituted with one or more groups selected from R 5 and R 6 ; R 5 and R 6 each independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclic group, -O-(C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclic group, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C6)alkyl, -C(=O)-N[(C1-C6)alkyl]2, -C(=O)-H and -C(=N-OH)-H, wherein the -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclic group, -O-(C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclic group, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH(C1-C6)alkyl and -C(=O)-N[(C1-C6)alkyl]2 are optionally substituted by one or more groups selected from hydrogen, halogen, oxo, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and N[(C1-C4)alkyl]2, or, R 5 and R 6 forms a 5-membered heterocyclic group with the carbon atom to which it is attached; Ring C is selected from -(C6-C 10 ) aryl and -(5-12 membered) heteroaryl, or, Ring C is selected from -(C6-C 10 ) arylene- and -(5-12 membered) heteroarylene-, said -(C6-C 10 ) arylene- and -(5-12 membered) heteroarylene- being optionally substituted by one or more R 7 substituents; R 7 Each independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclic group, -O-(C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclic group, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C6)alkyl, -C(=O)-N[(C1-C6)alkyl]2 and -NHC(=O)-(C1-C6)alkyl, wherein the -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, -(C3-C6)cycloalkyl, -(4-10 membered)heterocyclic group, -O-(C3-C6)cycloalkyl, -O-(4-10 membered)heterocyclic group, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH(C1-C6)alkyl, -C(=O)-N[(C1-C6)alkyl]2 and -NHC(=O)-(C1-C6)alkyl are optionally substituted by one or more groups selected from hydrogen, halogen, oxo, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2; m is 1, 2, 3, 4 or 5; R 8a 、R 8b 、R 9a and R 9b are each independently selected from hydrogen, halogen, cyano, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -OR, -N(R)R, -[(C1-C8)alkylene]R, -[(C1-C8)alkylene]OR, -[(C1-C8)alkylene]N(R)R, -[(C1-C8)alkylene]N(R)C(=O)R, -[(C1-C8)alkylene]N(R)C(=O)N(R)R, -C(=O)R, -C(=O)N(R)R, -C(=O)[(C1-C8)alkylene]N(R)R, -C(=O)OR, -C(=S)N(R)R, -SR, -S(=O)R, -S(=O)2R, -S(=O)2N(R)R, -N(R)C(=O)R, -N(R)C(=O)N(R)R, -P(=O)(OR)(OR), -(C6-C 10 )aryl, -(5-12 membered)heteroaryl, -(C3-C6)cycloalkyl, and -(4-10 membered)heterocycloalkyl, Each R is independently selected from hydrogen, -OH, -NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -(C1-C4)alkylene-O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -S(=O)2-(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(4-10-membered)heterocyclic group, -O-(C3-C6)cycloalkyl, -O-(4-10-membered)heterocyclic group, -C(=O)-H, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C6)alkyl, -C(=O)-N[(C1-C6)alkyl]2, -[(C1-C6)alkylene]-(C3-C6)cycloalkyl, -[(C1-C6)alkylene]-(4-10-membered)heterocyclic group, -(C6-C 10 )aryl, -[(C1-C6)alkylene]-(C6-C 10 )aryl and -(5-12-membered)heteroaryl, and the -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, -O-(C1-C6)alkyl, -(C1-C4)alkylene-O-(C1-C6)alkyl, -O-(C1-C6)haloalkyl, -S-(C1-C6)alkyl, -S(=O)2-(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(4-10-membered)heterocyclic group, -O-(C3-C6)cycloalkyl, -O-(4-10-membered)heterocyclic group, -C(=O)-(C1-C6)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C6)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH(C1-C6)alkyl, -C(=O)-N[(C1-C6)alkyl]2, -[(C1-C6)alkylene]-(C3-C6)cycloalkyl, -[(C1-C6)alkylene]-(4-10-membered)heterocyclic group, -(C6-C 10 )aryl, -[(C1-C6)alkylene]-(C6-C 10 )aryl and -(5-12-membered)heteroaryl are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, N[(C1-C4)alkyl]2 and (C1-C4)alkyl, Alternatively, R 8a and R 8b combine to form oxo, -(C2-C6) alkenyl, -(C3-C6) cycloalkyl or -(4-10 membered) heterocyclic group, Alternatively, R 9a and R 9b combine to form oxo, -(C2-C6) alkenyl, -(C3-C6) cycloalkyl or -(4-10 membered) heterocyclic group, Alternatively, R 8a and R 9a together with the carbon atom to which it is attached form a (C3-C6) cycloalkyl, (4-10 membered) heterocyclic group or (5-10 membered) heteroaryl group, which groups are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -O-(C1-C4) alkyl, -NH2, -NH(C1-C4) alkyl, -N[(C1-C4) alkyl]2, -(C3-C6) cycloalkyl, -(4-8 membered) heterocyclic group, -(5-6 membered) heteroaryl and -(C6-C 10 ) aryl groups, Alternatively, R 8b and R 9b together with the carbon atom to which it is attached form a (C3-C6) cycloalkyl, (4-10 membered) heterocyclic group or (5-10 membered) heteroaryl group, which is optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -O-(C1-C4) alkyl, -NH2, -NH(C1-C4) alkyl, -N[(C1-C4) alkyl]2, -(C3-C6) cycloalkyl, -(4-8 membered) heterocyclic group, -(5-6 membered) heteroaryl and -(C6-C 10 ) aryl groups; R 10 selected from hydrogen, cyano, -OH and -NH2, or R 10 and R 9a and the atom to which it is attached forms a (5- to 6-membered) heterocyclic group, which (5- to 6-membered) heterocyclic group is optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -(C1-C4)alkyl, -(C3-C6)cycloalkyl, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2.

2. The ligand-drug conjugate according to claim 1 or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, R m 、R w 、R y 、R q and R t are each independently selected from hydrogen, -(C1-C4)alkyl, -O-(C1-C4)alkyl, -(C1-C4)haloalkyl, and -O-(C1-C4)haloalkyl; Preferably, R m , R w , R y , R q and R t are each independently selected from hydrogen, methyl, ethyl, propyl, -O-methyl, -O-ethyl, and -O-propyl; Preferably, R m , R w , R y , R q , and R t are each independently hydrogen and methyl; Preferably, R m , R w , R y , R q and R t are each independently hydrogen.

3. The ligand-drug conjugate according to claim 1 or 2 or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, M is selected from -NH-, -O-, -(C1-C6)alkylene-O- and -(C1-C6)alkylene-NH-, and the -(C1-C6)alkylene-O- and -(C1-C6)alkylene-NH- are optionally substituted by 1, 2 or 3 groups selected from hydrogen, halogen, -OH, -O-methyl, -NH2, -NH-methyl, -N(methyl)2 and -N(ethyl)2; Preferably, M is selected from -NH-, -O-, -(C1-C6)alkylene-O- and -(C1-C6)alkylene-NH-; Preferably, M is selected from -NH-, -O-, -(C1-C4)alkylene-O- and -(C1-C4)alkylene-NH-; Preferably, M is selected from -NH-, -O-, -CH2O- and -CH2NH-; Preferably, M is selected from -NH-, -O-, *-CH2O- and *-CH2NH-, where the * end is connected to ring C; Preferably, M is selected from -NH-.

4. The ligand-drug conjugate according to claim 1 or 2 or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, W is absent, or is selected from -(C1-C6)alkylene-, -NH-, -N[(C1-C6)alkyl]- and -N[O(C1-C6)alkyl]-, Preferably, W is absent, or is selected from -(C1-C4)alkylene, -NH- and -N[-(C1-C4)alkyl]-, Preferably, W is absent, or is selected from methylene, ethylene, -NH-, -N(Me)- and -N(Et)-, Preferably, W is absent, or is selected from -NH- and -N(Me)-; U is selected from -(C1-C6)alkylene-, -(C3-C6)cycloalkylene- and -(4-10 membered)heteroalkylene-, Preferably, U is selected from -(C1-C4) alkylene-, -(C3-C6) cycloalkylene-, and -(4-6 membered) heteroalkylene-; Preferably, U is selected from methylene, ethylene, cyclopropylidene, azetidinylidene, and pyrrolidinylidene; Preferably, U is selected from methylene, ethylene and Preferably, U is selected from methylene, ethylene, wherein, the * end is connected to W, and when W does not exist, the * end is connected to the carbonyl group; Z does not exist, or is selected from -(C1-C4) alkylene-, -(C3-C6) cycloalkylene-, and -(4-6 membered) heteroalkylene-; Preferably, Z does not exist, or is selected from methylene, ethylene, cyclopropylidene, azetidinylidene, and pyrrolidinylidene; Preferably, Z does not exist; Y is absent or is selected from -O-, -N(R y )- and -N + (R y )2-, R y is selected from hydrogen, -(C1-C6)alkyl, and -O(C1-C6)alkyl, or R y forms with Z a -(4-10-membered) heteroalkylene-, Preferably, Y is absent or selected from -O-, -N(R y )- and -N + (R y )2-, R y is selected from hydrogen, -(C1-C4)alkyl, and -O(C1-C4)alkyl, or R y forms, together with Z, -(4-6 membered)heterocyclylene-, Preferably, Y is absent or selected from -O-, -N(R y )- and -N + (R y )2-, R y is selected from hydrogen, methyl, ethyl and -O-methyl, Preferably, Y is selected from -O-, -NH-, -N(CH3)-, and -N + (CH3)2-.

5. The ligand-drug conjugate according to claim 1 or 2, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein, Structural unit - W - U - Z - Y - is selected from - N(R w )-(C1-C6)alkylene - N(R y )-,-N(R w )-(C1-C6)alkylene - N + (R y )2-,-N(R w )-(C1-C6)alkylene - O-,-(C1-C6)alkylene - N(R y )-,-(C1-C6)alkylene - O-,-(C3-C6)cycloalkylidene - N(R y )-,-(C1-C6)alkylene - N + (R y )2-,-(C3-C6)cycloalkylidene - O-,-(4-6 membered)heterocyclidene - O-,-(4-6 membered)heterocyclidene - N(R y )-and - N(R w )-(4-6 membered)heterocyclidene -,wherein the - N(R w )-(C1-C6)alkylene - N(R y )-,-N(R w )-(C1-C6)alkylene - N + (R y )2-,-N(R w )-(C1-C6)alkylene - O-,-(C1-C6)alkylene - N(R y )-,-(C1-C6)alkylene - N + (R y )2-,-(C1-C6)alkylene - O-,-(C3-C6)cycloalkylidene - N(R y )-,-(C3-C6)cycloalkylidene - O-,-(4-6 membered)heterocyclidene - O-,-(4-6 membered)heterocyclidene - N(R y )-and - N(R w )-(4-6 membered)heterocyclidene - is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6 or 7) groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2; Preferably, the structural unit -W-U-Z-Y- is selected from -N(R w )-(C1-C6) alkylene -N(R y )-, -N(R w )-(C1-C6) alkylene -N + (R y )2-, -N(R w )-(C1-C6) alkylene -O-, -(C1-C6) alkylene -N(R y )-, -(C1-C6) alkylene -N + (R y )2-, -(C1-C6) alkylene -O-, -(4-6 membered) heterocyclic group -O- and -(4-6 membered) heterocyclic group -N(R y )- and -N(R w )-(4-6 membered) heterocyclic group -; Preferably, the structural unit -W-U-Z-Y- is selected from *-NH-CH2-CH2-NH-, *-N(CH3)-CH2-CH2-NH-, *-NH-CH2-CH2-O-, *-CH2-O-, *-CH2-NH-, *-CH2-N(CH3)-, *-CH2-N + (CH3)2- wherein, the * end is connected to the carbonyl group.

6. The ligand-drug conjugate according to claim 1 or 2, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein, R 12 selected from hydrogen, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(C=O)-(C1-C6)alkyl, -(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -(4-10 membered)heterocyclic group, and -O-(4-10 membered)heterocyclic group; Preferably, R 12 is selected from hydrogen, -(C1-C4)alkyl, -O-(C1-C4)alkyl, -(C=O)-(C1-C4)alkyl, -(C3-C6)cycloalkyl and -O-(C3-C6)cycloalkyl, Preferably, R 12 is selected from hydrogen, -(C1-C4)alkyl, -O-(C1-C4)alkyl, and -(C3-C6)cycloalkyl, Preferably, R 12 is selected from hydrogen and -(C1-C4) alkyl, Preferably, R 12 is selected from hydrogen, methyl and ethyl, Preferably, R 12 is selected from hydrogen and methyl, Preferably, R 12 is selected from hydrogen; L is absent or selected from -C(=O)-(C1-C4)alkylene-O-, -C(=O)-(C1-C4)alkylene-N(R L )-, -C(=O)-(C1-C4)alkylene-N + (R L )2-, -C(=O)NH-(C1-C4)alkylene-O-, -C(=O)NH-(C1-C4)alkylene-N(R L )- and -C(=O)NH-(C1-C4)alkylene-N + (R L )2-, R L is selected from hydrogen, -(C1-C4)alkyl and -(C1-C4)haloalkyl; Preferably, L is absent or selected from -C(=O)-(C1-C4)alkylene-O-, -C(=O)-(C1-C4)alkylene-N(R L )- and -C(=O)-(C1-C4)alkylene-N + (R L )2-, R L is selected from hydrogen, methyl and ethyl; Preferably, L is absent or selected from -C(=O)CH2O-, -C(=O)CH2CH2O-, -C(=O)CH2N(R L )-, -C(=O)CH2CH2N(R L )-, -C(=O)CH2N + (R L )2- and -C(=O)CH2CH2N + (R L )2-, where R L is selected from hydrogen, methyl, and ethyl; Preferably, L is absent or selected from *-C(=O)CH2O-, *-C(=O)CH2N(CH3)-, *-C(=O)CH2N + (CH3)2-, wherein the * end is connected to N.

7. The ligand-drug conjugate according to claim 1 or 2, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein, Q is selected from -NH-, -O-, -(C1-C6) alkylene-O-, and -(C1-C6) alkylene-NH-, and the -(C1-C6) alkylene-O- and -(C1-C6) alkylene-NH- are optionally substituted by 1, 2, or 3 groups selected from hydrogen, halogen, -OH, -O-methyl, -NH2, -NH-methyl, -N(methyl)2, and -N(ethyl)2; Preferably, Q is selected from -NH-, -O-, -(C1-C6) alkylene-O-, and -(C1-C6) alkylene-NH-; Preferably, Q is selected from -NH-, -O-, -(C1-C4) alkylene-O-, and -(C1-C4) alkylene-NH-; Preferably, Q is selected from -NH-, -O-, -CH2O-, and -CH2NH-; Preferably, Q is selected from -NH-, -O-, *-CH2O-, and *-CH2NH-, wherein the * end is connected to ring B; Preferably, Q is selected from -NH-.

8. The ligand-drug conjugate according to claim 1 or 2, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein, T is selected from -NH-, -O-, -(C1-C6) alkylene-O-, and -(C1-C6) alkylene-NH-, and the -(C1-C6) alkylene-O- and -(C1-C6) alkylene-NH- are optionally substituted by 1, 2, or 3 groups selected from hydrogen, halogen, -OH, -O-methyl, -NH2, -NH-methyl, -N(methyl)2, and -N(ethyl)2; Preferably, T is selected from -NH-, -O-, -(C1-C6) alkylene-O-, and -(C1-C6) alkylene-NH-; Preferably, T is selected from -NH-, -O-, -(C1-C4)alkylene-O- and -(C1-C4)alkylene-NH-; Preferably, T is selected from -NH-, -O-, -CH2O- and -CH2NH-; Preferably, T is selected from -NH-, -O-, *-CH2O- and *-CH2NH-, wherein the * end is connected to ring A; Preferably, T is selected from -NH-, *-CH2O- and *-CH2NH-, wherein the * end is connected to ring A; Preferably, T is selected from -NH- and *-CH2NH-, wherein the * end is connected to ring A.

9. The ligand-drug conjugate according to any one of claims 1-8, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, R 1 selected from hydrogen, halogen, cyano, -OH, -(C1-C4)alkyl, and -O-(C1-C4)alkyl; Preferably, R 1 is selected from hydrogen, fluorine, chlorine, cyano, -OH, methyl, ethyl, propyl, -O-methyl, -O-ethyl and -O-propyl; Preferably, R 1 is selected from hydrogen and -O-methyl, Preferably, X 1 is selected from N, CH, and C(OCH3).

10. The ligand-drug conjugate according to any one of claims 1-9, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, R 2 selected from hydrogen, halogen, cyano, -OH, -(C1-C4)alkyl, and -O-(C1-C4)alkyl; Preferably, R 2 is selected from hydrogen, fluorine, chlorine, cyano, -OH, methyl, ethyl, propyl, -O-methyl, -O-ethyl, and -O-propyl; Preferably, R 2 is hydrogen, Preferably, X 2 is selected from N and CH.

11. The ligand-drug conjugate according to any one of claims 1-10, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, R 3 selected from -(C3-C6) cycloalkyl, -(4-6 membered) heterocyclic group, -(C6-C 10 ) aryl and -(5-12 membered) heteroaryl, said -(C3-C6) cycloalkyl, -(4-6 membered) heterocyclic group, -(C6-C 10 ) aryl and -(5-12 membered) heteroaryl are optionally substituted by one or more R 31 substituted, Ring A is selected from -(C3-C6) cycloalkylene-, -(4-6 membered) heteroalkylene-, -(C6-C 10 ) arylene- and -(5-12 membered) heteroarylene-, and the -(C3-C6) cycloalkylene-, -(4-6 membered) heteroalkylene-, -(C6-C 10 ) arylene- and -(5-12 membered) heteroarylene- are optionally substituted by one or more R 31 substituents, R 31 selected from oxo, hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C4)alkyl, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NH2, -(C1-C4)alkylene-NH(C1-C4)alkyl, -(C1-C4)alkylene-N[(C1-C4)alkyl]2, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclic group, -O-(C3-C6)cycloalkyl, -O-(4-8 membered)heterocyclic group, -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C4)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C4)alkyl and -C(=O)-N[(C1-C4)alkyl]2; Preferably, R 31 is selected from oxo, hydrogen, halogen, cyano, -OH, -SH, -NH2, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -NH-(C1-C4)alkyl, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NH2, -(C1-C4)alkylene-NH(C1-C4)alkyl, and -(C1-C4)alkylene-N[(C1-C4)alkyl]2, Preferably, R 31 is selected from oxo, hydrogen, fluorine, chlorine, cyano, -OH, -SH, -NH2, methyl, halomethyl, -O-methyl, -CH2OH, -CH2NH2, and -CH2CH2N(CH3)2, Preferably, R 31 is selected from hydrogen, -NH2, -CH2OH, and -CH2NH2; Preferably, R 31 is selected from hydrogen; Preferably, R 3 is selected from -(C3-C6) cycloalkyl and -(4-6 membered) heterocyclic group, and the -(C3-C6) cycloalkyl and -(4-6 membered) heterocyclic group are optionally substituted with one or more R 31 , where the definition of R 31 is as described in this claim. Preferably, R 3 is selected from cyclopropyl, oxetanyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, morpholinyl, morpholinone, piperidinyl, piperazinyl, and piperazinone, and the cyclopropyl, oxetanyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, morpholinyl, morpholinone, piperidinyl, piperazinyl, and piperazinone are optionally substituted with 1, 2, or 3 R 31 groups, and the definition of R 31 is as described in this claim. Preferably, R 3 is selected from Preferably, R 3 is selected from phenyl, naphthyl and -(5-10 membered) heteroaryl, and the phenyl, naphthyl and -(5-10 membered) heteroaryl are optionally substituted with one or more R 31 groups, and the definition of R 31 is as described in this claim, Preferably, R 3 is selected from -(5- to 9-membered) heteroaryl, said -(5- to 9-membered) heteroaryl being optionally substituted by 1, 2, 3 or 4 R 31 groups, the definition of R 31 being as described in this claim, Preferably, R 3 is selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridazinoimidazolyl, pyrazinoimidazolyl and pyrimidinone group, and the oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridazinoimidazolyl, pyrazinoimidazolyl and pyrimidinone group are optionally substituted by 1, 2 or 3 R 31 groups, and the definition of R 31 is as described in this claim. Preferably, R 3 is selected from The Optionally substituted by 1, 2 or 3 Rs 31 wherein R 31 is as defined in this claim Preferably, R 3 is selected from Further preferably, R 3 is selected from Further preferably, R 3 is selected from Preferably, ring A is selected from phenylene, naphthylene and -(5-10 membered) heteroarylene-, and the phenylene, naphthylene and -(5-10 membered) heteroarylene- are optionally substituted by one or more R 31 substituents, and the definition of R 31 is as described in this claim Preferably, ring A is selected from -(5- to 9-membered) heteroarylene-, and said -(5- to 9-membered) heteroarylene- is optionally substituted by 1, 2, 3 or 4 R 31 substituents, and the definition of R 31 is as described in this claim Preferably, ring A is selected from -(5-6 membered) heteroarylene-, said -(5-6 membered) heteroarylene- being optionally substituted by 1, 2, 3 or 4 R 31 substituents, where the definition of R 31 is as described in this claim, Preferably, ring A is selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridazinimidazolyl, pyrazinimidazolyl and pyrimidinone group, and the oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridazinimidazolyl, pyrazinimidazolyl and pyrimidinone group are optionally substituted with 1, 2 or 3 R 31 as defined in this claim, 31 wherein the definition of R Preferably, ring A is selected from wherein the * end is connected to T; Preferably, ring A is selected from wherein the * end is connected to T.

12. The ligand-drug conjugate according to any one of claims 1-11, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, R 4 selected from hydrogen, halogen, cyano, -OH, -NH2, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl and -O-(C1-C4)haloalkyl; Preferably, R 4 is selected from hydrogen, fluorine, chlorine, cyano, -OH, -NH2 and methyl; Preferably, R 4 is hydrogen.

13. The ligand-drug conjugate according to any one of claims 1-12, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, X is selected from O, S, NH, N[(C1-C4)alkyl], N[C(=O)-R c , C(R a )(R b ), C(=O), C[=C(R a )R b , S(=O) and S(=O)2, R a and R b are each independently selected from hydrogen, halogen, cyano, -OR c , -SR c , -N(R c )R c , -(C1-C4)alkyl and -(C1-C4)haloalkyl, R c is selected from hydrogen, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl and -(C3-C6)cycloalkyl; Preferably, X is selected from O, S, NH and N[(C1-C4)alkyl], Preferably, X is selected from O, S and NH; More preferably, X is selected from O.

14. The ligand-drug conjugate according to any one of claims 1-13, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, Ring B is selected from -(C6-C 10 ) aryl and (5-10 membered) heteroaryl, or Ring B is selected from -(C6-C 10 ) arylene- and (5-10 membered) heteroarylene-, said -(C6-C 10 ) arylene- and (5-10 membered) heteroarylene- being optionally substituted by 1, 2 or 3 groups selected from R 5 and R 6 groups, Preferably, ring B is selected from phenyl, naphthyl and (5-6 membered) heteroaryl, Preferably, the structural unit For or Preferably, ring B is selected from phenylene, naphthylene and (5-6 membered) heteroarylene, and the phenylene, naphthylene and (5-6 membered) heteroarylene are optionally substituted with 1 or 2 groups selected from R 5 and R 6 groups. Preferably, ring B is a phenylene group, which is optionally substituted by one R 5 or R 6 substitution Preferably, ring B is the * end is connected to Q; R 5 and R 6 each independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclic group, -O-(C3-C6)cycloalkyl and -O-(4-8 membered)heterocyclic group, wherein the -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclic group, -O-(C3-C6)cycloalkyl and -O-(4-8 membered)heterocyclic group are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and N[(C1-C4)alkyl]2 Preferably, R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, -OH, -NH2, -(C1-C4)alkyl, -(C1-C4)alkyl-OH, -(C1-C4)alkyl-NH2, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, and -(C3-C6)cycloalkyl; Preferably, R 5 is selected from hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2, and -CH2NH2, Preferably, R 5 is selected from hydrogen, -OH, -NH2 and -CH2NH2; Preferably, R 6 is selected from hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH2, -O-methyl and cyclopropyl; Alternatively, R 5 and R 6 form with the atoms to which it is attached wherein * represents the position of the connected atom.

15. The ligand-drug conjugate according to any one of claims 1-14, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, Ring C is selected from -(C6-C 10 ) aryl and (5-10 membered) heteroaryl, or Ring C is selected from -(C6-C 10 ) arylene and (5-10 membered) heteroarylene, said -(C6-C 10 ) arylene and (5-10 membered) heteroarylene being optionally substituted by 1, 2 or 3 R 7 substituents, Preferably, ring C is selected from phenyl, naphthyl and (5-6 membered) heteroaryl, Preferably, the structural unit For or, Preferably, ring C is selected from phenylene, naphthylene and (5-6 membered) heteroarylene, said phenylene, naphthylene and (5-6 membered) heteroarylene being optionally substituted with 1 or 2 R 7 substituents, Preferably, ring C is a phenylene group, which is optionally substituted by one R 7 substituent Preferably, ring C is the * end is connected to M; R 7 each independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH2, -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8-membered)heterocyclic group, -O-(C3-C6)cycloalkyl, -O-(4-8-membered)heterocyclic group, and -NHC(=O)-(C1-C4)alkyl, wherein the -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -S-(C1-C4)alkyl, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl, -(4-8-membered)heterocyclic group, -O-(C3-C6)cycloalkyl, -O-(4-8-membered)heterocyclic group, and -NHC(=O)-(C1-C4)alkyl are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, and -N[(C1-C4)alkyl]2 Preferably, R 7 is independently selected from hydrogen, halogen, cyano, -OH, -NH2, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NH(C1-C4)alkyl, -(C1-C4)alkylene-N[(C1-C4)alkyl]2, -(C1-C4)alkylene-NH2 and -NHC(=O)-(C1-C4)alkylene-NH2, Preferably, R 7 is independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -NH2, -CH2OH, -CH2NH2, -NHC(=O)CH2NH2, and -NHC(=O)CH2CH2NH2, Preferably, R 7 each independently selected from hydrogen; Preferably, m is 1, 2 or 3.

16. The ligand-drug conjugate according to any one of claims 1-15, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, R 8a 、R 8b 、R 9a and R 9b are each independently selected from hydrogen, halogen, cyano, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -OR, -N(R)R, -[(C1-C6)alkylene]R, -[(C1-C6)alkylene]OR, -[(C1-C6)alkylene]N(R)R, -[(C1-C6)alkylene]N(R)C(=O)R, -[(C1-C6)alkylene]N(R)C(=O)N(R)R, -C(=O)R, -C(=O)N(R)R, -C(=O)[(C1-C6)alkylene]N(R)R, -C(=O)OR, -C(=S)N(R)R, -SR, -S(=O)R, -S(=O)2R, -S(=O)2N(R)R, -N(R)C(=O)R, -N(R)C(=O)N(R)R and -P(=O)(OR)(OR), where each R is independently selected from hydrogen, -OH, -NH2, -(C1-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -O-(C1-C4)haloalkyl, -(C1-C4)alkylene-O-(C1-C4)alkyl, -S-(C1-C4)alkyl, -S(=O)2-(C1-C4)alkyl, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclic group, -O-(C3-C6)cycloalkyl, -O-(4-8 membered)heterocyclic group, -C(=O)-H, -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl, -C(=O)-O-(C1-C4)alkyl, -C(=O)-O-(C3-C6)cycloalkyl, -C(=O)-NH2, -C(=O)-NH(C1-C4)alkyl, -[(C1-C4)alkylene]-(C3-C6)cycloalkyl, -C(=O)-N[(C1-C4)alkyl]2, -[(C1-C4)alkylene]-(4-8 membered)heterocyclic group, -(C6-C 10 )aryl, -[(C1-C4)alkylene]-(C6-C 10 )Aryl and -(5-10 membered) heteroaryl, said -(C1-C4) alkyl, -(C2-C4) alkenyl, -(C2-C4) alkynyl, -(C1-C4) haloalkyl, -O-(C1-C4) alkyl, -O-(C1-C4) haloalkyl, -(C1-C4) alkylene-O-(C1-C4) alkyl, -S-(C1-C4) alkyl, -S(=O)2-(C1-C4) alkyl, -(C3-C6) cycloalkyl, -(4-8 membered) heterocyclic group, -O-(C3-C6) cycloalkyl, -O-(4-8 membered) heterocyclic group, -C(=O)-(C1-C4) alkyl, -C(=O)-(C3-C6) cycloalkyl, -C(=O)-O-(C1-C4) alkyl, -C(=O)-O-(C3-C6) cycloalkyl, -C(=O)-NH(C1-C4) alkyl, -[(C1-C4) alkylene]-(C3-C6) cycloalkyl, -C(=O)-N[(C1-C4) alkyl]2, -[(C1-C4) alkylene]-(4-8 membered) heterocyclic group, -(C6-C 10 )Aryl, -[(C1-C4) alkylene]-(C6-C 10 )Aryl and -(5-10 membered) heteroaryl are optionally substituted with 1, 2, 3, 4, 5, 6 or 7 groups selected from hydrogen, halogen, -OH, -O-(C1-C4) alkyl, -NH2, -NH(C1-C4) alkyl, N[(C1-C4) alkyl]2 and (C1-C4) alkyl; Preferably, each R is independently selected from hydrogen, -OH, -NH2, -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -(C1-C4)alkylene-O-(C1-C6)alkyl, -O-(C1-C4)haloalkyl, -S(=O)2-(C1-C4)alkyl, -(C3-C6)cycloalkyl, -(4-8 membered) heterocyclic group, -C(=O)-H, -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl, -[(C1-C4)alkylene]-(C3-C6)cycloalkyl and -[(C1-C4)alkylene]-(4-8 membered) heterocyclic group, and the -(C1-C4)alkyl, -(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -(C1-C4)alkylene-O-(C1-C6)alkyl, -O-(C1-C4)haloalkyl, -S(=O)2-(C1-C4)alkyl, -(C3-C6)cycloalkyl, -(4-8 membered) heterocyclic group, -C(=O)-(C1-C4)alkyl, -C(=O)-(C3-C6)cycloalkyl, -[(C1-C4)alkylene]-(C3-C6)cycloalkyl and -[(C1-C4)alkylene]-(4-8 membered) heterocyclic group are optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, N[(C1-C4)alkyl]2, methyl and ethyl, Preferably, each R is independently selected from hydrogen, -OH, -NH2, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2NH2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2N(CH3)2, -CH(N(CH3)2)CH2OH, -CH2OCH2CH2OH, -OCH3, -C(=O)-H, -C(=O)CH3, -C(=O)CH2OH, -S(=O)2CH3, cyclobutyl-OH, oxetanyl, azetidinyl, azetidinyl-OH, pyrrolidinyl, piperazinyl, azetidinyl-CH3, piperazinyl-CH3, and -CH2-azetidinyl, More preferably, each R is independently selected from hydrogen, -OH, -NH2, -(C1-C4)alkyl, -O-(C1-C4)alkyl, and -(4-8 membered)heterocyclic group, and the -(C1-C4)alkyl, -O-(C1-C4)alkyl, and -(4-8 membered)heterocyclic group are optionally substituted with 1, 2, 3, 4, or 5 groups selected from hydrogen, halogen, -OH, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, and -O-(C1-C4)alkyl. More preferably, each R is independently selected from hydrogen, -OH, -(C1-C4)alkyl, -O-(C1-C4)alkyl, and -(4-8 membered)heterocyclic group, and the -(C1-C4)alkyl, -O-(C1-C4)alkyl, and -(4-8 membered)heterocyclic group are optionally substituted with 1, 2, or 3 groups selected from hydrogen, halogen, -OH, -NH2, -NH-methyl, and -N(methyl)2. More preferably, each R is independently selected from methyl, ethyl, propyl, -O-methyl, -O-ethyl, -O-propyl, oxetanyl, and azetidinyl, and the foregoing groups are each independently optionally substituted with 1, 2, or 3 groups selected from -OH and -NH2; Preferably, R 8a , R 8b , R 9a and R 9b are each independently selected from hydrogen, cyano, -OR, -N(R)R, -[(C1-C4)alkylene]R, -[(C1-C4)alkylene]OR, -[(C1-C4)alkylene]N(R)R, -[(C1-C4)alkylene]N(R)C(=O)R, -[(C1-C4)alkylene]N(R)C(=O)N(R)R, -C(=O)R, -C(=O)N(R)R, -C(=O)[(C1-C4)alkylene]N(R)R, -C(=O)OR, -C(=S)N(R)R, -S(=O)R, -S(=O)2R, -S(=O)2N(R)R, -N(R)C(=O)R and -N(R)C(=O)N(R)R, where R is as defined in this claim, Preferably, R 8a and R 8b are each independently selected from hydrogen, -methylene-R, -ethylene-R, -propylene-R, -methylene-OR, -ethylene-OR, -propylene-OR, -methylene-N(R)R, -ethylene-N(R)R, -propylene-N(R)R, -C(=O)R, -C(=O)N(R)R, and -C(=O)OR, where R is as defined in this claim, Preferably, R 8a and R 8b are each independently selected from hydrogen, -methylene-R, -methylene-OR, -methylene-N(R)R, -C(=O)R, -C(=O)OR and -C(=O)N(R)R, where R is as defined in this claim. For example, R is each independently selected from hydrogen, -OH, -NH2, -(C1-C4)alkyl, -O-(C1-C4)alkyl, -C(=O)-(C1-C4)alkyl, -S(=O)2(C1-C4)alkyl and -(4-8 membered)heterocyclic group, and the -(C1-C4)alkyl and -(4-8 membered)heterocyclic group are each optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -NH2, -NHCH3 and CH3; Preferably, R 8a is hydrogen, preferably Preferably, R 8b is selected from hydrogen, Preferably, R 8b is selected from hydrogen, Preferably, R 9a and R 9b are each independently selected from hydrogen, -CN, -OR, -NHR, -N(R)R, -NHC(=O)R, -methylene-R, -ethylene-R, -propylene-R, -methylene-N(R)R, -ethylene-N(R)R, -propylene-N(R)R, -methylene-NHC(=O)R and -methylene-NHC(=O)NHR, where R is as defined in this claim; Preferably, R 9a and R 9b each independently selected from hydrogen, -CN, -OR, -N(R)R, -NHC(=O)R, -methylene-N(R)R, -methylene-NHC(=O)R and -methylene-NHC(=O)NHR, where R is as defined in this claim. For example, R is each independently selected from hydrogen, -OH, -(C1-C4)alkyl, -(C1-C4)alkylene-O-(C1-C4)alkyl, -S(=O)2(C1-C4)alkyl, -(C3-C6)cycloalkyl, -(4-8 membered)heterocyclic group, -methylene-(C3-C6)cycloalkyl and -methylene-(4-8 membered)heterocyclic group, and the -(C1-C4)alkyl, -(C3-C6)cycloalkyl and -(4-8 membered)heterocyclic group are each optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -O-(C1-C4)alkyl and -(C1-C4)alkyl; Preferably, R 9a is selected from hydrogen, -CN, -N(R)R, -NHC(=O)R, -methylene-N(R)R, -methylene-NHC(=O)R and -methylene-NHC(=O)NHR, where R is as defined in this claim. For example, each R is independently selected from hydrogen, -OH, methyl, ethyl, -methylene-O-ethyl, -S(=O)2-methyl, cyclobutyl, azetidinyl, -methylene-cyclobutyl and -methylene-azetidinyl, and the foregoing groups are each independently optionally substituted by 1, 2 or 3 groups selected from -OH, OCH3, NHCH3, N(CH3)2 and CH3. Preferably, R 9a is selected from hydrogen, -CN, -NHCH3, -N(CH3)2, -NHC(=O)H, -NHC(=O)CH2OH, -NHC(=O)CH2OCH3, -NHC(=O)CH2NHCH3, -NHC(=O)CH2N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2N(CH3)(CH2CH3), -CH2NHC(=O)CH2OH, -CH2NHC(=O)CH2OCH3, -CH2NHC(=O)CH2NHCH3, -CH2NHC(=O)CH2N(CH3)2, -CH2NHC(=O)H, -CH2NHC(=O)CH3, -CH2NHC(=O)NHOH, -CH2NHC(=O)NHCH2CH2OH, -CH2NHC(=O)CH(N(CH3)2)CH2OH, -CH2NHC(=O)CH2NHCH3, -CH2NHC(=O)CH2N(CH3)2, -CH2NHC(=O)CH2N(CH2CH3)2, -CH2NHC(=O)CH2OCH2CH2OH, -CH2NHS(=O)2CH3, -CH2NHC(=O)cyclobutyl-OH, -CH2NHC(=O)-azetidinyl-CH3 and -CH2NHC(=O)CH2-azetidinyl, Preferably, R 9a is selected from hydrogen, Preferably, R 9a is Preferably, R 9b is selected from hydrogen and Preferably, R 9b is -OH, preferably Alternatively, R 8a and R 8b combine to form oxo, -(C2-C4) alkenyl, -(C3-C6) cycloalkyl or -(4-8 membered) heterocyclic group, Alternatively, R 9a and R 9b combine to form oxo, -(C2-C4) alkenyl, -(C3-C6) cycloalkyl or -(4-8 membered) heterocyclic group, Alternatively, R 8a and R 9a together with the carbon atom to which it is attached form a (C3-C6) cycloalkyl, (4- to 8-membered) heterocyclic group or (5- to 9-membered) heteroaryl group, which groups are optionally substituted by 1, 2, 3, 4, 5, 6 or 7 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl and -(C6-C 10 ) aryl groups, Alternatively, R 8b and R 9b together with the carbon atom to which it is attached form a (C3-C6) cycloalkyl group, a (4- to 8-membered) heterocyclic group or a (5- to 9-membered) heteroaryl group, said groups being optionally substituted by 1, 2, 3, 4, 5, 6 or 7 groups selected from hydrogen, halogen, -OH, -O-(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl]2, -(C3-C6)cycloalkyl and -(C6-C 10 ) aryl groups, Preferably, R 8a and R 9a do not exist, and R 8b and R 9b form with the atoms connected thereto wherein * represents the position of the connected atom.

17. The ligand-drug conjugate according to any one of claims 1-16, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, R 10 Selected from -OH, or R 10 and R 9a and the atom to which it is attached form a 5-membered nitrogen-containing heterocyclic group, and the 5-membered nitrogen-containing heterocyclic group is optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -(C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl and -N[(C1-C4)alkyl]2 Preferably, R 10 is -OH, or R 10 and the atom to which R 9a is attached form an imidazolinyl group, which imidazolinyl group is optionally substituted by 1, 2 or 3 groups selected from halogen, -OH, methyl, -NH2, -NH-methyl and -N(methyl)2, Preferably, R 10 is -OH, or R 10 and R 9a together with the atom to which it is attached form wherein * represents the position of the connected atom; Preferably, R 10 is -OH, preferably 18. The ligand-drug conjugate according to any one of claims 1-17, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, The pharmaceutical group is selected from: The structures shown in Formula I-A-1, II-A-1', III-A-1', IV-A-1 or V-A-1: Among them, X, X 1 , X 2 , ring A, ring B, ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9a , R 9b , R 10 , R 12 , the definitions of m, n, M, W, U, Z, Y, L, Q and T are as described in any one of claims 1-17; Alternatively, the structure represented by Formula I-A-5, II-A-5, III-A-5, IV-A-5 or V-A-5: Among them, X, R 1 , ring A, R 3 , R 5 , R 6 , R 7 , R 8b , R 9a , R 9b , R 12 , the definitions of n, M, W, U, Z, Y, L, Q and T are as described in any one of claims 1-17; Alternatively, the structures represented by Formula I-A-6 and I-A-7: Among them, R 1 , R 31 , R 5 , R 6 , R 8b , R 9a , R 9b and M are defined as described in any one of claims 1-17.

19. The ligand-drug conjugate according to any one of claims 1-18, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, The pharmaceutical group is selected from the structures shown in Table A.

20. The ligand-drug conjugate according to any one of claims 1-19, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, The linking group is -Tr-L 3 -L 2 -L 1 -, and the linking group is linked to the drug group to form a structure selected from the structures shown in Formula I-B, II-B', III-B', IV-B or V-B Wherein, X, X 1 , X 2 , ring A, ring B, ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9a , R 9b , R 10 , R 12 , the definitions of m, n, M, W, U, Z, Y, L, Q and T are as described in any one of claims 1 - 19; Tr is absent or Tr is any group; L 3 Absent or selected from polypeptide fragments and peptidomimetics; L 2 Absent or selected from linking segments; L 1 is a connecting unit; The wavy line indicates that through L 1 The nitrogen or carbon atom on the group is connected to the ligand.

21. The ligand-drug conjugate according to any one of claims 1-20, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein, L 1 is a connecting unit; L 2 is -(C(R L21 ))2) r -, r is a natural number from 0 to 50 L 2 Any C(R L21 )2 unit in it can be independently replaced by the following structural units: -Cy-, -C(=O)-, -NR L22 -, -O-, -S-, -S(=O)-, -S(=O)2-, -P(R L22 )-, -P(=O)(R L22 )-, -C(=S)-, -C(=NR L22 )-, -N=N-, -CH=N-, -N=CH-, -Cy- is selected from -phenylene-, -(5- to 8-membered) heteroarylene-, -(4- to 10-membered) heterocyclylene-, and -(C3-C 10 ) cycloalkylene-, wherein said -Cy- is unsubstituted or each independently substituted by one or more R Cx substituents, Each R L21 、R L22 and R Cx are each independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OR L2a 、-SR L2a 、-N(R L2a )2、-N + (R L2a )3、-C(=O)R L2a 、-C(=O)OR L2a 、-C(=O)-C(=O)R L2a 、-C(=O)CH2C(=O)R L2a 、-S(=O)R L2a 、-S(=O)2R L2a 、-C(=O)N(R L2a )2、-S(=O)2N(R L2a )2、-OC(=O)R L2a 、-N(R L2a )S(=O)2R L2b 、-N(R L2a )C(=O)R L2b 、-(CH2) y -C(=O)-(N(Me)CH2C(=O)) s -OR L2a 、-(CH2) y -C(=O)-(N(Me)CH2C(=O)) s -NHR L2a 、-(CH2) y -C(=O)-(N(Me)CH2C(=O)) s -N + (R L2a )3、-(CH2) y -NHC(=O)CH2(OCH2CH2)OR L2a 、-(CH2) y -NH(C(=O)CH2(N(Me)) s -R L2a 、-(CH2) y -C(=O)NH-(CH2CH2O) s -R L2a 、-(CH2) y -NHC(=O)-(CH2CH2O) s -R L2a 、-(CH2CH2O) s -R L2a 、-(C(=O)CH2N(Me)) s -R L2a 、 -C(=O)CH2(OCH2CH2) s -OR L2a 、 -C(=O)-(CH2CH2O) m -R L2a 、 -C(=O)-(CH2) y -C(=O)NH-(CH2CH2O) s -R L2a 、 -C(=O)-(CH2) y -NHC(=O)-(CH2CH2O) s -R L2a 、 -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, -(C3-C8) cycloalkyl, -(4-10 membered) heterocycloalkyl, -(C6-C 10 ) aryl and -(5-10 membered) heteroaryl, wherein the -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, -(C3-C8) cycloalkyl, -(4-10 membered) heterocycloalkyl, -(C6-C 10 ) aryl and -(5-10 membered) heteroaryl are optionally substituted by one or more R L2a substituted, s and y are each independently natural numbers from 0 to 50, R L2a and R L2b each independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OH, -SH, -NH2, -N(Me)2, -C(=O)OH, -S(=O)2Me, -S(=O)2OH, -C(=O)NH2, -S(=O)2NH2, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl; L 3 absent, or selected from an amino acid residue, a short peptide composed of 2 to 10 amino acid residues, -C(=O)-(C1-C6) alkylene-NH-, and any combination of the foregoing groups, wherein the amino acid residue is a natural amino acid residue or a non-natural amino acid residue, L 3 optionally modified by one or more protecting groups, preferably, the protecting group is selected from a polyethylene glycol fragment and -OtBu, wherein the polyethylene glycol fragment is linked to L through a structural unit -NH- 3 ; Tr does not exist, or is selected from and any combination of the foregoing groups, R Tr , R Tr1 and R Tr2 Each is independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH2, -SH, -OC(=O)NH2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -CH2C(=O)-(N(Me)CH2C(=O)) z -OR Tra , -CH2C(=O)-(N(Me)CH2C(=O)) z -NHR Tra 、-(CH2CH2O) z -R Tra 、-C(=O)NH-(CH2CH2O) z -R Tra , -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl, the -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl and -(5-10 membered)heteroaryl are optionally substituted with one or more R Tra replace; Each R Tra is independently hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH2, -SH, -N(Me)2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2Me, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C6-C 10 )aryl, and -(5-10 membered)heteroaryl, each z is independently a natural number from 0 to 50.

22. The ligand-drug conjugate according to any one of claims 1-21, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein, L 1 Selected from carbonyl, -(C1-C8)alkylene-C(=O)-, -(4-8 membered)heterocyclylene-, -(5-10 membered)heteroarylene-, and -(C1-C8)alkylene-(5-10 membered)heteroarylene-, wherein the -(C1-C8)alkylene-C(=O)-, -(4-8 membered)heterocyclylene-, -(5-10 membered)heteroarylene-, and -(C1-C8)alkylene-(5-10 membered)heteroarylene- are optionally substituted by 1, 2 or 3 oxo, -(C1-C4)alkylene-, and -(C1-C4)alkyl; Preferably, L 1 is selected from carbonyl, -(C1-C4)alkylene-C(=O)-, -(5-6-membered)heterocyclylene-, -(5-6-membered)heteroarylene-, and -(C1-C4)alkylene-(5-6-membered)heteroarylene-, and the -(C1-C4)alkylene-C(=O)-, -(5-6-membered)heterocyclylene-, -(5-6-membered)heteroarylene-, and -(C1-C4)alkylene-(5-6-membered)heteroarylene- are optionally substituted with 1, 2 or 3 oxo, -(C1-C4)alkylene-, and -(C1-C4)alkyl; Preferably, L 1 is selected from Preferably, L 1 is selected from Among them, the * end is connected to L 2 connected.

23. The ligand-drug conjugate according to any one of claims 1-22, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or its pharmaceutically acceptable salt or solvate, wherein, L 2 is -(C(R L21 )2) r -, r is a natural number from 0 to 10 (such as 1, 2, 3, 4, 5, 6, 7, 8 or 9), L 2 Any C(R L21 )2 unit in L22 can be independently replaced by the following structural units: -Cy-, -C(=O)-, -NR -, -O-, -S-, -S(=O)-, -Cy- is selected from -phenylene-, -4- to 6-membered heteroarylene- and -(C3-C6) cycloalkylene-, where said -Cy- is unsubstituted or is each independently substituted by 1, 2, 3, 4, 6 or 7 R Cx substituted Each R L21 、R L22 and R Cx are each independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OR L2a , -SR L2a , -N(R L2a )2, -C(=O)R L2a , -C(=O)OR L2a , -C(=O)-C(=O)R L2a , -C(=O)CH2C(=O)R L2a , -S(=O)R L2a , -S(=O)2R L2a , -C(=O)N(R L2a )2, -S(=O)2N(R L2a )2, -(CH2)2-C(=O)NH-(CH2CH2O) t -R L2a , -(C1-C6)alkyl and -(C2-C6)alkenyl, where the -(C1-C6)alkyl and -(C2-C6)alkenyl are optionally substituted with 1, 2, 3, 4, 5, 6 or 7 R L2a substituents, t is a natural number from 0 to 30, R L2a selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, -CN, -OH, -SH, -NH2, -N(Me)2, -C(=O)OH, -S(=O)2Me, -S(=O)2OH, -C(=O)2OH, -C(=O)NH2, -S(=O)2NH2, methyl, ethyl and vinyl; Preferably, L 2 is -(C(R L21 )2) r -, r is 2, 3, 4, 5, 6, 7, 8 or 9, L 2 Any C(R L21 )2 unit in it may be independently replaced by the following structural units: -Cy-, -C(=O)-, -NR L22 -, -O-, -S-, -S(=O)-, -Cy- is selected from cyclopropylidene, cyclobutylidene, cyclopentylidene, azetidinylidene, pyrrolidinylidene, piperazinylidene or piperidinylidene, wherein said -Cy- is unsubstituted or each independently substituted with 1, 2, 3, 4 or 5 R Cx , for example, -Cy- is Each R L21 、R L22 and R Cx are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, -CN, -OH, -SH, -NH2, -C(=O)OH, -C(=O)NH, -(CH2)2-C(=O)NH-(CH2CH2O) 11 -CH3, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, halogenated methyl, halogenated ethyl, methyl-OH, ethyl-OH, propyl-OH, vinyl-OH, vinyl, deuterated vinyl, halogenated vinyl; Preferably, L 2 is selected from Preferably, L 2 is selected from wherein the * end is connected to L3.

24. The ligand-drug conjugate or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-23, wherein, -L 1 -L 2 - Selected from: Preferably, -L 1 -L 2 - selected from: wherein the * end is connected to L3.

25. The ligand-drug conjugate or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-24, wherein L 3 selected from Val, D-Val, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, Arg, Ser, -Arg-Val-, -Arg-Leu-, -Val-Cit-, -Val-Ala-, -Val-Lys-, -Val-Lys(AC)-, -Phe-Lys-, -Phe-Lys(AC)-, -Leu-Lys-, -Leu-Lys(AC)-, -Ala-Ala-, -Ala-Lys-, -(D-Ala)-Ala-, -Gly-Glu-, -Gly-Asp-, -Gly-Asn-, -Val-Glu-, -Val-Asp-, -Asn-Asn-, -Asp-Asp-, -Asp-Glu-, -Ser-Val-, -Ser-Ala-, -Ser-Gly-, -Ser-Glu-, -Ser-Gln-, -Ser-Asp-, -Gly-Gln-, -Asn-Gly-, -Asn-Ala-, -Ala-Ala-Glu-, -Gly-Gly-Glu-, -Gly-Gly-Asp-, -Gly-Gly-Asn-, -Gly-Ala-Ala-, -Gly-Val-Ala-, -Gly-Val-Cit-, -Glu-Val-Cit-, -Ala-Ala-Ala-, -Ala-(D-Ala)-Ala-, -Ala-Ala-Asn-, -Ala-(D-Ala)-Asn-, -Ala-Ala-Asp-, -Val-Lys-Gly-, -(D-Val)-Leu-Lys-, -Gly-Gly-Arg-, -Gly-Gly-Gly-, -Lys-Ala-Asn-, -Gly-Phe-Gly-, -Gly-Gly-Phe-, -Asn-Pro-Val-, -Ala-Lys-Gly-, -Gly-Lys-Gly-, -Gly-Gly-Gly-Gly-, -Gly-Gly-Phe-Gly-, -Gly-Gly-Glu-Gly-, -Lys-Ala-Ala-Asn-, -Lys-Ala-Ala-Asp-, -Ala-Ala-Pro-Val-, -Ala-Ala-Pro-Nva- -C(=O)-(C1-C4)alkylene-NH- and any combination of the foregoing groups, wherein each of Asp and Glu is independently optionally substituted by -(CH2CH2O) t -R L3 modified, where (CH2CH2O) t -R L3 linked to Asp or Glu via the structural unit -NH-, R L3 is -(C1-C4)alkyl and t is an integer from 6 to 30 (for example 8, 9, 10, 11, 12, 13, 14, 15, 20, 21, 22, 23, 24, 25); Preferably, L 3 is selected from -Val-Cit-, -Arg-Val-, -Ala-Ala-, -Val-Ala-, -Gly-Glu-, -Ser-Val-, -Ser-Ala-, -Ser-Gly-, -Ser-Glu-, -Ser-Gln-, -Ser-Asp-, -Gly-Gln-, -Asn-Gly-, -Asn-Ala-, -Ala-Ala-Glu-, -Gly-Ala-Ala-, -Gly-Gly-Glu-, -Gly-Gly-Phe-Gly-, -Ala-Ala-Glu(NH-(CH2CH2O) t -R L3 )- and -C(=O)-CH2CH2-NH-, R L3 is a (C1-C4) alkyl, t is an integer from 6 to 30, for example -Ala-Ala-Glu(NH-(CH2CH2O) 11 -CH3)- or -Ala-Ala-Glu(NH-(CH2CH2O) 24 -CH3)-; Preferably, L 3 selected from -Val-Cit-*, *-Ala-Ala-, -Val-Ala-*, *-Gly-Glu-*, *-Ser-Val-*, *-Ser-Ala-*, *-Ser-Gly-*, *-Ser-Glu-*, *-Ser-Gln-*, *-Ser-Asp-*, -Gly-Gln-*, *-Gly-Gln-*, *-Asn-Gly-*, *-Asn-Ala-*, *-Gly-Ala-Ala-*, *-Gly-Gly-Glu-*, -Gly-Gly-Phe-Gly-*, *Ala-Ala-C(=O)-CH[CH2CH2-C(=O)-NH-(CH2CH2O) 11 -CH3]-NH- and wherein the * end is connected to Tr.

26. The ligand-drug conjugate or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-25, wherein, Tr does not exist or is selected from R Tr , R Tr1 and R Tr2 Each is independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH2, -SH, -OC(=O)NH2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -(CH2CH2O) z -R Tra 、-C(=O)NH-(CH2CH2O) z -R Tra , gluconolactone, glucuronic acid, -(C1-C4)alkyl and -(C2-C4)alkenyl, wherein the -(C1-C4)alkyl and -(C2-C4)alkenyl are optionally substituted by 1, 2, 3, 4 or 5 R Tra replace, Each R Tra is independently hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH2, -SH, -N(Me)2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2Me, -(C1-C4)alkyl, -(C2-C4)alkenyl, each z is independently an integer from 6 to 30; Preferably, R Tr , R Tr1 and R Tr2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, nitro, -CN, -OH, -NH2, -SH, -OC(=O)NH2, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -(CH2CH2O) z -R Tra , -C(=O)NH-(CH2CH2O) z -R Tra , gluconolactone, glucuronic acid, methyl, ethyl, -ethylene-OH and -CH2-COOH, Each R Tra is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, -CN, -OH, -NH2, -SH, -N(Me)2, -C(=O)OH, -C(=O)NH2, methyl, or ethyl, each z is independently an integer from 6 to 30 (for example, 8, 9, 10, 11, 12, 13, 14, 15, 20, 21, 22, 23, 24, 25); Preferably, R Tr is selected from hydrogen, -CH2-COOH, and Preferably, Tr is absent or selected from Preferably, Tr does not exist or is selected from Among them, the * end is connected to L 3 connected.

27. The ligand-drug conjugate or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-26, wherein, -L 3 -L 2 -L 1 - Selected from:

28. The ligand-drug conjugate according to any one of claims 1-27, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, the linking group is connected to the drug group to form a group selected from: The structures shown in Formula I-B-1, II-B-1', III-B-1', IV-B-1 or V-B-1 Among them, X, X 1 , X 2 , ring A, ring B, ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9a , R 9b , R 10 , R 12 , m, n, M, W, U, Z, Y, L, Q, T, Tr, L 1 , L 2 and L 3 are defined as described in any one of claims 1 - 27; Alternatively, the structure represented by Formula I-B-5, II-B-5, III-B-5, IV-B-5 or V-B-5, Among them, X, R 1 , ring A, R 3 , R 5 , R 6 , R 7 , R 8b , R 9a , R 9b , R 12 , n, M, W, U, Z, Y, L, Q, T, Tr, L 1 , L 2 and L 3 are defined as described in any one of claims 1-27; Alternatively, the structures represented by Formula I-B-6 and I-B-7 Among them, R 1 , R 31 , R 5 , R 6 , R 8b , R 9a , R 9b , M, Tr, L 1 , L 2 and L 3 are defined as described in any one of claims 1 - 27.

29. The ligand-drug conjugate according to any one of claims 1-28, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, the linking group is connected to the drug group to form a structure selected from those shown in Table B.

30. The ligand-drug conjugate according to any one of claims 1-29, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, The ligand-drug conjugate is selected from the compounds represented by Formula I-C, II-C', III-C', IV-C or V-C, wherein, X, X 1 , X 2 , ring A, ring B, ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9a , R 9b , R 10 , R 12 , m, n, M, W, U, Z, Y, L, Q, T, Tr, L 1 , L 2 and L 3 are defined as described in any one of claims 1 - 29; Ab is a ligand that binds to a target; k is the drug loading amount, which is an integer or a decimal from 1 to 16.

31. The ligand-drug conjugate according to any one of claims 1-30, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the Ab is coupled to L via an S atom 1 coupled Preferably, the Ab is a polypeptide, antibody or an antigen-binding fragment thereof that can specifically bind to a target, especially an antibody or an antigen-binding fragment thereof; Preferably, the antibody is selected from one or more of the following: (1) a fully human antibody, humanized antibody, murine antibody and chimeric antibody, (2) a probody, (3) a bispecific antibody and multispecific antibody, (4) a monoclonal antibody and polyclonal antibody, (5) an IgG antibody; Preferably, the antigen-binding fragment is selected from antigen-binding fragments of Fab, Fab’, F(ab’)2, Fv, scFv, Fd, dAb, VHH and complementarity-determining region (CDR) fragments; Preferably, the Ab is a monoclonal antibody, especially a monoclonal antibody with a thiol group as the conjugation site, or a site-directed mutant or modified monoclonal antibody with a thiol group as the conjugation site; Preferably, the Ab targets an antigen selected from the group consisting of: HER2, HER3, B7H3, B7H4, DLL3, TROP2, Claudin18.2, CD30, CD33, CD70, EGFR, GPC-3, ADAM9, BCMA, CEACAM5 and c-met; Preferably, the Ab is selected from antibodies against HER2, HER3, B7H3, TROP2, Claudin18.2, CD30, CD33, CD70, GPC-3, ADAM9, BCMA, CEACAM5 and c-met and antigen-binding fragments thereof; Preferably, the Ab is selected from Tusamitamab, DB1001, DB1002, DB1003, DB1004, DB1005, cetuximab, and panitumumab, as well as biosimilars of the antibody and antigen-binding fragments thereof; Preferably, the Ab is selected from Tusamitamab, DB1001, DB1002, DB1003, DB1004, and DB1005, as well as antigen-binding fragments of the antibody; Preferably, the Ab comprises the sequences of CDR1, CDR2, and CDR3 contained in the heavy chain as shown in SEQ ID NO:1, and / or the sequences of CDR1, CDR2, and CDR3 contained in the light chain as shown in SEQ ID NO:2; alternatively, the Ab comprises the sequences of CDR1, CDR2, and CDR3 contained in the heavy chain as shown in SEQ ID NO:3, and / or the sequences of CDR1, CDR2, and CDR3 contained in the light chain as shown in SEQ ID NO:4; alternatively, the Ab comprises the sequences of CDR1, CDR2, and CDR3 contained in the heavy chain as shown in SEQ ID NO:5, and / or the sequences of CDR1, CDR2, and CDR3 contained in the light chain as shown in SEQ ID NO:6; alternatively, the Ab comprises the sequences of CDR1, CDR2, and CDR3 contained in the heavy chain as shown in SEQ ID NO:25, and / or the sequences of CDR1, CDR2, and CDR3 contained in the light chain as shown in SEQ ID NO:26; alternatively, the Ab comprises the sequences of CDR1, CDR2, and CDR3 contained in the heavy chain as shown in SEQ ID NO:35, and / or the sequences of CDR1, CDR2, and CDR3 contained in the light chain as shown in SEQ ID NO:36; alternatively, the Ab comprises the sequences of CDR1, CDR2, and CDR3 contained in the heavy chain as shown in SEQ ID NO:15, and / or the sequences of CDR1, CDR2, and CDR3 contained in the light chain as shown in SEQ ID NO:16; Preferably, the Ab comprises a heavy chain variable region CDR1 as shown in SEQ ID NO:7, a heavy chain variable region CDR2 as shown in SEQ ID NO:8, a heavy chain variable region CDR3 as shown in SEQ ID NO:9, and / or a light chain variable region CDR1 as shown in SEQ ID NO:10, a light chain variable region CDR2 as shown in SEQ ID NO:11, a light chain variable region CDR3 as shown in SEQ ID NO:12; or a heavy chain variable region CDR1 as shown in SEQ ID NO:17, a heavy chain variable region CDR2 as shown in SEQ ID NO:18, a heavy chain variable region CDR3 as shown in SEQ ID NO:19, and / or a light chain variable region CDR1 as shown in SEQ ID NO:20, a light chain variable region CDR2 as shown in SEQ ID NO:21, a light chain variable region CDR3 as shown in SEQ ID NO:22; or a heavy chain variable region CDR1 as shown in SEQ ID NO:27, a heavy chain variable region CDR2 as shown in SEQ ID NO:28, a heavy chain variable region CDR3 as shown in SEQ ID NO:29, and / or a light chain variable region CDR1 as shown in SEQ ID NO:30, a light chain variable region CDR2 as shown in SEQ ID NO:31, a light chain variable region CDR3 as shown in SEQ ID NO:32; or a heavy chain variable region CDR1 as shown in SEQ ID NO:37, a heavy chain variable region CDR2 as shown in SEQ ID NO:38, a heavy chain variable region CDR3 as shown in SEQ ID NO:39, and / or a light chain variable region CDR1 as shown in SEQ ID NO:40, a light chain variable region CDR2 as shown in SEQ ID NO:41, a light chain variable region CDR3 as shown in SEQ ID NO:42; or a heavy chain variable region CDR1 as shown in SEQ ID NO:45, a heavy chain variable region CDR2 as shown in SEQ ID NO:46, a heavy chain variable region CDR3 as shown in SEQ ID NO:47, and / or a light chain variable region CDR1 as shown in SEQ ID NO:48, a light chain variable region CDR2 as shown in SEQ ID NO:49, a light chain variable region CDR3 as shown in SEQ ID NO:50; or a heavy chain variable region CDR1 as shown in SEQ ID NO:53, a heavy chain variable region CDR2 as shown in SEQ ID NO:54, a heavy chain variable region CDR3 as shown in SEQ ID NO:55, and / or a light chain variable region CDR1 as shown in SEQ ID NO:56, a light chain variable region CDR2 as shown in SEQ ID NO:57, a light chain variable region CDR3 as shown in SEQ ID NO:58; Preferably, the Ab comprises the sequence of the heavy chain variable region contained in the heavy chain as shown in SEQ ID NO:1, and / or the sequence of the light chain variable region contained in the light chain as shown in SEQ ID NO:2; or, the Ab comprises the sequence of the heavy chain variable region contained in the heavy chain as shown in SEQ ID NO:3, and / or the sequence of the light chain variable region contained in the light chain as shown in SEQ ID NO:4; or, the Ab comprises the sequence of the heavy chain variable region contained in the heavy chain as shown in SEQ ID NO:5, and / or the sequence of the light chain variable region contained in the light chain as shown in SEQ ID NO:6; or, the Ab comprises the sequence of the heavy chain variable region contained in the heavy chain as shown in SEQ ID NO:25, and / or the sequence of the light chain variable region contained in the light chain as shown in SEQ ID NO:26; or, the Ab comprises the sequence of the heavy chain variable region contained in the heavy chain as shown in SEQ ID NO:35, and / or the sequence of the light chain variable region contained in the light chain as shown in SEQ ID NO:36; or, the Ab comprises the sequence of the heavy chain variable region contained in the heavy chain as shown in SEQ ID NO:15, and / or the sequence of the light chain variable region contained in the light chain as shown in SEQ ID NO:16; Preferably, the Ab comprises the sequence of the heavy chain variable region as shown in SEQ ID NO:14 and / or the sequence of the light chain variable region as shown in SEQ ID NO:13; or, the Ab comprises the sequence of the heavy chain variable region as shown in SEQ ID NO:24 and / or the sequence of the light chain variable region as shown in SEQ ID NO:23; or, the Ab comprises the sequence of the heavy chain variable region as shown in SEQ ID NO:34 and / or the sequence of the light chain variable region as shown in SEQ ID NO:33; or, the Ab comprises the sequence of the heavy chain variable region as shown in SEQ ID NO:44 and / or the sequence of the light chain variable region as shown in SEQ ID NO:43; or, the Ab comprises the sequence of the heavy chain variable region as shown in SEQ ID NO:52 and / or the sequence of the light chain variable region as shown in SEQ ID NO:51; or, the Ab comprises the sequence of the heavy chain variable region as shown in SEQ ID NO:60 and / or the sequence of the light chain variable region as shown in SEQ ID NO:59; Preferably, the amino acid sequence of the heavy chain of the Ab is as shown in SEQ ID NO:1, and the amino acid sequence of the light chain of the Ab is as shown in SEQ ID NO:2; or the amino acid sequence of the heavy chain of the Ab is as shown in SEQ ID NO:3, and the amino acid sequence of the light chain of the Ab is as shown in SEQ ID NO:4; or the amino acid sequence of the heavy chain of the Ab is as shown in SEQ ID NO:5, and the amino acid sequence of the light chain of the Ab is as shown in SEQ ID NO:6; or the amino acid sequence of the heavy chain of the Ab is as shown in SEQ ID NO:25, and the amino acid sequence of the light chain of the Ab is as shown in SEQ ID NO:26; or the amino acid sequence of the heavy chain of the Ab is as shown in SEQ ID NO:35, and the amino acid sequence of the light chain of the Ab is as shown in SEQ ID NO:36; or the amino acid sequence of the heavy chain of the Ab is as shown in SEQ ID NO:15, and the amino acid sequence of the light chain of the Ab is as shown in SEQ ID NO:16; Preferably, the Ab is an anti-CEACAM5 antibody or an antigen-binding fragment thereof, such as Tusamitamab or an antigen-binding fragment or variant thereof; Preferably, the Ab comprises the heavy and light chains of an anti-CEACAM5 antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:1 or as shown in SEQ ID NO:1, and the amino acid sequence of the light chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:2 or as shown in SEQ ID NO:2; or, Preferably, the Ab is an anti-HER3 antibody or an antigen-binding fragment thereof, such as DB1001 or an antigen-binding fragment or variant thereof; Preferably, the Ab comprises the heavy and light chains of an anti-HER3 antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:3 or as shown in SEQ ID NO:3, and the amino acid sequence of the light chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:4 or as shown in SEQ ID NO:4; or, Preferably, the Ab is an anti-GPC-3 antibody or an antigen-binding fragment thereof, such as DB1002 or an antigen-binding fragment or variant thereof; Preferably, the Ab comprises a heavy chain and a light chain of an anti-GPC-3 antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:5 or as shown in SEQ ID NO:5, and the amino acid sequence of the light chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:6 or as shown in SEQ ID NO:6; or, Preferably, the Ab is an anti-ADAM9 antibody or an antigen-binding fragment thereof, such as DB1003 or an antigen-binding fragment or variant thereof; Preferably, the Ab comprises a heavy chain and a light chain of an anti-ADAM9 antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:25 or as shown in SEQ ID NO:25, and the amino acid sequence of the light chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:26 or as shown in SEQ ID NO:26; or, Preferably, the Ab is an anti-BCMA antibody or an antigen-binding fragment thereof, such as DB1004 or an antigen-binding fragment or variant thereof; Preferably, the Ab comprises a heavy chain and a light chain of an anti-BCMA antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:35 or as shown in SEQ ID NO:35, and the amino acid sequence of the light chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:36 or as shown in SEQ ID NO:36; or, Preferably, the Ab is an anti-c-met antibody or an antigen-binding fragment thereof, such as DB1005 or an antigen-binding fragment or variant thereof; Preferably, the Ab comprises a heavy chain and a light chain of an anti-c-met antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:15 or as shown in SEQ ID NO:15, and the amino acid sequence of the light chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:16 or as shown in SEQ ID NO:

16.

32. The ligand-drug conjugate according to any one of claims 1-31, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein k is an integer or a decimal selected from 1 to 10, preferably an integer or a decimal from 2 to 8, for example an integer or a decimal from 4 to 8 (such as about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8), for example an integer or a decimal from 6 to 8 (such as about 6.1, about 6.3, about 6.5, about 6.7, about 6.9, about 7.1, about 7.3, about 7.5, about 7.7, about 8), for example an integer or a decimal from 7 to 8 (such as about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8).

33. The ligand-drug conjugate according to any one of claims 1-32, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, The ligand-drug conjugate is selected from: A compound represented by Formula I-C-1, II-C-1', III-C-1', IV-C-1 or V-C-1; Among them, X, X 1 、X 2 、ring A, ring B, ring C, R 3 、R 4 、R 5 、R 6 、R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R 10 、R 12 、m, n, M, W, U, Z, Y, L, Q, T, Tr, L 1 、L 2 、L 3 、The definitions of Ab and k are as described in any one of claims 1-32; Alternatively, a compound represented by Formula I-C-5, II-C-5, III-C-5, IV-C-5 or V-C-5 Among them, X, R 1 , ring A, R 3 , R 5 , R 6 , R 7 , R 8b , R 9a , R 9b , R 12 , n, M, W, U, Z, Y, L, Q, T, Tr, L 1 , L 2 , L 3 , the definitions of Ab and k are as described in any one of claims 1 - 32; Alternatively, the compounds represented by Formula I-C-6 and I-C-7, wherein, R 1 , R 31 , R 5 , R 6 , R 8b , R 9a , R 9b , M, Tr, L 1 , L 2 , L 3 , Ab and k are defined as described in any one of claims 1-32.

34. The ligand-drug conjugate according to any one of claims 1-33, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, The ligand-drug conjugate is selected from the structures shown in Table C.

35. The ligand-drug conjugate according to any one of claims 1-34, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, The ligand-drug conjugate is selected from the structures shown in Table E.

36. A mixture of ligand-drug conjugates, comprising the ligand-drug conjugate according to any one of claims 1-35, its tautomer, its enantiomer, its diastereomer, its pharmaceutically acceptable salt or its solvate or consisting thereof, wherein, The ligand-drug conjugate has one, two or more k values.

37. A compound or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the structures represented by Formula I-D, II-D’, III-D’, IV-D or V-D Wherein, X, X 1 , X 2 , ring A, ring B, ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9a , R 9b , R 10 , R 12 , m, n, M, W, U, Z, Y, L, Q, T, Tr, L 2 and L 3 are defined as described in any one of claims 1 - 28; L 1a is a connecting unit.

38. The compound according to claim 37, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, L 1a selected from -C(=O)-(C1-C8)alkyl, -C(=O)O-(4-8-membered)heterocyclic group, -C(=O)O-(C6-C 10 )aryl, (4-8-membered)heterocyclic group and (5-10-membered)heteroaryl, wherein the -C(=O)-(C1-C8)alkyl, -C(=O)O-(4-8-membered)heterocyclic group, -C(=O)O-(C6-C 10 )aryl, (4-8-membered)heterocyclic group, (5-10-membered)heteroaryl are optionally substituted by 1, 2, 3, 4 or 5 oxo, halogen, =CH2, -(C2-C4)alkenyl, -S-CH2-phenyl, -S(=O)2-(C1-C4)alkyl, -O-S(=O)2-phenyl-(C1-C4)alkyl and -(C1-C4)alkyl; L 1a Selected from -C(=O)-(C1-C4)alkyl, -C(=O)O-(5-6 membered)heterocyclic group, -C(=O)O-phenyl, (5-6 membered)heterocyclic group and (5-6 membered)heteroaryl, wherein the -C(=O)-(C1-C4)alkyl, -C(=O)O-(5-6 membered)heterocyclic group, -C(=O)O-phenyl, (5-6 membered)heterocyclic group and (5-6 membered)heteroaryl are optionally substituted by 1, 2, 3, 4 or 5 oxo, fluorine, bromine, =CH2, vinyl, -S-CH2-phenyl, -S(=O)2CH3, -O-S(=O)2-phenyl-CH3 and methyl; Preferably, L 1a is selected from Preferably, L 1a is selected from 39. The compound according to claim 37 or 38, or a racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein, The compound is selected from the structures shown in Table D.

40. Use of the compound according to any one of claims 37-39, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of the ligand-drug conjugate according to any one of claims 1-36.

41. A pharmaceutical composition comprising at least one ligand-drug conjugate according to any one of claims 1-35, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or a mixture of at least one ligand-drug conjugate according to claim 36, or at least one compound according to any one of claims 37-39, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutical carriers and / or excipients.

42. Use of the ligand-drug conjugate according to any one of claims 1-35, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or a mixture of the ligand-drug conjugate according to claim 36, or the compound according to any one of claims 37-39, or its racemate, tautomer, stereoisomer, enantiomer, diastereoisomer, or a mixture thereof, or the pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 41, in the preparation of a drug for treating and / or preventing a disease or disorder or alleviating the severity of the disease or disorder, wherein the disease or disorder is a tumor or cancer; Preferably, the tumor or cancer is selected from leukemia, malignant lymphoma, multiple myeloma, gastric cancer, colorectal cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, liver cancer and lung cancer.