Cyclopeptide compounds and compositions as EGFR inhibitors

Abstract

The present disclosure provides cyclic peptide compounds of Formula (I) and Formula (II) as EGFR inhibitors, and compositions thereof and uses in treating EGFR-related diseases. (I) (II)

Description

Technical Field

[0001] This disclosure pertains to the field of medicinal chemistry, and more specifically, it provides cyclic peptide compounds as EGFR inhibitors, peptide drug conjugates thereof, compositions thereof, and their use in the treatment of EGFR-related diseases. Background Technology

[0002] EGFR (HER1 or ERBB1) is a member of the epidermal growth factor receptor (HER) family, which belongs to the receptor tyrosine kinase family and also includes HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). Structurally, it comprises an extracellular domain, a transmembrane domain, and an intracellular portion containing a tyrosine kinase domain and a C-terminal tail. Upon binding to its ligand, the receptor dimers, thereby activating the intracellular tyrosine kinase domain and leading to phosphorylation of the C-terminal tail. This subsequently activates the PI3K-Akt-mTOR and RAS-RAF-MEK-ERK pathways, resulting in cell proliferation, inhibition of apoptosis, and the development of the tumor microenvironment.

[0003] EGFR gene amplification, mutation, and overexpression have been observed in various cancer types, highlighting the crucial role of EGFR in cancer cell survival. EGFR mutations occur in the tyrosine kinase domain and are primarily found in NSCLC, but overexpression of wild-type EGFR has been reported in many other tumor types. Small molecule inhibitors targeting the intracellular tyrosine kinase domain and antibody therapies binding to the extracellular domain have been developed. However, due to resistance mechanisms and limited efficacy, novel anti-EGFR therapies are urgently needed.

[0004] Invention Summary

[0005] This disclosure provides cyclic peptide compounds as EGFR inhibitors and their peptide drug conjugates, as well as compositions and their use in the treatment of EGFR-related diseases.

[0006] In one aspect, this disclosure provides compounds of formula (I): (I) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: R is -C(O)C 1-6 Alkyl or -C(O)C 1-6 Halogenated alkyl groups, such as Ac; R 1a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 1-1 and R 1-2 Independently selected from H and C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl groups; Or R 1-1 and R 1-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 1-1 and R 1a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; n = 0 or 1; R 2a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 2x and R 2y Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl groups; Or R 2x and R 2y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 3a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 3-1 and R 3-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN or OR. a ; Or R 3-1 and R 3-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 3-1 and R 3a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; X3 is selected from O or S; R 4a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 4-1 and R 4-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 4-1 and R 4-2 Together with the atoms they are attached to, they form C3-8 cycloalkyl; or R 4-1 and R 4a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 5a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 5-1 and R 5-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 5-1 and R 5-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4- to 8-membered heterocyclic groups; or R 5-1 and R 5a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 6a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 6-1 and R 6-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 6-1 and R 6-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 6-1 and R 6a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 7a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 7-1 and R 7-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl groups; Or R 7-1 and R 7a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R8 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 9x and R 9y Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl groups; Or R 9x and R 9y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 10 Selected from H, C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, OR a NO2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)₂OH, NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 11-1 and R 11a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 12 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl or C 6-10 aryl; which is optionally substituted with 1, 2, 3 or more halogens, OR a SR a NMe3 + NHAc, NHR a ,NHC(O)CH2NR b R c , NHC(O)NH2, NHC(=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13-1 and R 13-2 Independently selected from H and C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl groups; Or R 13-1 and R 13-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 13-1 and R 13a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 14a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 14-1 and R 14-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b Rc C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 cycloalkyl, 4- to 8-membered heterocyclic groups, biphenyl, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl group or 5 to 10 heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN, OH, NO2, -C 0-6 Alkylene-C(O)OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 6-10 Aryl; Or R 14-1 and R 14-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 15 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R16x and R 16y Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl groups; Or R 16x and R 16y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; Y is selected from OH, NH2, or the following amino acids: Gly, Ala, Aib, Glu, Pro, D-Ala, Ahx (aminocaproic acid), Asp, D-Glu, D-Pro and D-Asp; preferably, OH, or the following amino acids: Gly, Ala, D-Ala and D-Pro; Each X is independently selected from C(O), S(O), or S(O)2; Where R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0007] On the other hand, this disclosure provides compounds of formula (I): (I) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: R is -C(O)C 1-6 Alkyl or -C(O)C 1-6 Halogenated alkyl groups, such as Ac; R 1a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 1-1 and R 1-2 Independently selected from H and C 1-6 Alkyl or C 1-6Halogenated alkyl groups; Or R 1-1 and R 1-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 1-1 and R 1a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; n = 0 or 1; R 2a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 2x and R 2y Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 2x and R 2y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 3a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 3-1 and R 3-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN or OH; Or R 3-1 and R 3-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 3-1 and R 3a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; X3 is selected from O or S; R 4a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 4-1 and R 4-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 4-1 and R 4-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 4-1 and R 4a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 5a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 5-1 and R 5-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 5-1 and R 5-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4- to 8-membered heterocyclic groups; or R 5-1 and R 5a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 6a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 6-1 and R 6-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 6-1 and R 6-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 6-1 and R 6a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 7a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 7-1 and R 7-2 Independently selected from H and C 1-6 Alkyl or C 1-6Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; Or R 7-1 and R 7a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R8 is selected from H and C. 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 9x and R 9y Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 9x and R 9y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 10 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, OR a NO2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)₂OH, NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 11-1 and R 11a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 12 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 6-10 aryl; which is optionally substituted with 1, 2, 3 or more halogens, OR a SR a NMe3 + NHAc, NHRa , NHC(O)NH2, NHC(=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13-1 and R 13-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; Or R 13-1 and R 13-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 13-1 and R 13a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 14a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 14-1 and R 14-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, biphenyl, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl group or 5 to 10 heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN, OH, NO2, -C 0-6 Alkylene-C(O)OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 6-10 Aryl; Or R 14-1 and R 14-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 15 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R16x and R 16y Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 16x and R 16y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; Y is selected from OH, NH2, or the following amino acids: Gly, Ala, Glu, D-Ala, Ahx (aminocaproic acid), Asp, D-Glu, and D-Asp; Each X is independently selected from C(O), S(O), or S(O)2; Where R a R b and R c Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R b and R c Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0008] On the other hand, this disclosure provides compounds of formula (II): (II) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key, , (-(Sar) p -) (-(Ser) q -) (-(Sar-Ser) w -) (-(Ser-Sar) w -) or -C(O)-4 to 11-membered heterocyclic group- (wherein the heterocyclic group is connected to L2); L2 is selected from the bond, -(CH2CH2O). m1 CH2C(O)- (where C(O)- is attached to L3) or -C(O)CH2(OCH2CH2) m1 NH- (where NH- is connected to L3); L3 is selected from the bond, -NH(CH2CH2O). m2 CH2C(O)- (where C(O)- is attached to L4), -C(O)CH2(OCH2CH2)m2 NH- (where NH- is attached to L4) or -Glu-C(O)CH2(OCH2CH2) m2 NH-, where Glu is ; L4 is selected from the key, (-Lys(L5)-L5-) or ; L5 is selected from key, , -C(O)CH2(OCH2CH2) m3 NH- (where NH- is attached to L6 or L) or -C(O)(CH2) m3 NH- (where NH- is connected to L6 or L); L6 is selected from the bond, -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-), where each S- is linked to a cleavable linker; L stands for -C(O)(CH2). m4 C(O)OH; Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; w = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m4 = 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24; The cleavable linker is selected from the following: , , , , , , , , , , , , , , , , , , , , ,and ; Among them, each of the above groups is connected to L6 on the left and to the payload on the right; p1 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p2 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p3 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors; Other variables are defined in the specification.

[0009] On the other hand, this disclosure provides compounds of formula (II): (II) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key, (-(Sar) p -) (-(Ser) q -) (-(Sar-Ser) w -) or -C(O)-4 to 11-membered heterocyclic groups-; L2 is selected from the bond or -C(O)CH2(OCH2CH2). m1 NH-; L3 is selected from the bond, -C(O)CH2(OCH2CH2). m2 NH- or -Glu-C(O)CH2(OCH2CH2)m2 NH-, where Glu is ; L4 is selected from key or (-Lys(L6)-L5-); L5 is selected from the bond or -C(O)(CH2). m3 NH-; L6 is selected from -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-); Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; w = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and each -S- in L6 is connected to a splittable connection base - payload; The cleavable linker is selected from the following: , , , , , , , , , , , , , , , , ,and ; Among them, each of the above groups is connected to L6 on the left and to the payload on the right; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors; Other variables are defined in the specification.

[0010] On the other hand, this disclosure provides pharmaceutical compositions comprising the compounds disclosed herein, or stereoisomers, tautomers, stable isotope variants or prodrugs thereof, or pharmaceutically acceptable salts thereof; pharmaceutically acceptable excipients; and optionally, one or more other therapeutic agents.

[0011] On the other hand, this disclosure provides a kit comprising: a first container containing the compound disclosed herein, or a stereoisomer, tautomer, stable isotope variant, or prodrug thereof, or a pharmaceutically acceptable salt thereof; and optionally, a second container containing one or more other therapeutic agents; and optionally, a third container containing a pharmaceutically acceptable excipient for diluting or suspending said compound and / or other therapeutic agents.

[0012] On the other hand, this disclosure provides the use of the compounds disclosed herein, or stereoisomers, tautomers, stable isotope variants or prodrugs thereof, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the treatment of EGFR-mediated diseases.

[0013] On the other hand, this disclosure provides the compounds disclosed herein, or stereoisomers, tautomers, stable isotope variants or prodrugs thereof, or pharmaceutically acceptable salts thereof, for the treatment of EGFR-mediated diseases.

[0014] On the other hand, this disclosure provides methods for treating EGFR-mediated diseases in subjects of need, including administering to the subject a compound disclosed herein, or a stereoisomer, tautomer, stable isotope variant, or prodrug, or a pharmaceutically acceptable salt thereof.

[0015] definition

[0016] Chemical definition

[0017] The definitions of specific functional groups and chemical terms are described in more detail below.

[0018] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0019] It should be understood that any of the following portions described herein may be substituted with various substituents, and the definitions are intended to include such substituted portions within the scope described below. Unless otherwise stated, the term "substitution" shall be defined as follows.

[0020] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl groups are preferred. C 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0021] -C 1-6 "alkylene-" refers to "C" as defined above. 1-6 Alkyl groups are divalent groups. 0-6 "alkylene-" refers to the bond and the "C" defined above. 1-6 Alkyl groups are divalent groups.

[0022] “C 1-6 "Alkylene" refers to the removal of C 1-6 The alkyl group is a divalent group formed by the other hydrogen atom of the alkyl group, and can be a substituted or unsubstituted alkylene group. In some embodiments, C 1-4Alkylenes are particularly preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0023] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0024] “C 1-6 "Halogenated alkyl" indicates the above "C" 1-6 An alkyl group is substituted with one or more halogen groups. Examples include monohalogen-substituted, dihalogen-substituted, and polyhalogenated alkyl groups, including fully halogenated ones. A monohalogen substituent may have one iodine, bromine, chlorine, or fluorine atom in the group; two-halogen substituents and multiple-halogen substituents may have two or more identical halogen atoms or combinations of different halogens. Preferred examples of alkyl halogens include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. The alkyl halogen group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0025] “C 3-8 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 4-6 cycloalkyl, more preferably C 5-6Cycloalkyl groups. Cycloalkyl groups also include ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the bonding point is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), and so on.

[0026] "3-11 membered heterocyclic groups" refer to groups having a cyclic carbon atom and 1 to 5 cyclic heteroatoms, comprising a 3 to 11 membered non-aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the linking point may be a carbon or nitrogen atom, provided the valence allows. In some embodiments, 4-8 membered heterocyclic groups are preferred, which are 4 to 8 membered non-aromatic ring systems having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, 4-7 membered heterocyclic groups are preferred, which are 4 to 7 membered non-aromatic ring systems having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; 3-6 membered heterocyclic groups are preferred, which are 3 to 6 membered non-aromatic ring systems having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; 4-7 membered heterocyclic groups are preferred, which are 4 to 7 membered non-aromatic ring systems having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Preferably, the heterocyclic group is a 4-6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; more preferably, it is a 5-6 membered heterocyclic group having a ring carbon atom and 1 to 3 ring heteroatoms. The heterocyclic group also includes a ring system in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the cycloalkyl ring, or a ring system in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridine propane, oxadicyclopropane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridine butane, oxadicyclobutane, and thiorenyl butane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, disulfuranyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptyl, and thioheptyl.Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0027] 3-11 membered heterocyclic groups also include spiroheterocyclic groups, i.e., groups in which two rings (e.g., heterocycles and carboalkyl groups) share a carbon atom, wherein at least one ring is a heterocyclic group as defined above. More specifically, the spiroheterocyclic group is a spirocycle formed by two 4-membered rings, two 5-membered rings, two 6-membered rings, one 4-membered ring and one 5-membered ring, one 4-membered ring and one 6-membered ring, or one 5-membered ring and one 6-membered ring, wherein at least one ring is a 4-6 membered heterocyclic group as defined above, preferably a 4-6 membered heterocyclic group containing one, two, or three O, N, or S heteroatoms, more preferably a 4-6 membered heterocyclic group containing one N heteroatom. Specific spiroheterocyclic groups include, but are not limited to: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0028] “C 6-10"Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system.

[0029] "5-10-membered heteroaryl" refers to a group comprising a 4n+2 aromatic ring system of a 5-10-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms (e.g., having 6 or 10 shared π electrons arranged in a ring), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6-membered heteroaryl is particularly preferred, which is a 4n+2 aromatic ring system of a 5-6-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azirheptatrienyl, oxaheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0030] “C 1-6 "alkoxy" and "C" 1-6 "Haloalkoxy" refers to -OC 1-6 Alkyl and -OC 1-6 Haloalkyl, wherein C 1-6 Alkyl and C 1-6 The definition of alkyl halogroups is as described above.

[0031] Alkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups, as defined herein, are optionally substituted groups. Generally, the term “substituted,” whether or not preceded by the term “optional,” means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, such as a substituent that, upon substitution, yields a stable compound, for example, a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, a “substituted” group has substituents at one or more substituted positions of the group, and when more than one position is substituted in any given structure, the substituents at each position are the same or different. The term “substituted” includes substitution with all permissible substituents of an organic compound (any substituent described herein that results in the formation of a stable compound). For the purposes of this disclosure, a heteroatom, such as nitrogen, may have hydrogen substituents and / or any suitable substituents described herein that satisfy the heteroatom's valence and result in the formation of a stable moiety.

[0032] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa -OC(=NR) bb )R aa -OC(=NR) bb ORaa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2、-BRaa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace; R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NRff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S; R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution; R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution; R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl group), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3、-C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 carbocyclic, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0033] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0034] Other definitions

[0035] The term "natural amino acid" refers to the basic structural units that make up proteins and are fundamental to subsequent protein modifications in organisms. There are a total of 20 natural amino acids. In addition, organisms synthesize derived amino acids such as hydroxyproline and hydroxylysine based on these basic amino acids. These biosynthesized amino acids are collectively called "natural amino acids." Natural amino acids are generally L-type. The 20 most common natural amino acids are shown in the table below:

[0036] The term "amino acid" includes both "natural amino acids" as described above and non-natural amino acids, such as D-type amino acids and Aib (2-aminoisobutyric acid).

[0037] As used herein, the term “treatment” refers to reversing, alleviating, inhibiting, or preventing the progression of an obstacle or condition to which the term applies, or one or more symptoms of such an obstacle or condition. The noun “treatment” as used herein also refers to the action of the verb “to treat,” as defined above.

[0038] As used herein, the term “pharmaceutically acceptable” means substances that, within the bounds of reliable medical judgment, are suitable for contact with patient tissues without producing undue toxicity, irritation, allergic reactions, etc., are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds disclosed herein.

[0039] The term "salt" refers to a relatively non-toxic inorganic-organic acid addition salt of the compounds disclosed herein. These salts can be prepared in situ during the final separation and purification of the compounds, or by reacting the purified compounds in their free basic form with a suitable organic or inorganic acid, followed by separation of the resulting salt.

[0040] Pharmaceutically acceptable base addition salts are those formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0041] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethanesulfonate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. It also covers amino acid salts, such as arginine salts, gluconates, galacturons, etc. (see, for example, Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0042] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0043] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0044] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0045] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds disclosed herein can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0046] Unless otherwise stated, the term "therapeuticly effective amount" of a compound as used herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0047] Unless otherwise stated, the “preventively effective amount” of a compound as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term “preventively effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0048] The term "payload" refers to a cytotoxic drug that kills cells. An ideal payload should possess sufficient toxicity, low immunogenicity, high stability, and modifiable functional groups. Common payloads include tubulin inhibitors and DNA damaging agents, with tubulin inhibitors accounting for more than half of ADC drugs in clinical development.

[0049] In one aspect, the compounds disclosed herein can be conjugated with payloads to form peptide-drug conjugates (PDCs) for the treatment of diseases such as cancer. The payload may include agents that affect microtubule function, including maytansine compounds such as DM1 and DM4; and auristatin compounds such as MMAE and MMAF. The payload may include topoisomerase 1 inhibitors composed of camptothecin-based and non-camptothecin-based compounds, such as eczema, delutec, and their derivatives; SN38, belotecone derivatives; and other topoisomerase 1 inhibitors. The payload may include topoisomerase 2 inhibitors, such as doxorubicin. The payload may include DNA alkylating agents, such as calichimycin; pyrrolobenzodiazepines (PBDs); indolinobenzodiazepines (IGNs) or cyclopropylbenzoindolones (CBIs). The payload may include transcription inhibitors; Bcl-xL inhibitors; and tyrosine kinase inhibitors.

[0050] The term "combination" and related terms refer to the simultaneous or sequential administration of the compound of this disclosure and other therapeutic agents. For example, the compound of this disclosure may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form.

[0051] The compounds disclosed herein may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds disclosed herein may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0052] It should be understood that, unless otherwise stated, compounds with asymmetric centers include all optical isomers and mixtures thereof. Furthermore, unless otherwise specified, all isomers included in this disclosure may have carbon-carbon double bonds in the forms of Z and E. Regarding compounds existing in different tautomeric forms, a said compound is not limited to any particular tautomer, but is intended to cover all tautomeric forms.

[0053] This disclosure also includes isotopically labeled compounds (isotopic variants, such as stable isotopic variants) that are equivalent to those described in formula (I), but with one or more atoms replaced by atoms of different atomic masses or mass numbers than those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds of this disclosure containing the aforementioned isotopes and / or other isotopes, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of this disclosure, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of this disclosure and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes and / or examples disclosed below.

[0054] Furthermore, prodrugs are also included in the context of this disclosure. As used herein, the term "prodrug" refers to a compound which is converted in vivo, for example, by hydrolysis in the blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series, Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs," Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference. Invention Details

[0056] This disclosure discloses compounds of formula (I): (I) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: R is -C(O)C 1-6 Alkyl or -C(O)C 1-6 Halogenated alkyl groups, such as Ac; R 1a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 1-1 and R 1-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl groups; Or R 1-1 and R 1-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 1-1 and R 1aTogether with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; n = 0 or 1; R 2a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 2x and R 2y Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl groups; Or R 2x and R 2y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 3a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 3-1 and R 3-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN or OR. a ; Or R3-1 and R 3-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 3-1 and R 3a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; X3 is selected from O or S; R 4a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 4-1 and R 4-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 4-1 and R 4-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 4-1 and R 4a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 5a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 5-1 and R 5-2 Independently selected from H and C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 5-1 and R 5-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4- to 8-membered heterocyclic groups; or R 5-1 and R 5a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 6a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 6-1 and R 6-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 6-1 and R 6-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 6-1 and R 6a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 7a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 7-1 and R 7-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; Or R 7-1 and R 7a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R8 is selected from H and C. 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 9x and R 9y Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl groups; Or R 9x and R 9y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 10 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR bR c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, OR a NO2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)₂OH, NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 11-1 and R 11aTogether with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 12 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl or C 6-10 aryl; which is optionally substituted with 1, 2, 3 or more halogens, OR a SR a NMe3 + NHAc, NHR a ,NHC(O)CH2NR b R c , NHC(O)NH2, NHC(=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13-1 and R 13-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; Or R 13-1 and R 13-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 13-1 and R 13a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 14a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 14-1 and R 14-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, biphenyl, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl group or 5 to 10 heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN, OH, NO2, -C 0-6 Alkylene-C(O)OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 6-10 Aryl; Or R 14-1 and R 14-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 15 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 16x and R 16y Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl groups; Or R 16x and R 16yTogether with the atoms they are attached to, they form C 3-8 cycloalkyl; Y is selected from OH, NH2, or the following amino acids: Gly, Ala, Aib, Glu, Pro, D-Ala, Ahx (aminocaproic acid), Asp, D-Glu, D-Pro and D-Asp; preferably, OH, or the following amino acids: Gly, Ala, D-Ala and D-Pro; Each X is independently selected from C(O), S(O), or S(O)2; Where R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0057] Furthermore, this disclosure discloses compounds of formula (I): (I) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: R is -C(O)C 1-6 Alkyl or -C(O)C 1-6 Halogenated alkyl groups, such as Ac; R 1a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 1-1 and R 1-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 1-1 and R 1-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 1-1 and R 1a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; n = 0 or 1; R 2a Selected from H, C1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 2x and R 2y Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 2x and R 2y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 3a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 3-1 and R 3-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN or OH; Or R 3-1 and R 3-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 3-1 and R 3a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; X3 is selected from O or S; R 4a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 4-1 and R 4-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OH, SRa NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 4-1 and R 4-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 4-1 and R 4a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 5a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 5-1 and R 5-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 5-1 and R 5-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4- to 8-membered heterocyclic groups; or R 5-1 and R 5aTogether with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 6a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 6-1 and R 6-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 6-1 and R 6-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 6-1 and R 6a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 7a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 7-1 and R 7-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C6-10 Aryl or 5 to 10-membered heteroaryl; Or R 7-1 and R 7a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R8 is selected from H and C. 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 9x and R 9y Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 9x and R 9y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 10 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, OR a NO2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)₂OH, NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 11-1 and R 11a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 12 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 6-10 aryl; which is optionally substituted with 1, 2, 3 or more halogens, OR a SR a NMe3 + NHAc, NHR a , NHC(O)NH2, NHC(=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13-1 and R 13-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; Or R 13-1 and R 13-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 13-1 and R 13a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 14a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 14-1 and R 14-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NRb R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, biphenyl, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl group or 5 to 10 heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN, OH, NO2, -C 0-6 Alkylene-C(O)OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 6-10 Aryl; Or R 14-1 and R 14-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 15 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 16x and R 16y Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 16x and R 16y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; Y is selected from OH, NH2, or the following amino acids: Gly, Ala, Glu, D-Ala, Ahx (aminocaproic acid), Asp, D-Glu, and D-Asp; Each X is independently selected from C(O), S(O), or S(O)2; Where R a R b and R c Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R b and R c Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0058] In addition, this disclosure also discloses compounds of formula (II): (II) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key, , (-(Sar) p -) (-(Ser) q -) (-(Sar-Ser) w -) (-(Ser-Sar) w -) or -C(O)-4 to 11-membered heterocyclic group- (wherein the heterocyclic group is connected to L2); L2 is selected from the bond, -(CH2CH2O). m1 CH2C(O)- (where C(O)- is attached to L3) or -C(O)CH2(OCH2CH2) m1 NH- (where NH- is connected to L3); L3 is selected from the bond, -NH(CH2CH2O). m2 CH2C(O)- (where C(O)- is attached to L4), -C(O)CH2(OCH2CH2) m2 NH- (where NH- is attached to L4) or -Glu-C(O)CH2(OCH2CH2) m2 NH-, where Glu is ; L4 is selected from the key, (-Lys(L5)-L5-) or ; L5 is selected from key, , -C(O)CH2(OCH2CH2) m3 NH- (where NH- is attached to L6 or L) or -C(O)(CH2) m3 NH- (where NH- is connected to L6 or L); L6 is selected from the bond, -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-), where each S- is linked to a cleavable linker; L stands for -C(O)(CH2). m4 C(O)OH; Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; w = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m4 = 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24; The cleavable linker is selected from the following: , , , , , , , , , , , , , , , , , , , , ,and ; Among them, each of the above groups is connected to L6 on the left and to the payload on the right; p1 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p2 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p3 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors; Other variables are defined in the specification.

[0059] In addition, this disclosure also discloses compounds of formula (II): (II) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key, (-(Sar) p -) (-(Ser) q -) (-(Sar-Ser) w -) or -C(O)-4 to 11-membered heterocyclic groups-; L2 is selected from the bond or -C(O)CH2(OCH2CH2). m1 NH-; L3 is selected from the bond, -C(O)CH2(OCH2CH2). m2 NH- or -Glu-C(O)CH2(OCH2CH2) m2 NH-, where Glu is ; L4 is selected from key or (-Lys(L6)-L5-); L5 is selected from the bond or -C(O)(CH2). m3 NH-; L6 is selected from -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-); Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; w = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and each -S- in L6 is connected to a splittable connection base - payload; The cleavable linker is selected from the following: , , , , , , , , , , , , , , , , ,and ; Among them, each of the above groups is connected to L6 on the left and to the payload on the right; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors; Other variables are defined in the specification. Detailed Implementation

[0060] R

[0061] In some implementations, R is -C(O)C 1-6 Alkyl; in some embodiments, R is -C(O)C 1-6 Halogenated alkyl; in some embodiments, R is Ac.

[0062] R 1a

[0063] In some implementation schemes, R 1a For H; in some implementations, R 1a C 1-6 Alkyl; in some embodiments, R 1a C 1-6 Halogenated alkyl; in some embodiments, R 1a C 2-6 alkenyl; in some embodiments, R 1a C 2-6 Halogenated alkenyl; in some embodiments, R 1a C 2-6 alkynyl group; in some implementations, R 1a C 2-6 Halogenated alkynyl group.

[0064] R 1-1 and R 1-2

[0065] In some implementation schemes, R 1-1 For H; in some implementations, R 1-1 C 1-6 Alkyl; in some embodiments, R 1-1 C 1-6 Halogenated alkyl groups.

[0066] In some implementation schemes, R 1-2 For H; in some implementations, R 1-2 C 1-6 Alkyl; in some embodiments, R 1-2 C 1-6 Halogenated alkyl groups.

[0067] In some implementation schemes, R 1-1 and R 1-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; in some embodiments, R 1-1 and R 1a Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0068] n

[0069] In some implementations, n = 0; in other implementations, n = 1.

[0070] R 2a

[0071] In some implementation schemes, R 2a For H; in some implementations, R 2a C 1-6 Alkyl; in some embodiments, R 2a C 1-6 Halogenated alkyl groups.

[0072] R 2x and R 2y

[0073] In some implementation schemes, R 2x For H; in some implementations, R 2x C 1-6 Alkyl; in some embodiments, R 2x C 1-6 Halogenated alkyl; in some embodiments, R 2x C 2-6 alkenyl; in some embodiments, R 2x C 2-6 Halogenated alkenyl; in some embodiments, R 2x C 2-6 alkynyl group; in some implementations, R 2x C 2-6 Halogenated alkynyl group.

[0074] In some implementation schemes, R 2y For H; in some implementations, R 2y C 1-6 Alkyl; in some embodiments, R 2y C 1-6 Halogenated alkyl; in some embodiments, R 2y C 2-6 alkenyl; in some embodiments, R 2y C 2-6 Halogenated alkenyl; in some embodiments, R 2y C 2-6 alkynyl group; in some implementations, R 2y C 2-6 Halogenated alkynyl group.

[0075] In some implementation schemes, R 2x and R 2y Together with the atoms they are attached to, they form C 3-8 Cycloalkyl.

[0076] R 3a

[0077] In some implementation schemes, R3a For H; in some implementations, R 3a C 1-6 Alkyl; in some embodiments, R 3a C 1-6 Halogenated alkyl groups.

[0078] R 3-1 and R 3-2

[0079] In some implementation schemes, R 3-1 For H; in some implementations, R 3-1 C 1-6 Alkyl; in some embodiments, R 3-1 C 1-6 Halogenated alkyl; in some embodiments, R 3-1 C 2-6 alkenyl; in some embodiments, R 3-1 C 2-6 Halogenated alkenyl; in some embodiments, R 3-1 C 2-6 alkynyl group; in some implementations, R 3-1 C 2-6 Halogenated alkynyl group; in some embodiments, R 3-1 C 3-8 cycloalkyl; in some embodiments, R 3-1 It is a 4- to 8-membered heterocyclic group; in some implementations, R 3-1 C 6-10 Aryl; in some implementations, R 3-1 It consists of 5 to 6 heteroaryl groups.

[0080] In some implementation schemes, R 3-2 For H; in some implementations, R 3-2 C 1-6 Alkyl; in some embodiments, R 3-2 C 1-6 Halogenated alkyl; in some embodiments, R 3-2 C 2-6 alkenyl; in some embodiments, R 3-2 C 2-6 Halogenated alkenyl; in some embodiments, R 3-2 C 2-6 alkynyl group; in some implementations, R 3-2 C 2-6 Halogenated alkynyl group; in some embodiments, R 3-2 C 3-8 cycloalkyl; in some embodiments, R 3-2 It is a 4- to 8-membered heterocyclic group; in some implementations, R3-2 C 6-10 Aryl; in some implementations, R 3-2 It consists of 5 to 6 heteroaryl groups.

[0081] In some implementation schemes, R 3-1 Or R 3-2 Substitution with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN or OR. a .

[0082] In some implementation schemes, R 3-1 and R 3-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; in some embodiments, R 3-1 and R 3a Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0083] X3

[0084] In some implementations, X3 is 0; in other implementations, X3 is S.

[0085] R 4a

[0086] In some implementation schemes, R 4a For H; in some implementations, R 4a C 1-6 Alkyl; in some embodiments, R 4a C 1-6 Halogenated alkyl groups.

[0087] R 4-1 and R 4-2

[0088] In some implementation schemes, R 4-1For H; in some implementations, R 4-1 C 1-6 Alkyl; in some embodiments, R 4-1 C 1-6 Halogenated alkyl; in some embodiments, R 4-1 C 2-6 alkenyl; in some embodiments, R 4-1 C 2-6 Halogenated alkenyl; in some embodiments, R 4-1 C 2-6 alkynyl group; in some implementations, R 4-1 C 2-6 Halogenated alkynyl group.

[0089] In some implementation schemes, R 4-2 For H; in some implementations, R 4-2 C 1-6 Alkyl; in some embodiments, R 4-2 C 1-6 Halogenated alkyl; in some embodiments, R 4-2 C 2-6 alkenyl; in some embodiments, R 4-2 C 2-6 Halogenated alkenyl; in some embodiments, R 4-2 C 2-6 alkynyl group; in some implementations, R 4-2 C 2-6 Halogenated alkynyl group.

[0090] In some implementation schemes, R 4-1 Or R 4-2 Substitution with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6Halogenated alkyl groups.

[0091] In some implementation schemes, R 4-1 and R 4-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; in some embodiments, R 4-1 and R 4a Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0092] R 5a

[0093] In some implementation schemes, R 5a For H; in some implementations, R 5a C 1-6 Alkyl; in some embodiments, R 5a C 1-6 Halogenated alkyl groups.

[0094] R 5-1 and R 5-2

[0095] In some implementation schemes, R 5-1 For H; in some implementations, R 5-1 C 1-6 Alkyl; in some embodiments, R 5-1 C 1-6 Halogenated alkyl; in some embodiments, R 5-1 C 2-6 alkenyl; in some embodiments, R 5-1 C 2-6 Halogenated alkenyl; in some embodiments, R 5-1 C 2-6 alkynyl group; in some implementations, R 5-1 C 2-6 Halogenated alkynyl group.

[0096] In some implementation schemes, R 5-2 For H; in some implementations, R 5-2 C 1-6 Alkyl; in some embodiments, R 5-2 C 1-6 Halogenated alkyl; in some embodiments, R 5-2 C 2-6 alkenyl; in some embodiments, R 5-2 C 2-6 Halogenated alkenyl; in some embodiments, R 5-2 C 2-6 alkynyl group; in some implementations, R 5-2 C 2-6 Halogenated alkynyl group.

[0097] In some implementation schemes, R 5-1 Or R 5-2 Substitution with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0098] In some implementation schemes, R 5-1 and R 5-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; in some embodiments, R 5-1 and R 5-2 Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; in some embodiments, R 5-1 and R 5a Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0099] R 6a

[0100] In some implementation schemes, R 6a For H; in some implementations, R 6a C 1-6 Alkyl; in some embodiments, R 6a C 1-6 Halogenated alkyl groups.

[0101] R 6-1 and R 6-2

[0102] In some implementation schemes, R 6-1 For H; in some implementations, R 6-1 C 1-6 Alkyl; in some embodiments, R 6-1C 1-6 Halogenated alkyl; in some embodiments, R 6-1 C 2-6 alkenyl; in some embodiments, R 6-1 C 2-6 Halogenated alkenyl; in some embodiments, R 6-1 C 2-6 alkynyl group; in some implementations, R 6-1 C 2-6 Halogenated alkynyl group.

[0103] In some implementation schemes, R 6-2 For H; in some implementations, R 6-2 C 1-6 Alkyl; in some embodiments, R 6-2 C 1-6 Halogenated alkyl; in some embodiments, R 6-2 C 2-6 alkenyl; in some embodiments, R 6-2 C 2-6 Halogenated alkenyl; in some embodiments, R 6-2 C 2-6 alkynyl group; in some implementations, R 6-2 C 2-6 Halogenated alkynyl group.

[0104] In some implementation schemes, R 6-1 Or R 6-2 Replacement of 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0105] In some implementation schemes, R 6-1 and R 6-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; in some embodiments, R 6-1 and R 6a Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0106] R 7a

[0107] In some implementation schemes, R 7a For H; in some implementations, R 7a C 1-6 Alkyl; in some embodiments, R 7a C 1-6 Halogenated alkyl groups.

[0108] R 7-1 and R 7-2

[0109] In some implementation schemes, R 7-1 For H; in some implementations, R 7-1 C 1-6 Alkyl; in some embodiments, R 7-1 C 1-6 Halogenated alkyl; in some embodiments, R 7-1 C 2-6 alkenyl; in some embodiments, R 7-1 C 2-6 Halogenated alkenyl; in some embodiments, R 7-1 C 2-6 alkynyl group; in some implementations, R 7-1 C 2-6 Halogenated alkynyl group.

[0110] In some implementation schemes, R 7-2 For H; in some implementations, R 7-2 C 1-6 Alkyl; in some embodiments, R 7-2 C 1-6 Halogenated alkyl; in some embodiments, R 7-2 C 2-6 alkenyl; in some embodiments, R 7-2 C 2-6 Halogenated alkenyl; in some embodiments, R 7-2 C 2-6 alkynyl group; in some implementations, R 7-2 C 2-6 Halogenated alkynyl group.

[0111] In some implementation schemes, R 7-1 Or R 7-2 Replacement of 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10 heteroaryl compounds.

[0112] In some implementation schemes, R 7-1 and R 7a Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0113] R8

[0114] In some implementations, R8 is H; in other implementations, R8 is C. 1-6 Alkyl; in some embodiments, R8 is C 1-6 Halogenated alkyl; in some embodiments, R8 is C 2-6 Alkenyl; in some embodiments, R8 is C 2-6 Haloalkenyl; in some embodiments, R8 is C 2-6 Alkyne group; in some embodiments, R8 is C 2-6 Halogenated alkynyl group; in some embodiments, R8 is substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0115] R 9x and R 9y

[0116] In some implementation schemes, R 9x For H; in some implementations, R 9x C 1-6 Alkyl; in some embodiments, R 9x C 1-6 Halogenated alkyl; in some embodiments, R 9x C 2-6 alkenyl; in some embodiments, R 9x C 2-6 Halogenated alkenyl; in some embodiments, R 9x C 2-6 alkynyl group; in some implementations, R 9x C 2-6 Halogenated alkynyl group.

[0117] In some implementation schemes, R 9y For H; in some implementations, R 9y C 1-6 Alkyl; in some embodiments, R 9y C 1-6 Halogenated alkyl; in some embodiments, R 9y C 2-6 alkenyl; in some embodiments, R 9y C 2-6 Halogenated alkenyl; in some embodiments, R 9y C 2-6 alkynyl group; in some implementations, R 9y C 2-6 Halogenated alkynyl group.

[0118] In some implementation schemes, R 9x and R 9y Together with the atoms they are attached to, they form C 3-8 Cycloalkyl.

[0119] R 10

[0120] In some implementation schemes, R 10 For H; in some implementations, R 10 C 1-6Alkyl; in some embodiments, R 10 C 1-6 Halogenated alkyl; in some embodiments, R 10 C 2-6 alkenyl; in some embodiments, R 10 C 2-6 Halogenated alkenyl; in some embodiments, R 10 C 2-6 alkynyl group; in some implementations, R 10 C 2-6 Halogenated alkynyl group; in some embodiments, R 10 Replacement of 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, OR a NO2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0121] R 11a

[0122] In some implementation schemes, R 11a For H; in some implementations, R 11a C 1-6 Alkyl; in some embodiments, R 11a C 1-6 Halogenated alkyl groups.

[0123] R 11

[0124] In some implementation schemes, R 11 For H; in some implementations, R 11 C 1-6 Alkyl; in some embodiments, R 11 C1-6 Halogenated alkyl; in some embodiments, R 11 C 2-6 alkenyl; in some embodiments, R 11 C 2-6 Halogenated alkenyl; in some embodiments, R 11 C 2-6 alkynyl group; in some implementations, R 11 C 2-6 Halogenated alkynyl group; in some embodiments, R 11 Replacement of 1, 2, 3 or more halogens, OR a SR a S(O)₂OH, NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0125] In some implementation schemes, R 11-1 and R 11a Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0126] R 12

[0127] In some implementation schemes, R 12 For H; in some implementations, R 12 C 1-6 Alkyl; in some embodiments, R 12 C 1-6 Halogenated alkyl; in some embodiments, R 12 C 2-6 alkenyl; in some embodiments, R 12 C 2-6 Halogenated alkenyl; in some embodiments, R 12 C2-6 alkynyl group; in some implementations, R 12 C 2-6 Halogenated alkynyl group; in some embodiments, R 12 C 6-10 Aryl; in some implementations, R 12 Replacement of 1, 2, 3 or more halogens, OR a SR a NMe3 + NHAc, NHR a ,NHC(O)CH2NR b R c , NHC(O)NH2, NHC(=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0128] R 13a

[0129] In some implementation schemes, R 13a For H; in some implementations, R 13a C 1-6 Alkyl; in some embodiments, R 13a C 1-6 Halogenated alkyl groups.

[0130] R 13-1 and R 13-2

[0131] In some implementation schemes, R 13-1 For H; in some implementations, R 13-1 C 1-6 Alkyl; in some embodiments, R 13-1 C 1-6 Halogenated alkyl; in some embodiments, R 13-1 C2-6 alkenyl; in some embodiments, R 13-1 C 2-6 Halogenated alkenyl; in some embodiments, R 13-1 C 2-6 alkynyl group; in some implementations, R 13-1 C 2-6 Halogenated alkynyl group.

[0132] In some implementation schemes, R 13-2 For H; in some implementations, R 13-2 C 1-6 Alkyl; in some embodiments, R 13-2 C 1-6 Halogenated alkyl; in some embodiments, R 13-2 C 2-6 alkenyl; in some embodiments, R 13-2 C 2-6 Halogenated alkenyl; in some embodiments, R 13-2 C 2-6 alkynyl group; in some implementations, R 13-2 C 2-6 Halogenated alkynyl group.

[0133] In some implementation schemes, R 13-1 Or R 13-2 Replacement of 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10 heteroaryl compounds.

[0134] In some implementation schemes, R 13-1 and R 13-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; in some embodiments, R 13-1 and R 13a Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0135] R 14a

[0136] In some implementation schemes, R 14a For H; in some implementations, R 14a C 1-6 Alkyl; in some embodiments, R 14a C 1-6 Halogenated alkyl groups.

[0137] R 14-1 and R 14-2

[0138] In some implementation schemes, R 14-1 For H; in some implementations, R 14-1 C 1-6 Alkyl; in some embodiments, R 14-1 C 1-6 Halogenated alkyl; in some embodiments, R 14-1 C 2-6 alkenyl; in some embodiments, R 14-1 C 2-6 Halogenated alkenyl; in some embodiments, R 14-1 C 2-6 alkynyl group; in some implementations, R 14-1 C 2-6 Halogenated alkynyl group; in some embodiments, R 14-1 C 3-8 cycloalkyl; in some embodiments, R 14-1 It is a 4- to 8-membered heterocyclic group; in some implementations, R 14-1 C 6-10 Aryl; in some implementations, R 14-1 It consists of 5 to 6 heteroaryl groups.

[0139] In some implementation schemes, R 14-2 For H; in some implementations, R 14-2 C 1-6 Alkyl; in some embodiments, R 14-2 C 1-6 Halogenated alkyl; in some embodiments, R 14-2 C 2-6 alkenyl; in some embodiments, R 14-2 C 2-6 Halogenated alkenyl; in some embodiments, R 14-2 C 2-6 alkynyl group; in some implementations, R 14-2 C 2-6 Halogenated alkynyl group; in some embodiments, R14-2 C 3-8 cycloalkyl; in some embodiments, R 14-2 It is a 4- to 8-membered heterocyclic group; in some implementations, R 14-2 C 6-10 Aryl; in some implementations, R 14-2 It consists of 5 to 6 heteroaryl groups.

[0140] In some implementation schemes, R 14-1 Or R 14-2 Replacement of 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, biphenyl, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl group or 5 to 10 heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN, OH, NO2, -C 0-6 Alkylene-C(O)OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 6-10 Aryl.

[0141] In some implementation schemes, R 14-1 and R 14-2 Together with the atoms they are attached to, they form C 3-8 Cycloalkyl.

[0142] R 15

[0143] In some implementation schemes, R 15 For H; in some implementations, R 15 C 1-6 Alkyl; in some embodiments, R 15 C 1-6 Halogenated alkyl; in some embodiments, R15 C 2-6 alkenyl; in some embodiments, R 15 C 2-6 Halogenated alkenyl; in some embodiments, R 15 C 2-6 alkynyl group; in some implementations, R 15 C 2-6 Halogenated alkynyl group; in some embodiments, R 15 Optionally replaces 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0144] R 16x and R 16y

[0145] In some implementation schemes, R 16x For H; in some implementations, R 16x C 1-6 Alkyl; in some embodiments, R 16x C 1-6 Halogenated alkyl; in some embodiments, R 16x C 2-6 alkenyl; in some embodiments, R 16x C 2-6 Halogenated alkenyl; in some embodiments, R 16x C 2-6 alkynyl group; in some implementations, R 16x C 2-6 Halogenated alkynyl group.

[0146] In some implementation schemes, R16y For H; in some implementations, R 16y C 1-6 Alkyl; in some embodiments, R 16y C 1-6 Halogenated alkyl; in some embodiments, R 16y C 2-6 alkenyl; in some embodiments, R 16y C 2-6 Halogenated alkenyl; in some embodiments, R 16y C 2-6 alkynyl group; in some implementations, R 16y C 2-6 Halogenated alkynyl group.

[0147] In some implementation schemes, R 16x and R 16y Together with the atoms they are attached to, they form C 3-8 Cycloalkyl.

[0148] Y

[0149] In some embodiments, Y is OH; in some embodiments, Y is NH2; in some embodiments, Y is an amino acid of Gly; in some embodiments, Y is an amino acid of Ala; in some embodiments, Y is an amino acid of Aib; in some embodiments, Y is an amino acid of Glu; in some embodiments, Y is an amino acid of Pro; in some embodiments, Y is an amino acid of D-Ala; in some embodiments, Y is an amino acid of Ahx (aminocaproic acid); in some embodiments, Y is an amino acid of Asp; in some embodiments, Y is an amino acid of D-Glu; in some embodiments, Y is an amino acid of D-Pro; in some embodiments, Y is an amino acid of D-Asp.

[0150] X

[0151] In some implementations, each X is C(O); in some implementations, each X is S(O); in some implementations, each X is S(O)2.

[0152] L1

[0153] In some implementations, L1 is the key; in other implementations, L1 is... In some implementation schemes, L1 is... (-(Sar) p -); In some implementations, L1 is (-(Ser) q -); In some implementations, L1 is (-(Sar-Ser) w -); In some implementations, L1 is (-(Ser-Sar) w -); In some embodiments, L1 is a -C(O)-4 to 11-membered heterocyclic group- (wherein the heterocyclic group is connected to L2).

[0154] L2

[0155] In some implementations, L2 is a bond; in others, L2 is -(CH2CH2O). m1 CH2C(O)- (where C(O)- is linked to L3); in some embodiments, L2 is -C(O)CH2(OCH2CH2). m1 NH- (where NH- is connected to L3).

[0156] L3

[0157] In some implementations, L3 is a bond; in others, L3 is -NH(CH2CH2O). m2 CH2C(O)- (where C(O)- is linked to L4); in some embodiments, L3 is -C(O)CH2(OCH2CH2). m2 NH- (wherein NH- is linked to L4); in some embodiments, L3 is -Glu-C(O)CH2(OCH2CH2). m2 NH-, where Glu is .

[0158] L4

[0159] In some implementations, L4 is the key; in other implementations, L4 is... (-Lys(L5)-L5-); In some implementations, L4 is .

[0160] L5

[0161] In some implementations, L5 is the key; in other implementations, L5 is... In some implementations, L5 is... In some implementations, L5 is -C(O)CH2(OCH2CH2) m3 NH- (wherein NH- is linked to L6 or L); in some embodiments, L5 is -C(O)(CH2). m3 NH- (where NH- is connected to L6 or L).

[0162] L6

[0163] In some embodiments, L6 is a bond; in some embodiments, L6 is -C(O)CH2CH2S-, wherein S- is linked to a cleavable linker; in some embodiments, L6 is (-Cys'-), where S- is linked to a cleavable linker; in some embodiments, L6 is... (-Cys-C(O)CH2CH2S-), where S- is attached to a cleavable linker.

[0164] L

[0165] In some implementations, L is -C(O)(CH2). m4 C(O)OH; in some embodiments, L is -C(O)(CH2). 14 C(O)OH.

[0166] p, q, w, m, m1, m2, m3 and m4

[0167] In some implementations, p=0; in some implementations, p=1; in some implementations, p=2; in some implementations, p=3; in some implementations, p=4; in some implementations, p=5; in some implementations, p=6; in some implementations, p=7; in some implementations, p=8; in some implementations, p=9; in some implementations, p=10.

[0168] In some implementations, q=0; in some implementations, q=1; in some implementations, q=2; in some implementations, q=3; in some implementations, q=4; in some implementations, q=5; in some implementations, q=6; in some implementations, q=7; in some implementations, q=8; in some implementations, q=9; in some implementations, q=10.

[0169] In some implementations, w=0; in some implementations, w=1; in some implementations, w=2; in some implementations, w=3; in some implementations, w=4; in some implementations, w=5; in some implementations, w=6; in some implementations, w=7; in some implementations, w=8; in some implementations, w=9; in some implementations, w=10.

[0170] In some implementations, m=0; in some implementations, m=1; in some implementations, m=2; in some implementations, m=3; in some implementations, m=4; in some implementations, m=5; in some implementations, m=6; in some implementations, m=7; in some implementations, m=8; in some implementations, m=9; in some implementations, m=10.

[0171] In some implementations, m1=0; in some implementations, m1=1; in some implementations, m1=2; in some implementations, m1=3; in some implementations, m1=4; in some implementations, m1=5; in some implementations, m1=6; in some implementations, m1=7; in some implementations, m1=8; in some implementations, m1=9; in some implementations, m1=10.

[0172] In some implementations, m2=0; in some implementations, m2=1; in some implementations, m2=2; in some implementations, m2=3; in some implementations, m2=4; in some implementations, m2=5; in some implementations, m2=6; in some implementations, m2=7; in some implementations, m2=8; in some implementations, m2=9; in some implementations, m2=10.

[0173] In some implementations, m3=0; in some implementations, m3=1; in some implementations, m3=2; in some implementations, m3=3; in some implementations, m3=4; in some implementations, m3=5; in some implementations, m3=6; in some implementations, m3=7; in some implementations, m3=8; in some implementations, m3=9; in some implementations, m3=10.

[0174] In some implementations, m4=5; in some implementations, m4=6; in some implementations, m4=7; in some implementations, m4=8; in some implementations, m4=9; in some implementations, m4=10; in some implementations, m4=11; in some implementations, m4=12; in some implementations, m4=13; in some implementations, m4=14; in some implementations, m4=15; in some implementations, m4=16; in some implementations, m4=17; in some implementations, m4=18; in some implementations, m4=19; in some implementations, m4=20; in some implementations, m4=21; in some implementations, m4=22; in some implementations, m4=23; in some implementations, m4=24.

[0175] Disintegrable linker

[0176] In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as , In some implementations, the cleavable linker is as follows: Such as ,and In some implementations, the cleavable linker is as follows: Such as ; In some implementations, the cleavable linker is as follows: Such as ; In some implementations, the cleavable linker is as follows: Such as ; In some implementations, the cleavable linker is as follows: Such as ;and In some implementations, the cleavable linker is as follows: ; In some of the above embodiments, p1=1; in some of the above embodiments, p1=2; in some of the above embodiments, p1=3; in some of the above embodiments, p1=4; in some of the above embodiments, p1=5; in some of the above embodiments, p1=6; in some of the above embodiments, p1=7; in some of the above embodiments, p1=8; in some of the above embodiments, p1=9; in some of the above embodiments, p1=10. In some of the above implementations, p2=1; in some of the above implementations, p2=2; in some of the above implementations, p2=3; in some of the above implementations, p2=4; in some of the above implementations, p2=5; in some of the above implementations, p2=6; in some of the above implementations, p2=7; in some of the above implementations, p2=8; in some of the above implementations, p2=9; in some of the above implementations, p2=10. In some of the above embodiments, p3=1; in some of the above embodiments, p3=2; in some of the above embodiments, p3=3; in some of the above embodiments, p3=4; in some of the above embodiments, p3=5; in some of the above embodiments, p3=6; in some of the above embodiments, p3=7; in some of the above embodiments, p3=8; in some of the above embodiments, p3=9; in some of the above embodiments, p3=10.

[0177] Payload

[0178] In some embodiments, the payload is an antitumor drug; in some embodiments, the payload is a topoisomerase 1 inhibitor; in some embodiments, the payload is a topoisomerase 2 inhibitor; in some embodiments, the payload is a DNA alkylating agent; in some embodiments, the payload is a transcription inhibitor; in some embodiments, the payload is a Bcl-xL inhibitor; in some embodiments, the payload is a tyrosine kinase inhibitor. This disclosure reveals the following plan: Scheme 1. Compound of formula (I): (I) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: R is -C(O)C 1-6 Alkyl or -C(O)C 1-6 Halogenated alkyl groups, such as Ac; R 1a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 1-1 and R 1-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; Or R 1-1 and R 1-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 1-1 and R 1a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; n = 0 or 1; R 2a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 2x and R 2y Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; Or R 2x and R 2y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 3a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 3-1 and R 3-2 Independently selected from H and C 1-6Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN or OR. a ; Or R 3-1 and R 3-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 3-1 and R 3a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; X3 is selected from O or S; R 4a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 4-1 and R 4-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 4-1 and R 4-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 4-1 and R 4a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 5a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 5-1 and R 5-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 5-1 and R 5-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4- to 8-membered heterocyclic groups; or R 5-1 and R 5a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 6a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 6-1 and R 6-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 6-1 and R 6-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 6-1 and R 6a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 7a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 7-1 and R7-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; Or R 7-1 and R 7a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R8 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C.1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 9x and R 9y Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl groups; Or R 9x and R 9y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 10 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, OR a NO2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)₂OH, NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 11-1 and R 11a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 12 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl or C 6-10 aryl; which is optionally substituted with 1, 2, 3 or more halogens, OR a SR a NMe3 + NHAc, NHR a ,NHC(O)CH2NR b R c , NHC(O)NH2, NHC(=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13-1 and R 13-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; Or R 13-1 and R 13-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 13-1 and R 13a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 14a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 14-1 and R 14-2 Independently selected from H and C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, biphenyl, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl group or 5 to 10 heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN, OH, NO2, -C 0-6 Alkylene-C(O)OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 6-10 Aryl; Or R 14-1 and R 14-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 15 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b Rc C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 16x and R 16y Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl groups; Or R 16x and R 16y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; Y is selected from OH, NH2, or the following amino acids: Gly, Ala, Aib, Glu, Pro, D-Ala, Ahx (aminocaproic acid), Asp, D-Glu, D-Pro and D-Asp; preferably, OH, or the following amino acids: Gly, Ala, D-Ala and D-Pro; Each X is independently selected from C(O), S(O), or S(O)2; Where R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0179] Scheme 2. Based on the compound of formula (I) from Scheme 1: (I) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: R is -C(O)C 1-6 Alkyl or -C(O)C 1-6 Halogenated alkyl groups, such as Ac; R 1a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 1-1 and R 1-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 1-1 and R 1-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 1-1 and R 1a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; n = 0 or 1; R 2a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 2x and R 2y Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 2x and R 2y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 3a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 3-1 and R 3-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R cC 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN or OH; Or R 3-1 and R 3-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 3-1 and R 3a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; X3 is selected from O or S; R 4a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 4-1 and R 4-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 4-1 and R 4-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 4-1 and R 4a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 5a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 5-1and R 5-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 5-1 and R 5-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4- to 8-membered heterocyclic groups; or R 5-1 and R 5a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 6a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 6-1 and R 6-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6Halogenated alkyl groups; Or R 6-1 and R 6-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 6-1 and R 6a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 7a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 7-1 and R 7-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; Or R 7-1 and R 7a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R8 is selected from H and C. 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R9x and R 9y Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 9x and R 9y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 10 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, OR a NO2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)₂OH, NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 11-1 and R 11a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 12 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 6-10 aryl; which is optionally substituted with 1, 2, 3 or more halogens, OR a SR a NMe3 + NHAc, NHR a , NHC(O)NH2, NHC(=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13-1 and R 13-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C6-10 Aryl or 5 to 10-membered heteroaryl; Or R 13-1 and R 13-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 13-1 and R 13a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 14a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 14-1 and R 14-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, biphenyl, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl group or 5 to 10 heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN, OH, NO2, -C 0-6 Alkylene-C(O)OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 6-10 Aryl; Or R 14-1 and R 14-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 15 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR aNHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 16x and R 16y Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 16x and R 16y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; Y is selected from OH, NH2, or the following amino acids: Gly, Ala, Glu, D-Ala, Ahx (aminocaproic acid), Asp, D-Glu, and D-Asp; Each X is independently selected from C(O), S(O), or S(O)2; Where R a R b and R c Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R b and R c Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

[0180] Scheme 3. A compound of formula (I) according to Scheme 1 or 2, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein R 1a For H.

[0181] Scheme 4. A compound of formula (I) according to any one of Schemes 1 to 3, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 1-2 For H and R 1-1 C 1-6 Alkyl groups, such as Me; or R 1-1 and R 1-2Together with the atoms they are attached to, they form C 3-6 Cycloalkyl groups, such as cyclopropyl groups.

[0182] Scheme 5. A compound of formula (I) according to any one of Schemes 1 to 4, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 2a For H.

[0183] Scheme 6. A compound of formula (I) according to any one of schemes 1 to 5, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein n=1.

[0184] Scheme 7. A compound of formula (I) according to any one of schemes 1 to 5, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein n=0.

[0185] Scheme 8. A compound of formula (I) according to any one of Schemes 1 to 7, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 3a Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, such as Me.

[0186] Scheme 9. A compound of formula (I) according to any one of Schemes 1 to 7, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 3a For H.

[0187] Scheme 10. A compound of formula (I) according to any one of schemes 1 to 9, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 3-1 and R 3-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OH or SR. a Or R 3-1 and R 3-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl, preferably C 5-6 cycloalkyl; preferably, R 3-2 For H and R 3-1 It is a side chain of Leu, Ile, Thr or Val, preferably a side chain of Leu or Val, preferably a side chain of Leu; Preferably, R 3-1 and R 3-2 Independently selected from H and C1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more OH groups; preferably, R 3-2 For H and R 3-1 It is a side chain of Leu, Ile, or Thr.

[0188] Scheme 11. A compound of formula (I) according to any one of Schemes 1 to 10, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein X3 is S.

[0189] Scheme 12. A compound of formula (I) according to any one of Schemes 1 to 11, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 4a For H.

[0190] Scheme 13. A compound of formula (I) according to any one of schemes 1 to 12, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 4-1 and R 4-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 5 to 10 heteroaryl groups; preferably, R 4-1 and R 4-2 One is a side chain of H and the other is a side chain of Trp; preferably, R 4-2 For H and R 4-1 It is a sidechain of Trp.

[0191] Scheme 14. A compound of formula (I) according to any one of schemes 1 to 13, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 5a For H.

[0192] Scheme 15. A compound of formula (I) according to any one of schemes 1 to 14, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 5-1 and R 5-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl groups, preferably all C10 ... 1-4 Alkyl or C 1-4 Halogenated alkyl groups, such as Me; or R 5-1 and R 5-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl, preferably C 4-6 Cycloalkyl.

[0193] Scheme 16. A compound of formula (I) according to any one of schemes 1 to 15, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 6a For H.

[0194] Scheme 17. A compound of formula (I) according to any one of schemes 1 to 16, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 6-1 and R 6-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more OH groups; preferably, R 6-1 and R 6-2 One of them is H and the other is a Ser side chain; preferably, R 6-2 For H and R 6-1 It is a sidechain of Ser.

[0195] Scheme 18. A compound of formula (I) according to any one of schemes 1 to 17, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 7a For H.

[0196] Scheme 19. A compound of formula (I) according to any one of schemes 1 to 18, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 7-1 and R 7-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more OH, C(O)OR a or C(O)NR b R c Or R 7-1 and R 7a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; preferably, R 7-1 and R 7-2 One of them is H and the other is a side chain of Asp, Thr, or Glu; Preferably, R 7-1 and R 7-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more C(O)OR a or C(O)NR b R c Or R 7-1 and R 7aTogether with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups, such as pyrrolidinyl groups; preferably, R 7-2 For H and R 7-1 It is a side chain of Asp or Glu; preferably an Asp side chain.

[0197] Scheme 20. A compound of formula (I) according to any one of schemes 1 to 19, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R8 is selected from C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a or SR a Preferably, R8 is a side chain of Ile, Leu, or Met; preferably, it is a side chain of Ile or Leu.

[0198] Scheme 21. A compound of formula (I) according to any one of schemes 1 to 20, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more C(O)OR a or C(O)NR b R c Preferably, R 10 It is a side chain of Gln; preferably, R 10 It has S-chirality.

[0199] Scheme 22. A compound of formula (I) according to any one of schemes 1 to 21, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 11a For H.

[0200] Scheme 23. A compound of formula (I) according to any one of schemes 1 to 22, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a C(O)OR a or C(O)NR b R c Preferably, R 11Side chains of Val, Glu, Ile, Ser, or Thr, preferably side chains of Val, Ile, Ser, or Thr, preferably side chains of Val, Glu, Ile, or Thr, preferably side chains of Val or Ile; preferably, R 11 The side chain is Glu, Val, or Ser, preferably a side chain of Glu or Val, and R is a side chain of Glu. 7-1 and R 7a Together with the atoms they are attached to, they form pyrrolidinyl groups; preferably, R 11 It has S-chirality.

[0201] Scheme 24. A compound of formula (I) according to any one of schemes 1 to 23, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 12 Selected from C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 5 to 10 heteroaryl groups; preferably, R 12 It is a side chain of Leu, Val, or His, preferably a side chain of Leu or Val; preferably, R 12 It has S-chirality.

[0202] Scheme 25. A compound of formula (I) according to any one of schemes 1 to 23, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 12 Selected from C 2-6 alkynyl or C 2-6 Halogenated alkynyl group.

[0203] Scheme 26. A compound of formula (I) according to any one of schemes 1 to 25, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 13a For H.

[0204] Scheme 27. A compound of formula (I) according to any one of schemes 1 to 26, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 13-1 and R 13-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more OH groups; preferably, R 13-2 For H and R 13-1 It is a sidechain of Ser.

[0205] Scheme 28. A compound of formula (I) according to any one of schemes 1 to 27, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 14a For H.

[0206] Scheme 29. A compound of formula (I) according to any one of schemes 1 to 28, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 14-1 and R 14-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 5 to 10 heteroaryl groups; or R 14-1 and R 14-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; Preferably, R 14-2 For H or Me, preferably Me and R 14-1 It is a side chain of Val or Ile; preferably a side chain of Val.

[0207] Scheme 30. A compound of formula (I) according to any one of schemes 1 to 29, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 15 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 5 to 10 heteroaryl groups; preferably, R 15 It is a side chain of Trp; preferably, R 15 It has S-chirality.

[0208] Scheme 31. A compound of formula (I) according to any one of schemes 1 to 30, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Y is OH.

[0209] Scheme 32. A compound of formula (I) according to any one of schemes 1 to 31, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein X is C(O).

[0210] Scheme 33. A compound of formula (I) according to Scheme 1 or 2, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from those in Table A.

[0211] Scheme 34. Compound of formula (II): (II) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key, , (-(Sar) p -) (-(Ser) q -) (-(Sar-Ser) w -) (-(Ser-Sar) w -) or -C(O)-4 to 11-membered heterocyclic group- (wherein the heterocyclic group is connected to L2); L2 is selected from the bond, -(CH2CH2O). m1 CH2C(O)- (where C(O)- is attached to L3) or -C(O)CH2(OCH2CH2) m1 NH- (where NH- is connected to L3); L3 is selected from the bond, -NH(CH2CH2O). m2 CH2C(O)- (where C(O)- is attached to L4), -C(O)CH2(OCH2CH2) m2 NH- (where NH- is attached to L4) or -Glu-C(O)CH2(OCH2CH2) m2 NH-, where Glu is ; L4 is selected from the key, (-Lys(L5)-L5-) or ; L5 is selected from key, , -C(O)CH2(OCH2CH2) m3 NH- (where NH- is attached to L6 or L) or -C(O)(CH2) m3 NH- (where NH- is connected to L6 or L); L6 is selected from the bond, -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-), where each S- is linked to a cleavable linker; L stands for -C(O)(CH2). m4 C(O)OH; Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; w = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m4 = 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24; The cleavable linker is selected from the following: , , , , , , , , , , , , , , , , , , , , ,and ; Among them, each of the above groups is connected to L6 on the left and to the payload on the right; p1 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p2 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p3 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors; And the other variables are defined in any of schemes 1 to 33.

[0212] Scheme 35. Compound of formula (II) according to Scheme 34: (II) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key, , (-(Sar) p -) (-(Ser) q -) (-(Sar-Ser) w -) (-(Ser-Sar) w -) or -C(O)-4 to 11-membered heterocyclic group- (wherein the heterocyclic group is connected to L2); L2 is selected from the bond, -(CH2CH2O). m1 CH2C(O)- (where C(O)- is attached to L3) or -C(O)CH2(OCH2CH2) m1 NH- (where NH- is connected to L3); L3 is selected from the bond, -NH(CH2CH2O). m2 CH2C(O)- (where C(O)- is attached to L4), -C(O)CH2(OCH2CH2) m2 NH- (where NH- is attached to L4) or -Glu-C(O)CH2(OCH2CH2) m2 NH-, where Glu is ; L4 is selected from the key, (-Lys(L5)-L5-) or ; L5 is selected from key, , -C(O)CH2(OCH2CH2) m3 NH- (where NH- is attached to L6 or L) or -C(O)(CH2) m3 NH- (where NH- is connected to L6 or L); L6 is selected from the bond, -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-), where each S- is linked to a cleavable linker; L stands for -C(O)(CH2). m4 C(O)OH; Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; w = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m4 = 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24; The cleavable linker is selected from the following: , , , , , , , , , , , , , , , , , , , , ,and ; Among them, each of the above groups is connected to L6 on the left and to the payload on the right; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors; And the other variables are defined in any of schemes 1 to 33.

[0213] Scheme 36. Compound of formula (II) according to Scheme 34: (II) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key, (-(Sar) p -) (-(Ser) q -) (-(Sar-Ser) w -) or -C(O)-4 to 11-membered heterocyclic groups-; L2 is selected from the bond or -C(O)CH2(OCH2CH2). m1 NH-; L3 is selected from the bond, -C(O)CH2(OCH2CH2). m2 NH- or -Glu-C(O)CH2(OCH2CH2) m2 NH-, where Glu is ; L4 is selected from key or (-Lys(L6)-L5-); L5 is selected from the bond or -C(O)(CH2). m3 NH-; L6 is selected from -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-); Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; w = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and each -S- in L6 is connected to a splittable connection base - payload; The cleavable linker is selected from the following: , , , , , , , , , , , , , , , , ,and ; Among them, each of the above groups is connected to L6 on the left and to the payload on the right; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors; And the other variables are defined in any of schemes 1 to 33.

[0214] Scheme 37. A compound of formula (II) according to any one of schemes 34 to 36, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein m = 1, 2, 3, 4, 5 or 6; preferably, m = 2, 3, 4; preferably, m = 3.

[0215] Scheme 38. A compound of formula (II) according to any one of schemes 34 to 37, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein m1 = 1, 2, 3 or 4; preferably, m1 = 2 or 3; preferably, m1 = 2.

[0216] Scheme 39. A compound of formula (II) according to any one of schemes 34 to 38, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein m2 = 1, 2, 3 or 4; preferably, m2 = 2 or 3; preferably, m2 = 2.

[0217] Scheme 40. A compound of formula (II) according to any one of schemes 34 to 39, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein m3 = 3, 4, 5, 6 or 7; preferably, m3 = 4, 5 or 6; preferably, m3 = 5.

[0218] Scheme 41. A compound of formula (II) according to any one of schemes 34 to 40, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein m4 = 10, 11, 12, 13, 14, 15, 16, 17 or 18; preferably, m4 = 12, 13, 14, 15 or 16; m4 = 13, 14 or 15; preferably, m4 = 14.

[0219] Scheme 42. A compound of formula (II) according to any one of schemes 34 to 41, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from bonds or (-(Sar) p -), where p = 1, 2 or 3.

[0220] Scheme 43. A compound of formula (II) according to any one of schemes 34 to 41, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein the -C(O)-4 to 11-membered heterocyclic group is selected from: , , or , where a=0, 1, 2, 3 or 4, b=0, 1, 2, 3 or 4, c=0, 1, 2, 3 or 4, d=0, 1, 2, 3 or 4, and a+b=2, 3, 4, 5, 6, 7 or 8, c+d=2, 3, 4, 5, 6, 7 or 8.

[0221] Scheme 44. A compound of formula (II) according to any one of schemes 34 to 43, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein L2 is selected from bond or -C(O)CH2(OCH2CH2). m1 NH-.

[0222] Scheme 45. A compound of formula (II) according to any one of schemes 34 to 44, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein L3 is selected from bond or -C(O)CH2(OCH2CH2). m2 NH-.

[0223] Scheme 46. A compound of formula (II) according to any one of Schemes 34 to 45, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein L4 is selected from bond or .

[0224] Scheme 47. A compound of formula (II) according to any one of schemes 34 to 46, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein L5 is selected from bond or -C(O)(CH2). m3 NH-.

[0225] Scheme 48. A compound of formula (II) according to any one of schemes 34 to 47, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein L6 is selected from the bond or -C(O)CH2CH2S-.

[0226] Scheme 49. A compound of formula (II) according to any one of schemes 34 to 48, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein the spacer group is selected from the following: -C(O)-4 to 11-membered heterocyclic group-C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2) m3 NH-C(O)CH2CH2S-、 -C(O)-4 to 11-membered heterocyclic group-C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-、 -(Sar) p -C(O)CH2(OCH2CH2) m1NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2) m3 NH-C(O)CH2CH2S-、 -(Sar) p -C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -(Sar) p -C(O)CH2(OCH2CH2) m1 NH-Glu-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -(Sar) p -C(O)(CH2) m3 NH-C(O)CH2CH2S-, -C(O)CH2(OCH2CH2) m1 NH-Glu-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, and C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2) m3 NH-C(O)CH2CH2S-; Preferably, the spacer base is selected from the following: -C(O)-7 to 11-membered bicyclic heterocyclic group-C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2)5NH-C(O)CH2CH2S-, -C(O)-7 to 11-membered bicyclic heterocyclic group-C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -(Sar) p -C(O)CH2(OCH2CH2) m1NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2)5NH-C(O)CH2CH2S-, -(Sar) p -C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -Sar-C(O)CH2(OCH2CH2) m1 NH-Glu-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2)5NH-C(O)CH2CH2S-, -(Sar) p -C(O)CH2(OCH2CH2) m1 NH-Glu-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -(Sar) p -C(O)(CH2)5NH-C(O)CH2CH2S-, -C(O)CH2(OCH2CH2) m1 NH-Glu-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, and C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2)5NH-C(O)CH2CH2S-; Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 1, 2, 3 or 4; m2 = 1, 2, 3 or 4; and -C(O)-7 to 11-membered bicyclic subheterocyclic groups are selected from the following: or Where a = 0, 1, 2, 3 or 4, b = 0, 1, 2, 3 or 4, c = 0, 1, 2, 3 or 4, d = 0, 1, 2, 3 or 4, and a+b = 2, 3, 4, 5, 6, 7 or 8, c+d = 2, 3, 4, 5, 6, 7 or 8; preferably, the 7- to 11-membered bicyclic subheterocyclic groups are selected from the following: , , , , , , , ,and ; Preferably, the spacer base is selected from the following: -Sar-C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2)5NH-C(O)CH2CH2S-, -Sar-C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -Sar-C(O)CH2(OCH2CH2) m1 NH-Glu-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, and -(Sar) 10 -C(O)(CH2)5NH-C(O)CH2CH2S-.

[0227] Scheme 50. A compound of formula (II) according to any one of schemes 34 to 49, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the cleavable linker is selected from the following: , , , ,and ; Preferably selected from the following: , ,and ; Preferably .

[0228] Scheme 51. A compound of formula (II) according to Scheme 34, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein

[0229] The spacer bases are -L1-L2-L3-L4-L5-L6-, where

[0230] L1 is selected from key, (-(Sar) p -)or (-(Ser) q -); L2 is selected from the bond or -C(O)CH2(OCH2CH2). m1 NH- (where NH- is attached to L3); L3 is selected from the bond or -C(O)CH2(OCH2CH2) m2 NH- (where NH- is connected to L4); L4 is selected from key or (-Lys(L5)-L5-); L5 is selected from the bond, -C(O)CH2(OCH2CH2). m3 NH- (where NH- is attached to L6 or L) or -C(O)(CH2) m3 NH- (where NH- is connected to L6); L6 is selected from the bond, -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-), where each S- is linked to a cleavable linker; Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The cleavable linker is selected from the following: , , , , , , , , , , , , , ,and ; Among them, each of the above groups is connected to L6 on the left and to the payload on the right; p1 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p2 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p3 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors; And the other variables are defined in any of schemes 1 to 33.

[0231] Scheme 52. A compound of formula (II) according to Scheme 34, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein

[0232] The spacer bases are -L1-L2-L3-L4-L5-L6-, where

[0233] L1 is selected from key, (-(Sar) p -)or (-(Ser) q -); L2 is selected from the bond or -C(O)CH2(OCH2CH2). m1 NH- (where NH- is attached to L3); L3 is selected from the bond or -C(O)CH2(OCH2CH2) m2 NH- (where NH- is connected to L4); L4 is selected from key or (-Lys(L5)-L5-); L5 is selected from the bond, -C(O)CH2(OCH2CH2). m3 NH- (where NH- is attached to L6 or L) or -C(O)(CH2) m3 NH- (where NH- is connected to L6); L6 is selected from the bond, -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-), where each S- is linked to a cleavable linker; Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The cleavable linker is selected from the following: , , , , , , , , , , , , , ,and ; Among them, each of the above groups is connected to L6 on the left and to the payload on the right; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors; And the other variables are defined in any of schemes 1 to 33.

[0234] Scheme 53. A compound of formula (II) according to Scheme 34, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein

[0235] The spacer bases are -L1-L2-L3-L4-L5-L6-, where

[0236] L1 is selected from key or (-(Sar) p -); L2 is selected from the bond or -C(O)CH2(OCH2CH2). m1 NH- (where NH- is attached to L3); L3 is selected from the bond or -C(O)CH2(OCH2CH2) m2 NH- (where NH- is connected to L4); L4 is selected from key or (-Lys(L5)-L5-); L5 is selected from the bond or -C(O)(CH2). m3 NH- (where NH- is connected to L6); L6 is selected from the bond or -C(O)CH2CH2S-; Where p = 1, 2 or 3; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The cleavable linker is selected from the following: , , , ,and ; Among them, each of the above groups is connected to L6 on the left and to the payload on the right; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors; And the other variables are defined in any of schemes 1 to 33.

[0237] Scheme 54. A compound of formula (II) according to Scheme 34, or a stereoisomer, tautomer, stable isotope thereof, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein

[0238] The spacer bases are -L1-L2-L3-L4-L5-L6-, where

[0239] L1 is selected from key or (-(Sar) p -); L2 is selected from the bond or -C(O)CH2(OCH2CH2). m1 NH- (where NH- is attached to L3); L3 is selected from the bond or -C(O)CH2(OCH2CH2) m2 NH- (where NH- is connected to L4); L4 is selected from key or (-Lys(L5)-L5-); L5 is selected from the bond or -C(O)(CH2). m3 NH- (where NH- is connected to L6); L6 is selected from the bond or -C(O)CH2CH2S-; Where p = 1, 2 or 3; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The cleavable linker is selected from the following: , , , ,and ; Among them, each of the above groups is connected to L6 on the left and to the payload on the right; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors; And the other variables are defined in any of schemes 1 to 33.

[0240] Scheme 55. A compound of formula (II) according to any one of schemes 34 to 54, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein the payload is a topoisomerase 1 inhibitor based on camptothecin compounds and non-camptothecin compounds, such as eczema, delutec and its derivatives, SN38, belotecone and its derivatives, or a topoisomerase 2 inhibitor, such as doxorubicin, or a DNA alkylating agent, such as calichimycin, pyrrolobenzodiazepines (PBD), indolinobenzodiazepines (IGN), or cyclopropylbenzoindolone (CBI); Preferably, the payload is selected from the following: , , ,and . Preferably, the payload is selected from the following: or .

[0241] Scheme 56. A compound of formula (II) according to Scheme 34, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from those in Table B.

[0242] Scheme 57. A pharmaceutical composition comprising: The compound of any one of schemes 1 to 56, or its stereoisomer, tautomer, stable isotope variant or prodrug, or its pharmaceutically acceptable salt; Pharmaceutically acceptable excipients; and Optionally, one or more other therapeutic agents, such as RAS inhibitors, RTK inhibitors, EGFR inhibitors, DNA repair inhibitors, immune checkpoint inhibitors such as PD-1 or PD-L1 inhibitors, etc.

[0243] Option 58. A reagent kit, comprising: A first container containing a compound according to any one of schemes 1 to 56, or a stereoisomer, tautomer, stable isotopic variant, or prodrug thereof, or a pharmaceutically acceptable salt thereof; and Optionally, a second container contains one or more other therapeutic agents; and Optionally, a third container contains pharmaceutically acceptable excipients for diluting or suspending the compound and / or other therapeutic agents such as RAS inhibitors, RTK inhibitors, EGFR inhibitors, DNA repair inhibitors, immune checkpoint inhibitors such as PD-1 or PD-L1 inhibitors, etc.

[0244] Scheme 59. Use of any compound of any one of Schemes 1 to 56, or a stereoisomer, tautomer, stable isotope variant or prodrug thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of EGFR-mediated diseases.

[0245] Scheme 60. A compound according to any one of Schemes 1 to 56, or a stereoisomer, tautomer, stable isotopic variant, or prodrug thereof, or a pharmaceutically acceptable salt thereof, for the treatment of EGFR-mediated diseases.

[0246] Scheme 61. A method for treating EGFR-mediated disease in a subject in need, comprising administering to the subject a compound according to any one of Schemes 1 to 56, or a stereoisomer, tautomer, stable isotope variant or prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0247] Option 62. The use described in Option 59, or the compound used in Option 60, or the method described in Option 61, wherein the EGFR-mediated disease is cancer.

[0248] Option 63. The use or compound or method described in Option 62, wherein the cancer is a solid tumor or a leukemia.

[0249] Option 64. The use or compound or method described in Option 62 or 63, wherein the cancer is selected from lung cancer, esophageal cancer, gastric cancer, colon cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, breast cancer, brain cancer, glioblastoma (GBM), kidney cancer, liver cancer, mesothelioma, prostate cancer, sarcoma, testicular cancer, thyroid cancer, uterine cancer, bile duct cancer, thyroid cancer, skin cancer, uveal melanoma; leukemia, malignant lymphoma, and multiple myeloma.

[0250] Option 65. The use or compound or method described in Option 62 or 63, wherein the cancer is head and neck cancer, biliary tract cancer, nasopharyngeal carcinoma, non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, endometrial cancer, cervical cancer, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphoblastic leukemia), CLL (chronic lymphoblastic leukemia), Hodgkin lymphoma, and non-Hodgkin lymphoma.

[0251] Scheme 66. The use of any one of Schemes 62-65 or the compound or method of use, wherein the cancer is associated with EGFR overexpression (by mRNA or protein); EGFR gene abnormalities (gene copy number amplification or mutation in codon regions); or EGFR pathway overactivation.

[0252] Scheme 67. The use or method of any one of Schemes 62-66, wherein the cancer is resistant to a known EGFR inhibitor (small molecule or antibody).

[0253] Option 68. The use or method of any of Options 59-67, including the use of other therapeutic agents such as RAS inhibitors, RTK inhibitors, EGFR inhibitors, DNA repair inhibitors, immune checkpoint inhibitors such as PD-1 or PD-L1 inhibitors.

[0254] Pharmaceutical Composition and Administration

[0255] In another aspect, this disclosure provides pharmaceutical compositions comprising a compound of this disclosure (also referred to as the "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of this disclosure. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of this disclosure. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the compound of this disclosure.

[0256] Pharmaceutically acceptable excipients used in this disclosure are non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that may be used in the compositions of this disclosure include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0257] This disclosure also includes kits (e.g., pharmaceutical packaging). The provided kits may include compounds of this disclosure, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of this disclosure and other therapeutic agents. In some embodiments, the provided kits may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of this disclosure and / or other therapeutic agents. In some embodiments, the compounds of this disclosure and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0258] The pharmaceutical compositions provided in this disclosure can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0259] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0260] Indications and treatment methods

[0261] The cyclic peptide compounds disclosed in this article may be used to treat cancer.

[0262] As used in this article, “cancer” and “cancerous” refer to or describe a physiological condition in mammals that is typically characterized by uncontrolled cell growth / proliferation. Examples of cancer include solid tumors and blood cancers. Further examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More specific examples of such cancers include lung cancer, esophageal cancer, thyroid cancer, stomach cancer, liver cancer, colon cancer, uterine cancer, ovarian cancer, pancreatic cancer, kidney cancer, bladder cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma. More specific examples of this type of cancer include brain tumors, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, rectal cancer, endometrial cancer, cervical cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocellular carcinoma, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphoblastic leukemia), CLL (chronic lymphoblastic leukemia), Hodgkin's lymphoma, non-Hodgkin's lymphoma, and other lymphoproliferative disorders, as well as various types of head and neck cancers. In one respect, "cancer" can refer to any cancer other than pancreatic cancer.

[0263] As used in this article, "cell proliferation disorder" and "proliferative disorder" refer to disorders associated with some degree of abnormal cell proliferation. In one respect, cell proliferation disorder is cancer.

[0264] As used in this article, “tumor” refers to the growth and proliferation of all proliferative cells as well as all precancerous and cancerous cells and tissues, whether malignant or benign.

[0265] The terms “cancer,” “cancerous,” “cell proliferation disorder,” “proliferative disorder,” and “tumor” used in this article are not mutually exclusive.

[0266] In one aspect, the cancers include cancers associated with EGFR protein overexpression, with or without DNA copy number amplification; cancers with EGFR gene amplification; cancers with EGFR gene mutations; or cancers with excessive activation of the EGFR pathway. EGFR protein overexpression refers to increased production of EGFR protein on cancer cells. Overexpression is sometimes due to an increase in the EGFR gene copy number, and sometimes due to other mechanisms. EGFR gene copy number amplification refers to the presence of an EGFR gene with a copy number higher than the normal copy number of the EGFR gene present on the chromosome. Mutations in the coding region of the EGFR gene refer to, for example, deletions, additions, or substitutions of one or more bases in the coding region of the EGFR gene. The cancers also include cancers associated with: excessive activation of the EGFR pathway due to overexpression of the EGFR protein or its ligands; compensatory excessive activation due to inhibition of other RTK pathways or downstream KRAS or PI3K pathways; or gene abnormalities involved in the regulation of the EGFR pathway.

[0267] Whether cancer exhibits EGFR overexpression can be determined, for example, by comparing the overall expression level of EGFR protein, the EGFR protein expression level in subjects without cancer, or the EGFR protein expression level in subjects before developing cancer. EGFR protein expression levels can be determined using techniques such as flow cytometry, Western blotting, IHC, or immunofluorescence studies. EGFR overexpression can also be examined by measuring EGFR mRNA levels using techniques such as reverse qPCR.

[0268] Whether a cancer is associated with EGFR gene copy number amplification can be determined by isolating DNA from cancer cells and measuring the DNA copy number using methods such as qPCR. Alternatively, commercially available in vitro diagnostic reagents capable of detecting EGFR gene amplification can be used.

[0269] Whether cancer is associated with EGFR gene mutations can be determined by identifying mutations in the nucleotide sequence of the EGFR gene coding region in a biological sample obtained from a subject with cancer. Any method can be used as long as it can detect mutations in the EGFR gene coding region in the biological sample of a subject with cancer. For example, DNA can be isolated from the biological sample obtained from a subject with cancer, the EGFR gene can be isolated and amplified by PCR or similar methods, and its nucleotide sequence can be directly determined using a sequencer or similar method. Alternatively, commercially available in vitro diagnostic reagents capable of detecting EGFR gene mutations can be used.

[0270] In one aspect, cancers include those associated with EGFR overexpression or EGFR gene abnormalities, including EGFR gene copy number amplification or mutation.

[0271] In one aspect, cancer can also include cancers caused by over-expression of receptors or ligands; or compensatory mechanisms; or abnormalities in genes involved in pathway regulation, leading to overactivation of the EGFR pathway.

[0272] In one respect, the compounds disclosed herein can be used as therapeutics or preventative agents for a subject's disease (preferably cancer). In another respect, the compounds disclosed herein can be used to treat or prevent a disease (preferably cancer).

[0273] In one aspect, this disclosure provides a method for treating or preventing a disease (preferably cancer). One aspect of this method involves administering an effective amount of the disclosed compound to a subject suffering from such a disease (preferably cancer).

[0274] In one aspect, this disclosure provides the use of the compounds disclosed herein in the manufacture or preparation of a medicament. In one aspect, the medicament is used to treat or prevent a disease, preferably cancer. In another aspect, a method of using the medicament to treat or prevent a disease, preferably cancer, includes administering an effective amount of the compounds disclosed herein to a subject suffering from cancer.

[0275] In one aspect, the compounds disclosed herein can be used as EGFR inhibitors in subjects. In one embodiment, EGFR inhibition may include inhibiting the binding between EGFR and its ligands (e.g., EGF binding) and inhibiting EGFR pathway signaling.

[0276] In one respect, the compounds disclosed herein can be used to deliver cytotoxins (payloads) to cancer cells expressing EGFR to selectively kill cancer cells expressing EGFR.

[0277] In one aspect, this disclosure provides a method for inhibiting EGFR in a subject. In one aspect, the method includes delivering a cytotoxin into cancer cells expressing EGFR to kill the cancer cells in the subject. In one aspect, the method includes administering an effective amount of the disclosed compound to the subject to inhibit EGFR. In one aspect, the method includes administering an effective amount of the disclosed compound to the subject to kill cancer cells expressing EGFR. In one embodiment, EGFR inhibition may include, for example, inhibiting the binding of an EGFR ligand (e.g., EGF) to EGFR.

[0278] On the other hand, this disclosure provides compounds disclosed herein for inhibiting EGFR and / or delivering cytotoxic agents to EGFR-expressing cancer cells to kill the cancer cells. In some embodiments, this disclosure provides compounds disclosed herein for inhibiting EGFR in a subject and / or killing EGFR-expressing cancer cells, including administering an effective amount of the disclosed compounds to the subject.

[0279] According to any of the above aspects, the "subject" is preferably a human being.

[0280] Examples of EGFR inhibition include inhibiting the binding between EGFR and EGF, or the binding of EGFR to EGFR (dimerization).

[0281] Drug combination

[0282] The compounds disclosed herein can be used alone or in combination with other pharmaceutical agents. In one aspect, the above embodiments also include administering an effective amount of at least one additional therapeutic agent to a subject. For example, the compounds disclosed herein can be administered co-administered with at least one additional therapeutic agent.

[0283] As described above, combination therapy includes combined administration (where two or more therapeutic agents are contained in the same or separate formulation) and monotherapy (where the compounds disclosed herein are administered separately from one or more therapeutic agents). Administration of the compounds disclosed herein may be before, simultaneously with, and / or after administration of additional therapeutic agents. In one aspect, administration of the compounds disclosed herein and administration of additional therapeutic agents may occur within about one month, or within about one, two, or three weeks, or within about one, two, three, four, five, or six days. The compounds disclosed herein may also be used in combination with radiotherapy.

[0284] The compounds disclosed herein (and any other therapeutic agents) may be administered via any of the following routes: oral, parenteral, pulmonary, nasal, and intralesional (if local treatment is required). Parenteral administration includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. Administration may be carried out via any suitable route, such as by injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is short-term or long-term. Various dosing regimens are covered herein, including but not limited to single doses or repeated doses at different time points, bolus doses, and pulsatile infusions.

[0285] The formulation, dosage, and administration of the compounds disclosed herein conform to good medical practice. Factors to be considered in this regard include the specific disease being treated, the specific mammal being treated, the individual patient's clinical symptoms, the cause of the disorder, the site of administration, the method of administration, the schedule, and other factors known to healthcare practitioners. The compounds may optionally (but not necessarily) be formulated with one or more agents currently used for the prevention or treatment of the disease in question.

[0286] The effective amount of such other agents depends on the amount of compounds present in the formulation, the type of disease or treatment, and other factors discussed above.

[0287] The “effective amount” of agents, compounds and drugs disclosed in this article is the amount that effectively achieves the desired therapeutic or preventive outcome.

[0288] Example

[0289] Compound preparation

[0290] The compounds disclosed herein can be prepared via solid-phase synthesis, which involves several challenging amide couplings. Procedures for achieving these challenging couplings, such as those in the following schemes, are described in the following references: Journal of Medicinal Chemistry 2022 65 (19), 13401-13412 Journal of the American Chemical Society 2023 145 (30), 16610-16620 Journal of the American Chemical Society 2023 145 (44), 24035-24051 The general manual synthetic procedure for preparing the compounds in Table 1 is as follows:

[0291] The peptide was synthesized using standard Fmoc chemistry following the steps outlined below.

[0292] 1) Resin Preparation: DIEA (139 mg, 0.80 mmol, 4.00 eq) was added to a solution of 2-CTC resin (0.20 mmol, 1.00 eq, Sub 0.30 mmol / g) and Fmoc-Cys(Trt)-OH (117 mg, 0.20 mmol, 1.00 eq) in DCM (5.0 mL). The mixture was then stirred at 25 °C with N2 for 2.0 h. MeOH (0.67 mL) was then added to the resin, and the mixture was stirred at 25 °C with N2 for 0.5 h. The resin was filtered and treated with DMF (10.0 mL). 4) Washing.

[0293] 2) Deprotection: Add 20% piperidine to DMF (5.0 mL) and continue stirring the resin under N2 for 10.00 minutes. Then, use DMF (5.00 mL) to remove the protective agent. 5) Wash the resin and filter it.

[0294] 3) Coupling: A solution of Fmoc-Trp(Boc)-OH (316 mg, 0.60 mmol, 3.00 eq), DIEA (209 mg, 1.20 mmol, 6.00 eq), and HBTU (217 mg, 0.57 mmol, 2.85 eq) in DMF (3.00 mL) was added to the resin and stirred at 40 °C under nitrogen for 30 minutes. min. Using DMF (15.0 mL) 4) Washing resin.

[0295] 4) Repeat steps 2 to 3 above to couple the following amino acids: (items 3-16).

[0296]

[0297] The cleavage and purification of peptides are performed according to the following steps: 1) After SPPS is complete, use DMF (5.00 mL) 5) MeOH (5.00 mL) 3) Wash the resin and then filter to obtain 1.10 g of resin.

[0298] 2) Then, at room temperature, the lysis solution (12.0 mL, 90.0% TFA, 2.50% TIS, 2.50% H2O, 5.0% 3-mercaptopropionic acid) was added to a flask containing resin and stirred for 2 hours.

[0299] 3) Precipitate the peptide using cold isopropyl ether (40 mL). Filter the mixture and precipitate with isopropyl ether (40 mL). 2) Washing the crude peptide. After vacuum drying for 2 hours, the crude peptide was obtained, yielding compound 1 (207 mg, 109.17 μmol, yield 54.58%, crude product, TFA salt). The peptide was analyzed by LCMS (R...). t = 1.491 minutes, MS calculated value: 1780.80, MS observed value: [M+2H] 2+ = 891.7) Analysis confirms the structure.

[0300]

[0301] To complete the synthesis, a solution of compound 1 (28.1 μmol, 50.0 mg, 1.00 eq, TFA) and TATA (26.65 μmol, 6.64 mg, 0.95 eq) in H₂O (200 mL) and ACN (100 mL) was treated with 1.0 MCs₂CO₃ (2.31 μL, 28.06 μmol, 1.00 eq) until the pH of the mixture reached 8–9. The reaction was then stirred at 25°C for 30 min. The reaction was monitored by LCMS (R0). t = 1.505 min). Next, the crude peptide was purified by preparative HPLC (0.075% TFA salt conditions; 30 °C, A: 0.075% TFA / H2O, B: CH3CN) to obtain E1316 (5.50 μmol, 10.3 mg, yield 19.62%, purity 98.41%, TFA) as a white solid. The plasma was further purified by LCMS (R... t = 1.336 minutes, MS calculated value: 2029.91, MS observed value: [M+2H] 2+ = 1015.97) and HPLC(R t = 13.334 minutes) Analysis confirmed the structure.

[0302] Purification conditions:

[0303] HPLC analysis conditions:

[0304] The compounds in Table 1 were prepared using the same general procedure, and these compounds were separated in the following amounts and purities: Compounds are listed in Table 1.

[0305]

[0306]

[0307]

[0308]

[0309]

[0310] The general automated solid-phase synthesis and manual cyclization procedures for preparing the compounds in Table 2 are as follows:

[0311] The peptide was synthesized using standard Fmoc chemistry on Biotage's Syro II following the steps outlined below.

[0312] 1) Resin preparation: DIEA (69.5 mg, 0.40 mmol, 4.00 eq) was added to a solution of 2-CTC resin (0.10 mmol, 1.00 eq, Sub 0.50 mmol / g) and Fmoc-Cys(Trt)-OH (58.6 mg, 0.10 mmol, 1.00 eq) in DCM (5.0 mL). The mixture was stirred at 25 °C under N2 for 2.00 h. Next, MeOH (0.20 mL) was added to the resin, and the mixture was stirred at 25 °C under N2 for 0.5 h. The resin was filtered and treated with DMF (5.0 mL). 4) Washing.

[0313] 2) Deprotection: Add 20% piperidine to DMF (5.00 mL), and continue stirring the resin under N2 for 10.0 minutes. Then, use DMF (5.00 mL) to remove the protective agent. 5) Wash the resin and filter it.

[0314] 3) Coupling: A solution of Fmoc-Trp(Boc)-OH (158 mg, 0.30 mmol, 3.00 eq), DIEA (102 mg, 0.60 mmol, 6.00 eq), and HBTU (108.3 mg, 0.29 mmol, 2.85 eq) in DMF (5.00 mL) was added to the resin and stirred at 40 °C under nitrogen for 30 min. The solution was then used with DMF. (5.0 mL 4) Washing resin.

[0315] 4) Repeat steps 2 to 3 above to couple the following amino acids: (items 3-16).

[0316]

[0317] The cleavage and purification of peptides are performed according to the following steps: 1) After SPPS is complete, use DMF (5.0 mL) 5), MeOH (5.0 mL) 3) Wash the resin and then filter to obtain 0.70g of resin.

[0318] 2) Then, at room temperature, the lysis solution (7.00 mL, 90.0% TFA, 2.50% TIS, 2.50% H2O, 5.0% 3-mercaptopropionic acid) was added to a flask containing resin and stirred for 2 hours.

[0319] 3) Precipitate the peptide in cold isopropyl ether (40 mL) and centrifuge (3000 rpm for 2 minutes). Filter the mixture and precipitate with isopropyl ether (40 mL). 2) Washing the crude product. After vacuum drying for 2 hours, a crude peptide was obtained, yielding compound 2 (125 mg, 39.1 μmol, yield 26.1%, purity 65.1%, TFA salt). The compound was analyzed by LCMS (R...). t = 1.473 minutes, MS calculated value: 1965.73, MS observed value: [M+2H] 2+ = 984.1) Analysis confirms the structure.

[0320]

[0321] To complete the synthesis, 1 M Cs₂CO₃ (18.8 μmol, 1.00 eq, TFA) and TATA (4.44 mg, 17.8 μmol, 0.95 eq) were added to a solution of compound 2 (18.8 μmol, 1.00 eq) in H₂O (30.0 mL) and ACN (30.0 mL) until the pH of the mixture reached 8–9. The reaction was stirred at 25 °C for 1.5 h. The reaction was monitored by LCMS (R0). t = 1.487 minutes). After the reaction was complete, the crude peptide was purified by preparative HPLC (0.075% TFA salt conditions; 30 °C, A: 0.075% TFA / H2O, B: CH3CN) to obtain E1403 (17.1 mg, 7.12 μmol, yield 38.0%, purity 96.9%, TFA) as a white solid. The final product was analyzed by LCMS (R... t =1.129 minutes, MS calculated value: 2214.84, MS observed value: [M+H] + = 2215.85) and HPLC(R t = 11.287 minutes) Analysis confirmed the structure.

[0322] Purification conditions:

[0323] HPLC analysis conditions:

[0324] The compounds in Table 2 were prepared using the same general procedure, and these compounds were separated in the following amounts and purities: Compounds Table 2

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333] The general automated solid-phase synthesis and manual cyclization procedures for preparing the compounds in Table 3 are as follows:

[0334] The peptide was synthesized using standard Fmoc chemistry following the steps outlined below.

[0335] 1) Resin preparation: DIEA (69.5 mg, 0.40 mmol, 4.00 eq) was added to a solution of 2-CTC resin (0.10 mmol, 1.00 eq, Sub 0.50 mmol / g) and Fmoc-Cys(Trt)-OH (58.6 mg, 0.10 mmol, 1.00 eq) in DCM (5.00 mL), and the mixture was stirred at 25 °C under N2 for 2.0 h. Next, MeOH (0.20 mL) was added to the resin, and the mixture was stirred at 25 °C under N2 for 0.50 h. The resin was then filtered and treated with DMF (5.00 mL). 4) Washing.

[0336] 2) Deprotection: Add 20% piperidine (5.00 mL) to DMF, and stir the resin again under N2 for 10.0 minutes. Then use DMF (5.00 mL) 5) Wash the resin and filter it.

[0337] 3) Coupling: A solution of Fmoc-Trp(Boc)-OH (158 mg, 0.30 mmol, 3.00 eq), DIEA (102 mg, 0.60 mmol, 6.00 eq), and HATU (108 mg, 0.29 mmol, 2.85 eq) in DMF (5.00 mL) was added to the resin, and the mixture was stirred at 40 °C under nitrogen for 30.0 min. Then, DMF (50.0 mL) was added... 4) Washing resin.

[0338] 4) Repeat steps 2 and 3 above to couple the following amino acids: (3-17). For amino acids following sterically hindered residues, higher equivalence and concentrations are used. The completion of the reaction is monitored using a ninhydrin assay.

[0339]

[0340] The cleavage and purification of peptides are performed according to the following steps: 1) After SPPS is complete, use DMF (5.00 mL) 5) MeOH (5.00mL) 3) Wash the resin and then filter to obtain 0.60 g of resin.

[0341] 2) Next, the lysis solution (6.0 mL, 90.0% TFA, 2.50% TIS, 2.50% H2O, 5.00% 3-mercaptopropionic acid) was added to the resin-containing flask at room temperature and stirred for 1.50 hours.

[0342] 3) Precipitate the peptide in cold isopropyl ether (40.0 mL) and centrifuge (3000 rpm, 2.00 min). Filter the mixture and precipitate with isopropyl ether (40.0 mL). 2) Washing the crude peptide. After vacuum drying for 2.0 hours, crude peptide was obtained, yielding crude compound 3 (186 mg, 98.6 μmol, 98.6% yield, TFA salt). The crude peptide was analyzed by LCMS (R...). t = 1.678 minutes, MS calculated value: 1881.26, MS observed value: [M+2H] 2+ = 963.2) Analysis confirms the structure.

[0343]

[0344] Next, 1.0 M Cs2CO was added to a solution of compound 3 (18.8 μmol, 60.0 mg, 1.00 eq, TFA) and TATA (4.44 mg, 17.8 μmol, 0.95 eq) in H2O (30.0 mL) and ACN (30.0 mL). 3. (18.8 μL, 18.8 μmol, 1.00 eq) until the pH of the mixture reaches 8–9. The reaction was stirred at 25 °C for 1.5 h. The reaction was monitored by LCMS (R0). t= 1.607 min). The crude peptide was purified by preparative HPLC (0.075% TFA salt conditions; 30 °C, solvent A: 0.075% TFA / H2O, solvent B: CH3CN) to give E1450 (17.1 mg, 8.03 μmol, yield 42.7%, purity 96.9%, TFA) as a white solid. The plasma was further purified by LCMS (R...). t = 1.260 minutes, MS calculated value: 2129.99, MS observed value: [M+2H] 2+ =1066.00) and HPLC(R t = 11.486 minutes) Analysis confirmed the structure.

[0345] Purification conditions:

[0346] The compounds in Table 3 were prepared using the same general procedure, and these compounds were separated in the following amounts and purities: Compounds Table 3

[0347]

[0348] HPLC analysis conditions:

[0349] The compounds in Table 3A were prepared using the same general procedure, analyzed according to the methods listed above, and separated with the following amounts and purities: Compounds Table 3A

[0350]

[0351] The general synthetic procedure for preparing the conjugates in Table 4 is as follows:

[0352] The peptide was synthesized using standard Fmoc chemistry following the steps outlined below.

[0353] 1) Resin Preparation: DIEA (350 μL, 2.00 mmol, 4.00 eq) was added to a solution of 2-CTC resin (0.50 mmol, 1.00 eq, Sub 0.50 mmol / g) and Fmoc-Cys(Trt)-OH (293 mg, 0.50 mmol, 1.00 eq) in DCM (20.0 mL). The mixture was stirred at 25 °C under N2 for 2.00 h. Next, MeOH (1.00 mL) was added to the resin, and the mixture was stirred at 25.0 °C under N2 for 0.50 h. The resin was filtered and treated with DMF (20.0 mL). 5) Washing.

[0354] 2) Deprotection: Add 20% piperidine (20.0 mL) to the DMF, and continue stirring the resin under N2 for 8.00 minutes. Use DMF (20.0 mL) 5) Wash the resin and filter it.

[0355] 3) Coupling: A solution of Fmoc-Trp(Boc)-OH (790 mg, 1.50 mmol, 3.00 eq), DIEA (408 mg, 3.0 mmol, 6.00 eq), and HBTU (1.62 g, 1.50 mmol, 2.85 eq) in DMF (7.0 mL) was added to the resin and stirred at 20 °C under nitrogen for 30 minutes. Then, DMF (20.0 mL) was added... 5) Washing resin.

[0356] 4) Repeat steps 2 to 3 above to couple the following amino acids: (items 3-20).

[0357]

[0358] The cleavage and purification of peptides are performed according to the following steps: 1) After coupling with the last amino acid, add 20% piperidine in DMF (20.0 mL) to remove the N-terminal Fmoc. Stir the mixture under N2 for 8.00 minutes. Add 20.0 mL of DMF... 5) MeOH (20.0 mL) 3) Wash the resin and then filter it to obtain 1.50 g of resin.

[0359] 2) Next, the lysis solution (15.0 mL, 90.0% TFA, 2.50% TIS, 2.50% H2O, 5.0% 3-mercaptopropionic acid) was added to the resin-containing flask at room temperature and stirred for 2 hours.

[0360] 3) Precipitate the peptide in cold isopropyl ether (50.0 mL). Filter the mixture and precipitate with isopropyl ether (50.0 mL). 2) Washing the crude peptide. The crude peptide was obtained after drying under vacuum for 2 hours, yielding compound 4 (1.00 g). The residue was analyzed by LCMS (R...). t = 1.452 min, MS calculated value: 2298.1, MS observed value: [M+2H] 2+ = 1149.3) Analysis confirms the structure.

[0361] 4) The crude peptide was purified by preparative HPLC (TFA conditions: A: 0.075% TFA in water, B: ACN) to give compound 4 (350 mg, 145 μmol, yield 29.0%, TFA), as a white solid. The purified compound was further purified by LCMS (R...). t = 1.506 minutes, MS calculated value: 2298.1, MS observed value: [M+2H] 2+ = 1150.7) and HPLC (R t = 12.499 minutes) Analysis confirmed the structure.

[0362] Purification conditions:

[0363]

[0364] The general steps for preparing compound 5 are as follows: Compound 4 (0.35 g, 152 μmol, 1.00 eq, TFA salt) and TATA (36.0 mg, 145 μmol, 0.95 eq) were added to a solution of H₂O (200 mL) and ACN (100 mL) with 1 M NH₄HCO₃ aqueous solution until pH = 8–9. The reaction was stirred at 25 °C for 30 min. The reaction was monitored by LCMS (Reflectance Spectrometry). t = 1.55 min). The crude peptide was purified by preparative HPLC (0.075% TFA; 30 °C, A: 0.075% TFA / H2O, B: CH3CN) to give compound 5 (150 mg, 56.3 μmol, yield 37.0%, TFA salt) as a white solid. The crude peptide was further purified by LCMS (R... t = 1.414 minutes, MS calculated value: 2547.22, MS observed value: [M+2H] 2+ = 1275.4) and HPLC (R t = 12.620 minutes) Analysis confirmed the structure.

[0365] Purification conditions:

[0366]

[0367] The general steps for preparing compound 7 are as follows: DIEA (21.8 mg, 169 μmol, 29.4 μL, 3.00 eq) was added to a solution of compound 5 (150 mg, 56.3 μmol, 1.00 eq, TFA salt) and MPa(Trt)-OSu (30.1 mg, 67.6 μmol, 1.20 eq) in DMF (0.50 mL), and the mixture was stirred at 25°C for 30 min. The reaction was then analyzed by LC-MS (R...). t = 1.562 min) to monitor the reaction. The mixture was then precipitated in cold isopropyl ether (50.0 mL). The mixture was filtered and the crude product was washed twice with isopropyl ether (50.0 mL). The crude peptide was dried under vacuum for 0.5 h to give 0.30 g of compound 6. Next, 5.00 mL of lysis buffer (90.0% TFA / 10.0% H2O) was added to the flask containing compound 6, and the mixture was stirred for 0.2 h. The peptide was precipitated in cold isopropyl ether (50.0 mL). The mixture was filtered and the crude product was washed twice with isopropyl ether (50.0 mL). The crude peptide was dried under vacuum for 2 h to give 0.15 g of crude peptide. The precipitate was analyzed by LCMS (R t = 1.436 minutes) to confirm the structure. The crude peptide was purified by preparative HPLC (0.075% TFA; 30 °C, A: 0.075% TFA / H2O, B: CH3CN) to give compound 7 (50.0 mg, 18.2 μmol, yield 32.3%, TFA salt), a white solid, which was analyzed by LCMS (R t = 1.44 minutes, MS calculated value: 2635.22, MS observed value: [M+2H] 2+ = 1319.2) and HPLC(R t = 11.93 minutes) Analysis confirmed the structure.

[0368] Purification conditions:

[0369]

[0370] General steps for preparing E2012: DIEA (1.47 mg, 11.4 μmol, 1.98 μL, 3.00 eq) was added to a solution of compound 7 (10.0 mg, 3.79 μmol, 1.00 eq) in DMF (0.10 mL). The mixture was stirred at 25 °C for 10.0 min. The reaction was monitored by LCMS (Resistance Measurement). t = 1.442 min). The crude product was purified by preparative HPLC (0.075% TFA; 30 °C, A: 0.075% TFA / H2O, B: CH3CN) to give E2012 (9.67 mg, 2.22 μmol, yield 58.6%, purity 97.4%, TFA salt), as a white solid. The crude product was further purified by LCMS (R... t = 1.36 minutes, MS calculated value: 4080.04, MS observed value: [M+3H] 3+ = 1361.68) and HPLC(R) t = 11.1 minutes) Analysis confirms the structure.

[0371] Purification conditions:

[0372] The compounds in Table 4 were prepared using the same general procedure, and these compounds were separated in the following amounts and purities: Compounds Table 4

[0373] Analysis conditions:

[0374] The compounds in Table 4A were prepared using the same general procedure, and these compounds were analyzed using the methods described above and separated in the following quantities and purities: Compounds Table 4A

[0375] Analysis conditions:

[0376] The compounds in Table 4B were prepared using the same general procedure, and these compounds were analyzed using the methods described above and separated in the following amounts and purities: Compounds Table 4B

[0377] Analysis conditions:

[0378] The compounds in Table 4C were prepared using the same general procedure, and these compounds were analyzed using the methods described above and separated in the following quantities and purities: Compound Table 4C

[0379] The general synthetic procedure for preparing the conjugates in Table 5 is as follows:

[0380] The peptide was synthesized using standard Fmoc chemistry following the steps outlined below.

[0381] 1) Resin Preparation: DIEA (700 μL, 4.00 mmol, 4.00 eq) was added to a solution of 2-CTC resin (1.00 mmol, 1.00 eq, Sub 0.50 mmol / g) and Fmoc-Cys(Trt)-OH (586 mg, 1.00 mmol, 1.00 eq) in DCM (100.0 mL). The mixture was then stirred at 25 °C under N2 for 2.0 h. Next, MeOH (2.00 mL) was added to the resin, and the mixture was stirred at 25.0 °C under N2 for 0.5 h. The resin was filtered and treated with DMF (60.0 mL). 5) Washing.

[0382] 2) Deprotection: Add 20% piperidine to DMF (100 mL), and stir the resin under N2 for another 8.00 minutes. Then use DMF (100 mL) 5) Wash the resin and filter it.

[0383] 3) Coupling: A solution of Fmoc-Trp(Boc)-OH (1.58 g, 3.00 mmol, 3.00 eq), DIEA (816 mg, 6.0 mmol, 6.00 eq), and HBTU (3.24 g, 3.00 mmol, 2.85 eq) in DMF (30.0 mL) was added to the resin and stirred at 20 °C under nitrogen for 30 minutes. Then, the solution was added to the resin using DMF. (100 mL 5) Washing resin.

[0384] 4) Repeat steps 2 and 3 above to couple the following amino acids: (3-20). For amino acids following sterically hindered residues, higher equivalence and concentrations are used. The completion of the reaction is monitored using a ninhydrin assay.

[0385]

[0386] The cleavage and purification of peptides are performed according to the following steps: 1) After the last amino acid is coupled, 20% piperidine is added to DMF (100 mL) to remove the N-terminal Fmoc. The mixture is stirred under N2 for 8.0 minutes. Then, it is dissolved in DMF (100 mL). 5) MeOH (100 mL) 3) Wash the resin and filter to obtain 3.50 g of resin.

[0387] 2) Next, the lysis solution (35.0 mL, 90.0% TFA, 2.50% TIS, 2.50% H2O, 5.0% 3-mercaptopropionic acid) was added to the resin-containing flask at room temperature and stirred for 2 hours.

[0388] 3) Precipitate the peptide in cold isopropyl ether (350 mL). Filter the mixture and precipitate with isopropyl ether (350 mL). 2) Washing the crude peptide. After vacuum drying for 2 hours, the crude peptide was obtained, yielding compound 8 (2.40 g). The peptide was analyzed by LCMS (R...). t = 1.596 min, MS calculated value: 2542.07, MS observed value: [M+2H] 2+ = 1271.9) Analysis confirms the structure.

[0389]

[0390] To a solution of compound 8 (2.40 g, 944 μmol, 1.00 eq, TFA salt) and TATA (224 mg, 896 μmol, 0.95 eq) in H₂O (1400 mL) and ACN (600 mL), 1 M NH₄HCO₃ aqueous solution was added until pH = 8–9. The reaction was stirred at 25 °C for 30 min. The reaction was monitored by LCMS (Reflectance Spectrometry). t = 1.406 min). The crude peptide was purified by preparative HPLC (0.075% TFA; 30 °C, solvent A: 0.075% TFA / H2O, solvent B: CH3CN) to give compound 9 (200 mg, 71.6 μmol, yield 8.3%, TFA salt) as a white solid. The plasma was further purified by LCMS (R... t = 1.411 minutes, MS calculated value: 2791.34, MS observed value: [M+2H] 2+ = 1396.5) and HPLC (R t = 12.170 minutes) Analysis confirms the structure.

[0391] Purification conditions:

[0392]

[0393] DIEA (27.7 mg, 215 μmol, 37.4 μL, 3.00 eq) was added to a solution of compound 9 (200 mg, 71.6 μmol, 1.00 eq, TFA salt) and MPa(Trt)-OSu (76.5 mg, 172 μmol, 2.40 eq) in DMF (0.50 mL). The reaction was stirred at 25°C for 30 min. The reaction was measured by LC-MS (R t = 1.677 minutes) for analysis and monitoring. Next, the mixture was precipitated in cold isopropyl ether (50.0 mL). The mixture was filtered, and the crude product was washed twice with isopropyl ether (50.0 mL). The crude peptide was dried under vacuum for 0.5 hours to give 0.20 g of compound 10. Next, 5.0 mL of lysis buffer (90.0% TFA / 10.0% H2O) was added to the flask containing compound 10, and the mixture was stirred for 0.3 hours. The peptide was precipitated in cold isopropyl ether (50.0 mL). The mixture was filtered, and the crude product was washed twice with isopropyl ether (50.0 mL). The crude peptide was dried under vacuum for 0.5 hours to give 0.15 g of crude peptide. Analyzed by LCMS (R t = 1.456 min) to confirm the structure. The crude peptide was purified by preparative HPLC (0.075% TFA; 30℃, solvent A: 0.075% TFA / H2O, solvent B: CH3CN) to give compound 11 (78.0 mg, 26.3 μmol, yield 39.0%, TFA salt), as a white solid. The structure was further confirmed by LCMS (R...). t = 1.242 minutes, MS calculated value: 2967.59, MS observed value: [M+2H] 2+ = 1484.2) and HPLC (R t = 11.844 minutes) Analysis confirmed the structure.

[0394] Purification conditions:

[0395]

[0396] DIEA (0.87 mg, 6.74 μmol, 9.09 μL, 3.00 eq) was added to a solution of compound 11 (10.0 mg, 3.37 μmol, 1.00 eq, TFA salt) and MC-EVA-PABC-Exa (7.98 mg, 7.41 μmol, 2.00 eq) in DMF (0.10 mL). The mixture was stirred at 25°C for 10.0 min. The reaction was monitored by LCMS (R t = 1.832 min). The crude peptide was purified by preparative HPLC (0.075% TFA; 30℃, solvent A: 0.075% TFA / H2O, solvent B: CH3CN) to give E2025 (8.70 mg, 1.70 μmol, yield 50.4%, purity 94.0%, TFA salt), as a white solid. The residue was further purified by LCMS (R... t =1.61 minutes, MS calculated value: 5121.85, MS observed value: [M+3H] 3+ = 1708.2) and HPLC(R t = 10.535 minutes) Analysis confirmed the structure.

[0397] Purification conditions:

[0398] The compounds in Table 5 were prepared using the same general procedure, and these compounds were separated in the following amounts and purities: Compounds Table 5

[0399] Analysis conditions:

[0400] The compounds in Table 5A were prepared using the same general procedure, and these compounds were analyzed using the methods described above and separated in the following quantities and purities: Compound Table 5A

[0401] Analysis conditions:

[0402] The compounds in Table 5B were prepared using the same general procedure, and these compounds were analyzed using the methods described above and separated in the following amounts and purities: Compounds Table 5B

[0403] Analysis conditions:

[0404] The compounds in Table 5C were prepared using the same general procedure, and these compounds were analyzed using the methods described above and separated in the following amounts and purities: Compound Table 5C

[0405] Analysis conditions:

[0406] The compounds in Table 5D were prepared using the same general procedure, and these compounds were analyzed using the methods described above and separated in the following quantities and purities: Compound Table 5D

[0407] Analysis conditions:

[0408] The compounds in Table 5E were prepared using the same general procedure, and these compounds were analyzed using the methods described above and separated in the following quantities and purities: Compound Table 5E

[0409] Structure: Table A

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679] Table B

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726] SPR data, LCMS data, and methods:

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755] HPLC data and methods:

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803] Several embodiments of the invention have been described. However, it should be understood that various modifications can be made without departing from the spirit and scope of the invention. Therefore, other embodiments are within the scope of the following claims.

Claims

1. Compounds of formula (I): (I) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: R is -C(O)C 1-6 Alkyl or -C(O)C 1-6 Halogenated alkyl groups, such as Ac; R 1a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 1-1 and R 1-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; Or R 1-1 and R 1-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 1-1 and R 1a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; n = 0 or 1; R 2a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 2x and R 2y Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; Or R 2x and R 2y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 3a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 3-1 and R 3-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN or OR. a ; Or R 3-1 and R 3-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 3-1 and R 3a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; X3 is selected from O or S; R 4a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 4-1 and R 4-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 4-1 and R 4-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 4-1 and R 4a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 5a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 5-1 and R 5-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 5-1 and R 5-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4- to 8-membered heterocyclic groups; or R 5-1 and R 5a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 6a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 6-1 and R 6-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 6-1 and R 6-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 6-1 and R 6a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 7a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 7-1 and R 7-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; Or R 7-1 and R 7a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R8 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 9x and R 9y Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; Or R 9x and R 9y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 10 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, OR a NO2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)₂OH, NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 11-1 and R 11a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 12 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl or C 6-10 aryl; which is optionally substituted with 1, 2, 3 or more halogens, OR a SR a NMe3 + NHAc, NHR a ,NHC(O)CH2NR b R c , NHC(O)NH2, NHC(=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13-1 and R 13-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; Or R 13-1 and R 13-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 13-1 and R 13a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 14a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 14-1 and R 14-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 cycloalkyl, 4- to 8-membered heterocyclic groups, biphenyl, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl group or 5 to 10 heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN, OH, NO2, -C 0-6 Alkylene-C(O)OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 6-10 Aryl; Or R 14-1 and R 14-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 15 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 16x and R 16y Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; Or R 16x and R 16y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; Y is selected from OH, NH2, or the following amino acids: Gly, Ala, Aib, Glu, Pro, D-Ala, Ahx (aminocaproic acid), Asp, D-Glu, D-Pro and D-Asp; preferably, OH, or the following amino acids: Gly, Ala, D-Ala and D-Pro; Each X is independently selected from C(O), S(O), or S(O)2; Where R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

2. The compound of formula (I) according to claim 1: (I) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: R is -C(O)C 1-6 Alkyl or -C(O)C 1-6 Halogenated alkyl groups, such as Ac; R 1a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 1-1 and R 1-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 1-1 and R 1-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 1-1 and R 1a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; n = 0 or 1; R 2a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 2x and R 2y Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 2x and R 2y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 3a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 3-1 and R 3-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN or OH; Or R 3-1 and R 3-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 3-1 and R 3a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; X3 is selected from O or S; R 4a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 4-1 and R 4-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 4-1 and R 4-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 4-1 and R 4a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 5a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 5-1 and R 5-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OH, SR a NH2, NHC (=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH groups, or C groups. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 5-1 and R 5-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 4- to 8-membered heterocyclic groups; or R 5-1 and R 5a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 6a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 6-1 and R 6-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 6-1 and R 6-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 6-1 and R 6a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 7a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 7-1 and R 7-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; Or R 7-1 and R 7a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R8 is selected from H and C. 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 9x and R 9y Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 9x and R 9y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 10 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, OR a NO2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 11 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)₂OH, NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 11-1 and R 11a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 12 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 6-10 aryl; which is optionally substituted with 1, 2, 3 or more halogens, OR a SR a NMe3 + NHAc, NHR a , NHC(O)NH2, NHC(=NH)NH2, C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 13-1 and R 13-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; Or R 13-1 and R 13-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; or R 13-1 and R 13a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; R 14a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 14-1 and R 14-2 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a S(O)R a S(O)2R a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclic groups, biphenyl, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl group or 5 to 10 heteroaryl group is further optionally substituted with 1, 2, 3 or more halogens, CN, OH, NO2, -C 0-6 Alkylene-C(O)OR a C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 6-10 Aryl; Or R 14-1 and R 14-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; R 15 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a SR a NHAc, NHR a ,NHC(=NH)NH2,C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic groups, C 6-10 The aryl or 5- to 10-membered heteroaryl groups are further optionally substituted with 1, 2, 3 or more halogens, OH, NO2, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 16x and R 16y Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R 16x and R 16y Together with the atoms they are attached to, they form C 3-8 cycloalkyl; Y is selected from OH, NH2, or the following amino acids: Gly, Ala, Glu, D-Ala, Ahx (aminocaproic acid), Asp, D-Glu, and D-Asp; Each X is independently selected from C(O), S(O), or S(O)2; Where R a R b and R c Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R b and R c Together with the atoms they are attached to, they form 4 to 8-membered heterocyclic groups.

3. The compound of formula (I) according to claim 1 or 2, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a For H.

4. A compound of formula (I) according to any one of claims 1 to 3, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 1-2 For H and R 1-1 C 1-6 Alkyl groups, such as Me; or R 1-1 and R 1-2 Together with the atoms they are attached to, they form C 3-6 Cycloalkyl groups, such as cyclopropyl groups.

5. A compound of formula (I) according to any one of claims 1 to 4, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 2a For H.

6. The compound of formula (I) according to any one of claims 1 to 5, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein n=1.

7. The compound of formula (I) according to any one of claims 1 to 5, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein n = 0.

8. A compound of formula (I) according to any one of claims 1 to 7, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 3a Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, such as Me.

9. A compound of formula (I) according to any one of claims 1 to 7, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 3a For H.

10. A compound of formula (I) according to any one of claims 1 to 9, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 3-1 and R 3-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OH or SR. a Or R 3-1 and R 3-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl, preferably C 5-6 cycloalkyl; preferably, R 3-2 For H and R 3-1 It is a side chain of Leu, Ile, Thr or Val, preferably a side chain of Leu or Val, preferably a side chain of Leu; Preferably, R 3-1 and R 3-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more OH groups; preferably, R 3-2 For H and R 3-1 It is a side chain of Leu, Ile, or Thr.

11. The compound of formula (I) according to any one of claims 1 to 10, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein X3 is S.

12. A compound of formula (I) according to any one of claims 1 to 11, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 4a For H.

13. A compound of formula (I) according to any one of claims 1 to 12, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 4-1 and R 4-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 5 to 10 heteroaryl groups; preferably, R 4-1 and R 4-2 One of them is H and the other is a Trp sidechain; preferably, R 4-2 For H and R 4-1 It is a sidechain of Trp.

14. A compound of formula (I) according to any one of claims 1 to 13, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 5a For H.

15. A compound of formula (I) according to any one of claims 1 to 14, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 5-1 and R 5-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl groups, preferably all C10 ... 1-4 Alkyl or C 1-4 Halogenated alkyl groups, such as Me; or R 5-1 and R 5-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl, preferably C 4-6 Cycloalkyl.

16. A compound of formula (I) according to any one of claims 1 to 15, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 6a For H.

17. A compound of formula (I) according to any one of claims 1 to 16, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 6-1 and R 6-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more OH groups; preferably, R 6-1 and R 6-2 One of them is H and the other is a Ser side chain; preferably, R 6-2 For H and R 6-1 It is a sidechain of Ser.

18. A compound of formula (I) according to any one of claims 1 to 17, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 7a For H.

19. A compound of formula (I) according to any one of claims 1 to 18, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 7-1 and R 7-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more OH, C(O)OR a or C(O)NR b R c Or R 7-1 and R 7a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups; preferably, R 7-1 and R 7-2 One of them is H and the other is a side chain of Asp, Thr, or Glu; Preferably, R 7-1 and R 7-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more C(O)OR a or C(O)NR b R c Or R 7-1 and R 7a Together with the atoms they are attached to, they form 4- to 8-membered heterocyclic groups, such as pyrrolidinyl groups; preferably, R 7-2 For H and R 7-1 It is a side chain of Asp or Glu; preferably an Asp side chain.

20. A compound of formula (I) according to any one of claims 1 to 19, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R8 is selected from C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a or SR a Preferably, R8 is a side chain of Ile, Leu, or Met; preferably, it is a side chain of Ile or Leu.

21. A compound of formula (I) according to any one of claims 1 to 20, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more C(O)OR a or C(O)NR b R c Preferably, R 10 For the side chain of Gln, preferably, R 10 It has S-chirality.

22. A compound of formula (I) according to any one of claims 1 to 21, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 11a For H.

23. A compound of formula (I) according to any one of claims 1 to 22, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more halogens, OR a C(O)OR a or C(O)NR b R c Preferably, R 11 Side chains of Val, Glu, Ile, Ser, or Thr, preferably side chains of Val, Ile, Ser, or Thr, preferably side chains of Val, Glu, Ile, or Thr, preferably side chains of Val or Ile; preferably, R 11 The side chain is Glu, Val, or Ser, preferably a side chain of Glu or Val, and R is a side chain of Glu. 7-1 and R 7a Together with the atoms they are attached to, they form pyrrolidinyl groups; preferably, R 11 It has S-chirality.

24. A compound of formula (I) according to any one of claims 1 to 23, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 12 Selected from C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 5 to 10 heteroaryl groups; preferably, R 12 It is a side chain of Leu, Val, or His, preferably a side chain of Leu or Val; preferably, R 12 It has S-chirality.

25. A compound of formula (I) according to any one of claims 1 to 23, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 12 Selected from C 2-6 alkynyl or C 2-6 Halogenated alkynyl group.

26. A compound of formula (I) according to any one of claims 1 to 25, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 13a For H.

27. A compound of formula (I) according to any one of claims 1 to 26, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 13-1 and R 13-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 1, 2, 3 or more OH groups; preferably, R 13-2 For H and R 13-1 It is a sidechain of Ser.

28. A compound of formula (I) according to any one of claims 1 to 27, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 14a For H.

29. A compound of formula (I) according to any one of claims 1 to 28, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 14-1 and R 14-2 Independently selected from H and C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 5 to 10 heteroaryl groups; or R 14-1 and R 14-2 Together with the atoms they are attached to, they form C 3-8 cycloalkyl; Preferably, R 14-2 It is H or Me, preferably Me and R 14-1 It is a side chain of Val or Ile; preferably a side chain of Val.

30. A compound of formula (I) according to any one of claims 1 to 29, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 15 Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; optionally substituted with 5 to 10 heteroaryl groups; preferably, R 15 It is a side chain of Trp; preferably, R 15 It has S-chirality.

31. A compound of formula (I) according to any one of claims 1 to 30, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Y is OH.

32. The compound of formula (I) according to any one of claims 1 to 31, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein X is C(O).

33. The compound of formula (I) according to claim 1 or 2, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from those in Table A.

34. Compound of formula (II): (II) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key, , (-(Sar) p -) (-(Ser) q -) (-(Sar-Ser) w -) (-(Ser-Sar) w -) or -C(O)-4 to 11-membered subheterocyclic group- (wherein the subheterocyclic group is connected to L2); L2 is selected from the bond, -(CH2CH2O). m1 CH2C(O)- (where C(O)- is attached to L3) or -C(O)CH2(OCH2CH2) m1 NH- (where NH- is attached to L3); L3 is selected from the bond, -NH(CH2CH2O). m2 CH2C(O)- (where C(O)- is attached to L4), -C(O)CH2(OCH2CH2) m2 NH- (where NH- is attached to L4) or -Glu-C(O)CH2(OCH2CH2) m2 NH-, where Glu is ; L4 is selected from the key, (-Lys(L5)-L5-) or ; L5 is selected from key, , -C(O)CH2(OCH2CH2) m3 NH- (where NH- is attached to L6 or L) or -C(O)(CH2) m3 NH- (where NH- is connected to L6 or L); L6 is selected from the bond, -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-), where each S- is linked to a cleavable linker; L stands for -C(O)(CH2). m4 C(O)OH; Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; w = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m4 = 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24; The cleavable linker is selected from the following: , , , , , , , , , , , , , , , , , , , , ,and ； Among them, each of the above groups is connected to L6 on the left and to the payload on the right; p1 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p2 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p3 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors. And the other variables are defined in any one of claims 1 to 33.

35. The compound of formula (II) according to claim 34: (II) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key, , (-(Sar) p -) (-(Ser) q -) (-(Sar-Ser) w -) (-(Ser-Sar) w -) or -C(O)-4 to 11-membered subheterocyclic group- (wherein the subheterocyclic group is connected to L2); L2 is selected from the bond, -(CH2CH2O). m1 CH2C(O)- (where C(O)- is attached to L3) or -C(O)CH2(OCH2CH2) m1 NH- (where NH- is attached to L3); L3 is selected from the bond, -NH(CH2CH2O). m2 CH2C(O)- (where C(O)- is attached to L4), -C(O)CH2(OCH2CH2) m2 NH- (where NH- is attached to L4) or -Glu-C(O)CH2(OCH2CH2) m2 NH-, where Glu is ; L4 is selected from the key, (-Lys(L5)-L5-) or ; L5 is selected from key, , -C(O)CH2(OCH2CH2) m3 NH- (where NH- is attached to L6 or L) or -C(O)(CH2) m3 NH- (where NH- is connected to L6 or L); L6 is selected from the bond, -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-), where each S- is linked to a cleavable linker; L stands for -C(O)(CH2). m4 C(O)OH; Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; w = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m4 = 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24; The cleavable linker is selected from the following: , , , , , , , , , , , , , , , , , , , , ,and ； Among them, each of the above groups is connected to L6 on the left and to the payload on the right; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors. And the other variables are defined in any one of claims 1 to 33.

36. The compound of formula (II) according to claim 34: (II) Or its stereoisomers, tautomers, stable isotopes, or prodrugs, or pharmaceutically acceptable salts thereof, wherein: The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key, (-(Sar) p -) (-(Ser) q -) (-(Sar-Ser) w -) or -C(O)-4 to 11-membered heterocyclic groups-; L2 is selected from the bond or -C(O)CH2(OCH2CH2). m1 NH-; L3 is selected from the bond, -C(O)CH2(OCH2CH2). m2 NH- or -Glu-C(O)CH2(OCH2CH2) m2 NH-, where Glu is ; L4 is selected from key or (-Lys(L6)-L5-); L5 is selected from the bond or -C(O)(CH2). m3 NH-; L6 is selected from -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-); Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; w = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and each -S- in L6 is connected to a splittable connection base - payload; The cleavable linker is selected from the following: , , , , , , , , , , , , , , , , ,and ； Among them, each of the above groups is connected to L6 on the left and to the payload on the right; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors. And the other variables are defined in any one of claims 1 to 33.

37. The compound of formula (II) according to any one of claims 34 to 36, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein m = 1, 2, 3, 4, 5 or 6; preferably, m = 2, 3, or 4; preferably, m = 3.

38. The compound of formula (II) according to any one of claims 34 to 37, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein m1 = 1, 2, 3 or 4; preferably, m1 = 2 or 3; preferably, m1 = 2.

39. The compound of formula (II) according to any one of claims 34 to 38, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein m2 = 1, 2, 3 or 4; preferably, m2 = 2 or 3; preferably, m2 = 2.

40. The compound of formula (II) according to any one of claims 34 to 39, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein m3 = 3, 4, 5, 6 or 7; preferably, m3 = 4, 5 or 6; preferably, m3 = 5.

41. The compound of formula (II) according to any one of claims 34 to 40, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein m4 = 10, 11, 12, 13, 14, 15, 16, 17 or 18; preferably, m4 = 12, 13, 14, 15 or 16; m4 = 13, 14 or 15; preferably, m4 = 14.

42. A compound of formula (II) according to any one of claims 34 to 41, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from a bond or (-(Sar) p -), where p = 1, 2 or 3.

43. A compound of formula (II) according to any one of claims 34 to 41, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the -C(O)-4 to 11-membered heterocyclic group is selected from: , , or , where a=0, 1, 2, 3 or 4, b=0, 1, 2, 3 or 4, c=0, 1, 2, 3 or 4, d=0, 1, 2, 3 or 4, and a+b=2, 3, 4, 5, 6, 7 or 8, c+d=2, 3, 4, 5, 6, 7 or 8.

44. The compound of formula (II) according to any one of claims 34 to 43, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein L2 is selected from bond or -C(O)CH2(OCH2CH2). m1 NH-.

45. The compound of formula (II) according to any one of claims 34 to 44, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein L3 is selected from bond or -C(O)CH2(OCH2CH2). m2 NH-.

46. ​​A compound of formula (II) according to any one of claims 34 to 45, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein L4 is selected from a bond or .

47. A compound of formula (II) according to any one of claims 34 to 46, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein L5 is selected from bond or -C(O)(CH2). m3 NH-.

48. The compound of formula (II) according to any one of claims 34 to 47, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein L6 is selected from the bond or -C(O)CH2CH2S-.

49. A compound of formula (II) according to any one of claims 34 to 48, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the spacer group is selected from: -C(O)-4 to 11-membered heterocyclic group-C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2) m3 NH-C(O)CH2CH2S-、 -C(O)-4 to 11-membered heterocyclic group-C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-、 -(Sar) p -C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2) m3 NH-C(O)CH2CH2S-、 -(Sar) p -C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -(Sar) p -C(O)CH2(OCH2CH2) m1 NH-Glu-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -(Sar) p -C(O)(CH2) m3 NH-C(O)CH2CH2S-, -C(O)CH2(OCH2CH2) m1 NH-Glu-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, and C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2) m3 NH-C(O)CH2CH2S-; Preferably, the spacer base is selected from the following: -C(O)-7 to 11-membered bicyclic heterocyclic group-C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2)5NH-C(O)CH2CH2S-, -C(O)-7 to 11-membered bicyclic heterocyclic group-C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -(Sar) p -C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2)5NH-C(O)CH2CH2S-、 -(Sar) p -C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -Sar-C(O)CH2(OCH2CH2) m1 NH-Glu-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2)5NH-C(O)CH2CH2S-、 -(Sar) p -C(O)CH2(OCH2CH2) m1 NH-Glu-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -(Sar) p -C(O)(CH2)5NH-C(O)CH2CH2S-, -C(O)CH2(OCH2CH2) m1 NH-Glu-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, and C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2)5NH-C(O)CH2CH2S-; Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 1, 2, 3 or 4; m2 = 1, 2, 3 or 4; and -C(O)-7 to 11-membered bicyclic subheterocyclic groups are selected from the following: or Where a = 0, 1, 2, 3 or 4, b = 0, 1, 2, 3 or 4, c = 0, 1, 2, 3 or 4, d = 0, 1, 2, 3 or 4, and a+b = 2, 3, 4, 5, 6, 7 or 8, c+d = 2, 3, 4, 5, 6, 7 or 8; preferably, the 7- to 11-membered bicyclic subheterocyclic groups are selected from the following: , , , , , , , ,and ; Preferably, the spacer base is selected from the following: -Sar-C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)(CH2)5NH-C(O)CH2CH2S-、 -Sar-C(O)CH2(OCH2CH2) m1 NH-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, -Sar-C(O)CH2(OCH2CH2) m1 NH-Glu-C(O)CH2(OCH2CH2) m2 NH-C(O)CH2CH2S-, and -(Sar) 10 -C(O)(CH2)5NH-C(O)CH2CH2S-。 50. A compound of formula (II) according to any one of claims 34 to 49, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the cleavable linker is selected from: , , , ,and ； Preferably selected from the following: , ,and ； Preferably .

51. The compound of formula (II) according to claim 34, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key, (-(Sar) p -)or (-(Ser) q -); L2 is selected from the bond or -C(O)CH2(OCH2CH2). m1 NH- (where NH- is attached to L3); L3 is selected from the bond or -C(O)CH2(OCH2CH2). m2 NH- (where NH- is connected to L4); L4 is selected from key or (-Lys(L5)-L5-); L5 is selected from the bond, -C(O)CH2(OCH2CH2). m3 NH- (where NH- is attached to L6 or L) or -C(O)(CH2) m3 NH- (where NH- is connected to L6); L6 is selected from the bond, -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-), where each S- is linked to a cleavable linker; Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The cleavable linker is selected from the following: , , , , , , , , , , , , , ,and ； in, The above groups are connected to L6 on the left and to the payload on the right; p1 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p2 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p3 = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors. And the other variables are defined in any one of claims 1 to 33.

52. The compound of formula (II) according to claim 34, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key, (-(Sar) p -)or (-(Ser) q -); L2 is selected from the bond or -C(O)CH2(OCH2CH2). m1 NH- (where NH- is attached to L3); L3 is selected from the bond or -C(O)CH2(OCH2CH2). m2 NH- (where NH- is connected to L4); L4 is selected from key or (-Lys(L5)-L5-); L5 is selected from the bond, -C(O)CH2(OCH2CH2). m3 NH- (where NH- is attached to L6 or L) or -C(O)(CH2) m3 NH- (where NH- is connected to L6); L6 is selected from the bond, -C(O)CH2CH2S-, (-Cys'-) or (-Cys-C(O)CH2CH2S-), where each S- is linked to a cleavable linker; Where p = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The cleavable linker is selected from the following: , , , , , , , , , , , , , ,and ； in, The above groups are connected to L6 on the left and to the payload on the right; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors. And the other variables are defined in any one of claims 1 to 33.

53. The compound of formula (II) according to claim 34, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key or (-(Sar) p -); L2 is selected from the bond or -C(O)CH2(OCH2CH2). m1 NH- (where NH- is attached to L3); L3 is selected from the bond or -C(O)CH2(OCH2CH2). m2 NH- (where NH- is connected to L4); L4 is selected from key or (-Lys(L5)-L5-); L5 is selected from the bond or -C(O)(CH2). m3 NH- (where NH- is connected to L6); L6 is selected from the bond or -C(O)CH2CH2S-; Where p = 1, 2 or 3; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The cleavable linker is selected from the following: , , , ,and ； in, The above groups are connected to L6 on the left and to the payload on the right; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors. And the other variables are defined in any one of claims 1 to 33.

54. The compound of formula (II) according to claim 34, or a stereoisomer, tautomer, stable isotope, or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein The spacer bases are -L1-L2-L3-L4-L5-L6-, where L1 is selected from key or (-(Sar) p -); L2 is selected from the bond or -C(O)CH2(OCH2CH2). m1 NH- (where NH- is attached to L3); L3 is selected from the bond or -C(O)CH2(OCH2CH2). m2 NH- (where NH- is connected to L4); L4 is selected from key or (-Lys(L5)-L5-); L5 is selected from the bond or -C(O)(CH2). m3 NH- (where NH- is connected to L6); L6 is selected from the bond or -C(O)CH2CH2S-; Where p = 1, 2 or 3; m1 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m2 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m3 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The cleavable linker is selected from the following: , , , ,and ； in, The above groups are connected to L6 on the left and to the payload on the right; The payload is an antitumor agent, for example, selected from topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, DNA alkylating agents, transcription inhibitors, Bcl-xL inhibitors, or tyrosine kinase inhibitors. And the other variables are defined in any one of claims 1 to 33.

55. The compound of formula (II) according to any one of claims 34 to 54, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein the payload is a topoisomerase 1 inhibitor based on camptothecin compounds and non-camptothecin compounds, such as eczemab, delutec and its derivatives, SN38, belotecone and its derivatives, or a topoisomerase 2 inhibitor, such as doxorubicin, or a DNA alkylating agent, such as calichimycin, pyrrolobenzodiazepines (PBD), indolinobenzodiazepines (IGN), or cyclopropylbenzoindolone (CBI); Preferably, the payload is selected from the following: , , ,and ; Preferably, the payload is selected from the following: or .

56. The compound of formula (II) according to claim 34, or a stereoisomer, tautomer, stable isotope, or prodrug, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from those in Table B.

57. A pharmaceutical composition comprising: The compound according to any one of claims 1 to 56, or a stereoisomer, tautomer, stable isotope variant or prodrug thereof, or a pharmaceutically acceptable salt thereof; Pharmaceutically acceptable excipients; and Optionally, one or more other therapeutic agents, such as RAS inhibitors, RTK inhibitors, EGFR inhibitors, DNA repair inhibitors, immune checkpoint inhibitors such as PD-1 or PD-L1 inhibitors, etc.

58. A reagent kit comprising: The first container contains a compound according to any one of claims 1 to 56, or a stereoisomer, tautomer, stable isotope variant or prodrug thereof, or a pharmaceutically acceptable salt thereof. as well as Optionally, a second container contains one or more other therapeutic agents; as well as Optionally, a third container contains pharmaceutically acceptable excipients for diluting or suspending the compound and / or other therapeutic agents, wherein the other therapeutic agents are, for example, RAS inhibitors, RTK inhibitors, EGFR inhibitors, DNA repair inhibitors, immune checkpoint inhibitors such as PD-1 or PD-L1 inhibitors, etc.

59. Use of the compound or stereoisomer, tautomer, stable isotope variant or prodrug of any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating EGFR-mediated diseases.

60. The compound of any one of claims 1 to 56, or a stereoisomer, tautomer, stable isotope variant or prodrug thereof, or a pharmaceutically acceptable salt thereof, for the treatment of EGFR-mediated diseases.

61. A method for treating EGFR-mediated disease in a subject in need, comprising administering to the subject a compound according to any one of claims 1 to 56, or a stereoisomer, tautomer, stable isotope variant, or prodrug thereof, or a pharmaceutically acceptable salt thereof.

62. The use as described in claim 59, the compound used as described in claim 60, or the method as described in claim 61, wherein the EGFR-mediated disease is cancer.

63. The use or compound or method of claim 62, wherein the cancer is a solid tumor or a leukemia.

64. The use or compound or method of claim 62 or 63, wherein the cancer is selected from lung cancer, esophageal cancer, gastric cancer, colon cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, breast cancer, brain cancer, glioblastoma (GBM), kidney cancer, liver cancer, mesothelioma, prostate cancer, sarcoma, testicular cancer, thyroid cancer, uterine cancer, bile duct cancer, thyroid cancer, skin cancer, uveal melanoma; leukemia, malignant lymphoma, and multiple myeloma.

65. The use or compound or method of claim 62 or 63, wherein the cancer is head and neck cancer, biliary tract cancer, nasopharyngeal carcinoma, non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, endometrial cancer, cervical cancer, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphoblastic leukemia), CLL (chronic lymphoblastic leukemia), Hodgkin lymphoma, and non-Hodgkin lymphoma.

66. The use or compound or method of any one of claims 62-65, wherein the cancer is associated with EGFR overexpression (by mRNA or protein); EGFR gene abnormalities (gene copy number amplification or mutation in a codon region); or EGFR pathway overactivation.

67. The use or compound or method of any one of claims 62-66, wherein the cancer is resistant to a known EGFR inhibitor (small molecule or antibody).

68. The use of any one of claims 59-67 or the compound or method of use, comprising the use of other therapeutic agents, such as RAS inhibitors, RTK inhibitors, EGFR inhibitors, DNA repair inhibitors, immune checkpoint inhibitors such as PD-1 or PD-L1 inhibitors, etc.

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