Cyclic peptide compound, pharmaceutical composition and use thereof

Abstract

Provided are a cyclic peptide compound, a pharmaceutical composition and a use thereof. Provided is the use of the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or the pharmaceutical composition or a pharmaceutical formulation thereof in the preparation of drugs, especially drugs for diagnosing, preventing or treating diseases or conditions related to GPC3 activity.

Description

Cyclic peptide compounds, pharmaceutical compositions and their applications

[0001] This application is based on and claims priority to the following fourteen Chinese patent applications, the contents of which are incorporated herein by reference in their entirety:

[0002] Chinese patent application with application number 2024119862047 and application date of December 31, 2024;

[0003] Chinese patent application with application number 2025100282627 and application date of January 8, 2025;

[0004] Chinese patent application with application number 2025100593880 and application date of January 14, 2025;

[0005] Chinese patent application with application number 2025102316755 and application date of February 28, 2025;

[0006] Chinese patent application with application number 2025103050693 and application date of March 14, 2025;

[0007] Chinese patent application with application number 2025103766735 and application date of March 27, 2025;

[0008] Chinese patent application with application number 2025104527017 and application date of April 11, 2025;

[0009] Chinese patent application with application number 2025106299195 and application date of May 15, 2025;

[0010] Chinese patent application with application number 2025108840180 and application date of June 27, 2025;

[0011] Chinese patent application with application number 2025110760521 and application date of August 1, 2025;

[0012] Chinese patent application with application number 2025113039436 and application date of September 12, 2025;

[0013] Chinese patent application with application number 2025115810103 and application date of October 31, 2025;

[0014] Chinese patent application with application number 2025118413492 and application date of December 8, 2025;

[0015] Chinese patent application with application number 2025119988976 and application date of December 26, 2025. Technical Field

[0016] This invention relates to the field of radiopharmaceutical technology. This document provides cyclic peptide compounds targeting GPC3, and also relates to their radionuclide markers, pharmaceutical compositions, and medical applications. Background Technology

[0017] Phosphatidylinositol proteoglycan 3 (GPC3) is a heparan sulfate proteoglycan containing a 580-amino acid core protein and two C-terminal HS chains. The GPC3 core protein is anchored to the cell membrane surface via glycosylphosphatidylinositol (GPI) and can be cleaved into an approximately 40 kDa N-terminal soluble protein (sGPC3) and a 30 kDa C-terminal membrane protein (Takahiro Nishida, Hiroaki Kataoka. Glypican3-Targeted Therapy in Hepatocellular Carcinoma, Cancers 2019, 11(9), 1339).

[0018] GPC3 regulates cell proliferation signaling by binding to growth factors such as Wnt, fibroblast growth factor, and insulin-like growth factor, playing a crucial role in embryonic cell proliferation and differentiation. The GPC3 gene is located on the X chromosome (Xq26) and shows high homology between humans and mice. Mutations and deletions in the GPC3 gene lead to gigantism with various malformations in humans and Simpson-Golabi-Behmel syndrome, with similar phenotypes observed in mice.

[0019] On the surface of tumor cells, GPC3 recruits heparin-binding growth factors (fibroblast growth factor and hepatocyte growth factor) and presents them to corresponding receptors on the cell membrane, thereby activating the ERK and AKT signaling pathways and exerting its tumor regulatory role. Furthermore, GPC3 recruits Wnt to Frizzleed via its HS side chain on the cell surface, thereby activating the downstream Wnt signaling pathway. Subsequently, activation of the ERK, AKT, and Wnt pathways promotes the transcription of a series of oncogenes, including c-Myc (Yong le Wu, Hui Liu, Hui guo Ding. GPC-3 in hepatocellular carcinoma: current perspectives, J Hepatocell Carcinoma. 2016; 3:63–67.).

[0020] GPC3 is significantly expressed throughout the fetal period. From birth to adulthood, except for weak expression in the placenta, mammary gland, mesoderm, ovary, lung, and kidney tissues, it is almost not expressed or expressed at low levels in other tissues (Yukihiro Haruyama, Hiroaki Kataoka, Glypican-3 is a prognostic factor and an immunotherapeutic target in hepatocellular carcinoma. World J Gastroenterol. 2016 Jan 7; 22(1):275–283). GPC3 is specifically expressed in tumors such as hepatocellular carcinoma and uterine carcinosarcoma (Yasuhiro Shimizu, Toshihiro Suzuki, Toshiaki Yoshikawa, Itaru Endo, Tetsuya Nakatsura. Next-Generation Cancer Immunotherapy Targeting Glypican-3. Front Oncol. 2019; 9:248.). It is particularly highly expressed in hepatocellular carcinoma, showing a significant difference in expression compared to normal or adjacent tissues. The types of drugs developed for the GPC3 target include antibodies (mono / bi / triple antibodies, nanobodies), ADCs, RDCs, and cell therapies (CAR-T, CAR-NK). Monoclonal antibodies have progressed the fastest to Phase II, but the primary endpoint was not reached in Phase II, and the efficacy was poor.

[0021] In summary, GPC3 is an attractive selective target for liver cancer, and there is a need to develop novel and highly effective peptide-conjugated radionuclide drugs to meet clinical needs.

[0022] Summary of the Invention

[0023] This invention provides a cyclic peptide compound and its radionuclide label, which has one or more of the following advantages: novel structure; can be used for targeted diagnosis and / or treatment of diseases involving abnormal cell proliferation (e.g., tumors); high stability; and good pharmacokinetic properties. Another object of this invention is to provide a pharmaceutical composition and the pharmaceutical application of the above-mentioned compound or pharmaceutical composition.

[0024] The first aspect of this invention provides a ligand compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, said compound having the structure of formula (I02):

[0025] in:

[0026] X 1 X3 and X 5 Each is independently selected from N and CH, preferably X. 1 and X 3 Each is independently selected from N and CH, X 5 Selected from CH;

[0027] X 6 and X 7 Each is independently selected from N and CH, preferably X. 6 and X 7 Both are CH, or X 6 Selected from CH, X 7 Selected from N;

[0028] X 2 Selected from -CR t1 R t2 -, -CH2CR t1 R t2 -, -NH- and -N(CH3)-;

[0029] R 1 R 4 R 8 R 10 Each is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 The cycloalkyl groups are optionally each selected independently by one or more elements chosen from D, halogen, -OH, -CN, -CONR. 12 R 13 Substitution with -COOH substituents;

[0030] R 2 and R 6 Each is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6Each cycloalkyl group is optionally surrounded by one or more elements independently selected from halogens, D, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0031] R 3 and R 5 Each is independently selected from H, D, halogens, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. c Replace; or R 3 and R5 Together with the atoms it is attached to, they form 7-18 membered heterocyclic groups;

[0032] R 7 Selected from H, D, halogens, -OH, -CN, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 -OR 14 -OC(=O)R 14 -OP(=O)(OR) 13 (OR) 14 -P(=O)(OR) 13 (OR) 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -L 1 -C 3-8 cycloalkyl-, -L 1 -(3-8 membered heterocyclic group)-, -L 1 -C 6-10 Aryl- and -L 1 -(5-10 heteroaryl)-, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. d replace;

[0033] L1 Selected from C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S-, -NH- and -N(CH3)-;

[0034] R 9 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected halogens, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, -SO2R 14 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of haloalkyl groups;

[0035] R′ and R″ are each independently selected from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH;

[0036] R 11a and R 11Each is independently selected from H, D, OH, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl groups, amino acid residues, and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl group, amino acid residue, and 3-8 membered heterocyclic group are each optionally selected independently from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substitution by haloalkoxy groups, -OH, -NH2-, -CN, -COOH, and -CONH2; or R 11a and R 11 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally composed of one or more atoms independently selected from H, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 and -OC(=O)R 14 Substituents of the substituents;

[0037] R t1 and R t2 Each independently selected from H, D, C 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 Deuterated alkyl; or R t1 and R t2 Together with the atoms it is attached to, they form C 3-6 cycloalkyl;

[0038] R 12 and R 13 Each occurrence is independently selected from H, D, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8The cycloalkyl group and the 3-8 membered heterocyclic group are each optionally substituted by one or more substituents selected independently from D, halogen, -OH, -CN, and -COOH; or R 12 and R 13 Together with the atoms it is attached to, they form 3-8 membered heterocyclic groups;

[0039] R 14 Each time it appears, it is independently selected from H, D, halogen, -OH, -NH2, -NHCH3, -N(CH3)2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0040] R 16 R 17 R 18 R 19 Each is independently selected from H, D, halogens, -OH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl;

[0041] R 20 Selected from -CONR 12 R 13 -COR 13 -OSO2R 14 -NHCOR 14 -SOR 14 -SO2R 14 -OR 14 -OC(=O)R 14 -P(=O)(OR) 13 (OR) 14 ) and -OP(=O)(OR 13 (OR) 14 );

[0042] R a Chelating groups selected from non-radioactive or radioactive nuclides;

[0043] R c and R dEach occurrence is independently selected from H, D, halogen, =O, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally surrounded by one or more independently selected from halogen, D, OH, -COOH, -CH2COOH, -CH2CH2COOH, -CONH2, -CH2CONH2, CN, -NH2, =CR′R″, -SO2R 14 and C 1-6 Alkyl substituents; preferably, R c and R d Each occurrence is independently selected from H, D, halogen, =O, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally surrounded by one or more groups independently selected from halogens, D, OH, -COOH, -CH2COOH, -CH2CH2COOH, -CONH2, -CH2CONH2, CN, -NH2, and C. 1-6 Alkyl substituents;

[0044] L is Where “*” represents the connection point with Y;

[0045] X a X b X c X d X e X f X h and X i It does not exist, or it is selected independently from -O-, -S-, -Se-, -CR each time it appears. x R y -、-NR z -, -C(=O)-, -C(=S)-, -C(=CH2)-, -S(=O)-, -S(=O)2-, -CR x =CR y -、-C≡C-、-N=CR x -、-C(=N-OH)-、C 3-6 Cycloalkylene, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic, phenylene and 5-6 membered heteroaryl, wherein C 3-6 Cycloalkylene, C 3-6 The cycloene group, the 4-8 membered heterocyclic group, the phenylene group, and the 5-6 membered heteroaryl group are each optionally selected by one or more independently selected from halogen, D, =O, -OH, -CN, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; condition is when L is And R 1 R 4 R 8 R 10 CH3, R 9 For phenyl and pyrazolyl groups, R 11 and R 11a Let H be the integer part of the set, k1, k2, k3, k4, k5, k6, k7, k8, and k9 all be 0, k10 be 2, and R be the integer part of the set. 16 R 17 R 18 and R 19 For H, R 3 R 20 For -COOH, R 5 For -C(O)NH2, X 5 When X is -CH-, 2 Not -CH2-;

[0046] R x and R y Each is independently selected from H, halogen, D, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group may be optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH;

[0047] R z Selected from H, C 1-6 Alkyl and C 1-6 Deuterated alkyl groups;

[0048] X g Selected from CH, N and Among them, ring B is selected from C. 3-6 Cycloalkanes, 4-8 membered heterocycles, C 6-10 Aromatic rings and 5-12 membered heteroaromatic rings, wherein ring B is optionally selected by one or more elements, each independently selected from halogens, D, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0049] Each time Y appears, it is independently selected from chemical bonds, -(CR) f R g ) m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6-10 aryl groups, amino acid residues, and 5-12 heteroaryl groups; the C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6- 10 The aryl group, amino acid residue, and 5-12 heteroaryl group are each optionally substituted by one or more groups selected from: D, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O;

[0050] R f and R g Each occurrence is independently selected from H, D, halogen, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -NHCO-(CH2CH2O) m -(CH2) m -NHCO-(CH2) m -C 6-10 Aryl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6- 10 The aryl group and the 5-12 heteroaryl group are each optionally surrounded by one or more elements independently selected from halogen, D, OH, -COOH, -CONH2, CN, -NH2, and C. 1-6 Alkyl substituents;

[0051] Each time m appears, it is independently selected from any integer in the range of 1-20;

[0052] n is any integer selected from the range 0 to 20;

[0053] J1, J2, J3, and J4 are each independently selected from 0, 1, 2, or 3 each time they appear;

[0054] k1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0055] k2, k3, k4, k5, k6, k7, k8, k9, and k10 are each independently selected from 0, 1, or 2 each time they appear.

[0056] A second aspect of the invention provides chelates or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites, or prodrugs thereof, said chelates comprising a compound of formula (I02) and a non-radioactive or radioactive nuclide chelated with the compound of formula (I02).

[0057] A third aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, said compound having the structure shown in formula (III02):

[0058] Where X 1 X 2 X 3 X 5 X 6 X 7 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a R 16 R 17 R 18 R 19 R 20 J1, J2, J3, J4, k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n are as defined above for the compound of formula I02, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3).

[0059] A fourth aspect of the present invention provides a pharmaceutical composition comprising a diagnostically, preventively, or therapeutically effective amount of a ligand compound of the first aspect of the present invention, a chelate of the second aspect, or a compound of the third aspect, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug, and one or more pharmaceutically acceptable carriers.

[0060] The fifth aspect of the invention provides the use of the ligand compound of the first aspect, the chelate of the second aspect, or the compound of the third aspect, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug of the invention, or the pharmaceutical composition of the invention, in the preparation of a medicament, particularly for the diagnosis, prevention, or treatment of diseases or conditions related to GPC3 activity.

[0061] The sixth aspect of the present invention provides a ligand compound of the first aspect, a chelate of the second aspect, or a compound of the third aspect, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention, for the diagnosis, prevention, or treatment of diseases or conditions associated with GPC3 activity.

[0062] The seventh aspect of the invention provides a method for diagnosing, preventing, or treating a disease or condition associated with GPC3 activity, the method comprising administering to a subject in need an effective amount of a ligand compound of the first aspect of the invention, a chelate of the second aspect, or a compound of the third aspect, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug of the invention, or a pharmaceutical composition of the invention. Detailed Implementation

[0063] definition

[0064] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0065] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps, although such other unlisted elements or method steps may not necessarily exist (i.e., these terms also cover the terms “consistently made up of” and “composed of”).

[0066] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example, 1 to 6 carbon atoms or 1 to 4 carbon atoms. For example, as used herein, the term "C 1-6"Alkyl" refers to a linear or branched group having 1-6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl), optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogens (in which case the group is called "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C" 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0067] As used herein, the term "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise expressly stated in this specification, alkylene may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkylene is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH(CH3)CH2-.

[0068] As used herein, the term "alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds. For example, the term "C" as used herein... 2-4 "Alkenyl" refers to an alkenyl group (such as vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, etc.) having 2-4 carbon atoms and one, two, or three carbon-carbon double bonds, optionally substituted by one or more (e.g., 1-3) substituents described herein. The term "C" as used herein... 2-4 "Ideenyl" refers to C 2-4 An alkenyl group is formed by losing a hydrogen atom to form a divalent group.

[0069] As used herein, the term "alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. For example, the term "C" as used herein... 2-4 "Alynyl" refers to an alkynyl group (such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl) having 2-4 carbon atoms and one, two, or three carbon-carbon triple bonds, optionally substituted by one or more (e.g., 1-3) substituents described herein. The term "C" as used herein... 2-4 "Immyneyl" refers to C 2-4 An alkynyl group is a divalent group formed by losing a hydrogen atom.

[0070] As used herein, the term "heteroalkyl" refers to an alkyl group having one or more skeletal chain atoms in its main chain that are independently selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges (e.g., C) can be given. 2-6 A heteroalkyl group (C3-CH2OCH2CH3) refers to the number of carbon atoms in the chain, which in this example includes 2-6 carbon atoms. For example, the -CH2OCH2CH3 group is called a C3 heteroalkyl group, and the -CH2OCH2CH2NHCH3 group is called a C4 heteroalkyl group. Connection to the rest of the molecule can be made via heteroatoms or carbon atoms in the heteroalkyl chain.

[0071] As used herein, the term "heteroalkylene" refers to a divalent heteroalkylene. Examples of such heteroalkyleneenes include: -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CH2O, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0072] As used herein, the term "halogenated alkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms, e.g., Chalogenated. 1-8 Haloalkyl, C 1-6 Haloalkyl, C 1-4 Halogenated alkyl groups, etc. The term "C" 1-8 "Halogenated alkyl", "C" 1-6 "Halogenated alkyl" and "C" 1-4 "Halogenated alkyl" refers to alkyl haloatoms having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0073] As used herein, the term "hydroxyalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with hydroxyl groups, such as C10. 1-6 Hydroxyalkyl or C 1-4 Hydroxyalkyl groups, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH3, etc.

[0074] As used herein, the term "alkoxy" means -O-alkyl, where the alkyl group is as defined above, for example, C... 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkyl group. C 1-6Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, etc., wherein the alkoxy group is optionally substituted by one or more (such as 1 to 3) identical or different substituents. The term "haloalkoxy" refers to an alkoxy group in which the hydrogen atom is substituted by one or more (such as 1 to 3) identical or different halogen atoms.

[0075] As used herein, the term "hydroxyalkoxy" refers to a group formed by replacing a hydrogen atom in an alkoxy group with one or more hydroxyl groups, such as C. 1-6 hydroxyalkoxy or C 1-4 Hydroxyalkoxy compounds, examples of which include, but are not limited to, hydroxymethoxy, hydroxyethoxy, hydroxypropoxy, hydroxybutoxy, -OCH2CH(OH)(CH3)2, etc.

[0076] As used herein, the terms “fused ring,” “dense ring,” or “fused together” refer to a ring system formed by two or more ring structures sharing two adjacent atoms.

[0077] As used herein, the term "spiroring" refers to a ring system consisting of two or more ring structures that share a single ring atom.

[0078] As used in this article, the term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.

[0079] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon cycloyl group, including but not limited to monocyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicyclic alkyl groups, including spirocyclic, fused-ring (fused-ring), or bridged-ring systems (i.e., spirocyclic alkyl, fused-ring (fused-ring) alkyl, and bridged-ring alkyl groups, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, etc.). In this invention, the cycloalkyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atom on the cycloalkyl group is optionally substituted with an oxo group (i.e., forming C=O). The term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 cyclic carbon atoms, such as C10. 3-6 Cycloalkyl groups can be monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or they can be bicycloalkyl, such as C10, C20, C30, C40, C50, C60, C7 ... 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 fused cycloalkyl, C 5-6 Spirocycloalkyl, C 5-6 Bridged cycloalkyl or C 5-6Fused cycloalkyl groups. In this article, "cycloalkylene oxide" refers to a divalent group formed by the loss of a hydrogen atom from a cycloalkyl group.

[0080] As used herein, the term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon cycloyl group containing at least one unsaturated double bond, such as C10. 3-8 Cycloalkenyl or C 3-6 Cycloalkenyl groups include cyclobutenyl, cyclopentenyl, and cyclohexenyl groups. The term "cycloalkenyl-deoxygenyl" as used in this article refers to a divalent group formed by the loss of a hydrogen atom from a cycloalkenyl group.

[0081] As used herein, the term "cycloalkoxy" refers to -O-cycloalkyl, where the cycloalkyl group is as defined above. Representative examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0082] As used herein, the term "heterocycle" refers to an aliphatic monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) ring having two or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, said heteroatoms including, but not limited to, oxygen, nitrogen, and sulfur atoms, wherein the carbon atoms and heteroatoms on said heterocycle are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2), or optionally substituted with one or more (such as 1 to 3) heteroatoms independently selected from halogens and C. 1-3Alkyl substituents. The term "saturated heterocycle" refers to a fully saturated heterocycle, such as tetrahydrofuran ring, piperidine ring, morpholine ring, tetrahydropyran ring, piperazine ring, etc. The term "partially saturated heterocycle" refers to a heterocycle that contains both saturated single bonds and unsaturated double bonds, such as 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 4,5-dihydroisoxazole, 4,5-dihydrooxazole, 2,5-dihydrooxazole, 2,3-dihydrooxazole, etc. As used herein, the term "heterocyclic group" refers to a monovalent group formed from the aforementioned heterocycles, including but not limited to 4-11 membered heterocyclic groups, 4-10 membered heterocyclic groups, 4-9 membered heterocyclic groups, 4-8 membered heterocyclic groups, 4-7 membered heterocyclic groups, 5-6 membered heterocyclic groups, 3-8 membered heterocyclic groups, 3-7 membered heterocyclic groups, 4-7 membered nitrogen-containing heterocyclic groups, 4-7 membered oxygen-containing heterocyclic groups, 4-7 membered sulfur-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, and 5-6 membered sulfur-containing heterocyclic groups. Each of the "nitrogen-containing heterocyclic group," "oxygen-containing heterocyclic group," and "sulfur-containing heterocyclic group" optionally also contains one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. As used herein, the term "3-8 membered heterocyclic group" refers to a heterocyclic group containing 3-8 ring atoms, including but not limited to 3-8 membered heterocyclic groups, 3-7 membered heterocyclic groups, 3-6 membered heterocyclic groups, 4-8 membered heterocyclic groups, 4-7 membered heterocyclic groups, 4-6 membered heterocyclic groups, 5-6 membered heterocyclic groups, 5-8 membered heterocyclic groups (e.g., 5-8 membered saturated or partially saturated heterocycles), 4-7 membered nitrogen-containing heterocyclic groups, 4-7 membered oxygen-containing heterocyclic groups, 4-7 membered sulfur-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 5-6 membered sulfur-containing heterocyclic groups, etc. Examples of 3-8 membered heterocyclic groups include but are not limited to ethylene oxide, aziridinyl, aziridine, oxobutyl, tetrahydrofuranyl, pyrrolylalkyl, pyrrolidone (e.g.) (Imidazolyl, pyrazolyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl. The term "subheterocyclic group" refers to a divalent group formed by losing one hydrogen atom from the above heterocyclic groups.)

[0083] In this invention, the heterocyclic group can form a fused ring structure with a heterocyclic group or a cycloalkyl group. The connection point of the fused ring structure with other groups can be on any heterocyclic group or on a cycloalkyl group. Therefore, the heterocyclic group of this invention also includes (but is not limited to) heterocyclic fused heterocyclic groups, heterocyclic fused cycloalkyl groups, monoheterocyclic fused monoheterocyclic groups, and monoheterocyclic fused monocycloalkyl groups, such as 3-7 membered (mono)heterocyclic fused 3-7 membered (mono)heterocyclic groups, 3-7 membered (mono)heterocyclic fused (mono)cycloalkyl groups, and 3-7 membered (mono)heterocyclic fused C 4-6(Mono)cycloalkyl groups, examples of which include, but are not limited to, pyrrolidinylcyclopropyl, cyclopentylazirylpropyl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, and piperidinylmorpholinyl.

[0084] In this invention, the heterocyclic group also includes bridged heterocyclic groups and spiroheterocyclic groups.

[0085] As used herein, the term "bridged heterocycle" refers to a ring structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, and / or sulfur atoms) formed by two rings sharing two non-directly connected ring atoms. This includes, but is not limited to, 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc., for example... The "nitrogen-bridged heterocycle", "oxygen-bridged heterocycle", and "sulfur-bridged heterocycle" may optionally also contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0086] As used herein, the term "spiroheterocycle" refers to a ring structure consisting of two or more rings sharing a single ring atom and containing one or more heteroatoms (e.g., oxygen, nitrogen, sulfur), including but not limited to 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, etc. The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", and "sulfur-containing spiroheterocycle" may optionally also contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. The term "6-10-membered nitrogen-containing spiroheterocycle group" refers to a spiroheterocycle group containing a total of 6-10 ring atoms, of which at least one ring atom is a nitrogen atom.

[0087] Examples of groups obtained by fusion of heterocyclic groups and aryl groups include, but are not limited to:

[0088] As used herein, the term "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic aromatic ring having a conjugated π-electron system. As used herein, the term "C 6-10 "Aryl" refers to a monovalent group formed by an aromatic ring containing 6 to 10 carbon atoms, preferably phenyl or naphthyl. The aryl group may optionally be substituted by one or more (such as 1 to 3) identical or different substituents (e.g., halogen, OH, CN, NO2, C1-C6 alkyl, etc.). The term "arylene" refers to a divalent group formed by the loss of one hydrogen atom from the aforementioned aryl group.

[0089] As used herein, the term "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic ring containing one or more identical or different heteroatoms, including monocyclic heteroaromatic rings and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, for example 5, 6, 7, 8, 9 or 10 ring atoms, and in each case may additionally be benzofused. The heteroatom may be oxygen, nitrogen or sulfur. The carbon atom and heteroatom on the heteroaryl group are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2).

[0090] As used herein, the terms "5-10-membered heteroaryl" or "5-10-membered heteroaryl ring" refer to a heteroaryl (heteroaryl ring) containing 5 to 10 (e.g., 5 to 6) ring atoms, including 5-10-membered nitrogen-containing heteroaryl, 5-10-membered oxygen-containing heteroaryl, 5-10-membered sulfur-containing heteroaryl, 5-6-membered nitrogen-containing heteroaryl, 5-6-membered oxygen-containing heteroaryl, 5-6-membered sulfur-containing heteroaryl, etc. Each of the "nitrogen-containing heteroaryl," "oxygen-containing heteroaryl," and "sulfur-containing heteroaryl" may optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of such groups include, but are not limited to, thiopheneyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., as well as 5-10 membered fused cyclic groups containing these groups. The term "heteroaryl" refers to a divalent group formed by the loss of one hydrogen atom from the aforementioned heteroaryl groups.

[0091] In this invention, a heteroaryl group (e.g., a monoheteroaryl group) can share two adjacent atoms with an aryl group (e.g., a monocyclic aryl group, such as a phenyl group), a heterocyclic group (e.g., a monoheterocyclic group), a cycloalkyl group (e.g., a monocycloalkyl group), or another heteroaryl group (e.g., another monoheteroaryl group) to form a fused ring structure. The connection point can be on any heteroaryl ring or other rings, including but not limited to (mono)heteroaryl fused (mono)heteroaryl, (mono)heteroaryl fused (monocyclic) aryl, (mono)heteroaryl fused (mono)heterocyclic, and (mono)heteroaryl fused (mono)cycloalkyl, such as 5-6 membered (mono)heteroaryl fused 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl fused phenyl, 5-6 membered (mono)heteroaryl fused 5-6 membered (mono)heterocyclic, or 5-6 membered (mono)heteroaryl fused C 4-6 (Mono)cycloalkyl groups (e.g., 5-6-membered heteroarylcyclobutyl, 5-6-membered heteroarylcyclopentyl, or 5-6-membered heteroarylcyclohexyl), examples of which include, but are not limited to, benzothiazolyl, indolyl, isoyindolyl, indolyl, benzimidazole, quinolinyl, isoquinolinyl, wait.

[0092] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br or I.

[0093] The term "amino acid residue" refers to the structural unit remaining after a natural or non-natural amino acid loses some groups (such as H, OH). Natural amino acids are the 20 L-configuration α-amino acids directly encoded by the standard genetic code in living organisms, including: glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), aspartic acid (Asp), asparagine (Asn), glutamic acid (Glu), glutamine (Gln), serine (Ser), threonine (Thr), cysteine ​​(Cys), methionine (Met), lysine (Lys), arginine (Arg), histidine (His), and proline (Pro). The term "natural amino acid" includes both its unmodified form and derivatives resulting from post-translational modifications in living organisms (e.g., phosphorylated, methylated, or acetylated products). Non-natural amino acids refer to any amino acid or its derivatives that do not fall under the category of natural amino acids mentioned above, including but not limited to: (i) D-configuration isomers of natural amino acids; (ii) derivatives of natural amino acids whose side chains have been chemically modified (e.g., alkylation, halogenation, hydroxylation, phosphorylation, sulfonation, glycosylation, introduction of unsaturated bonds, introduction of alkyne groups, azido groups, ketone carbonyl groups, photocrosslinking groups, etc.); (iii) amino acids with modified main chain structures (e.g., α,α-disubstituted amino acids, β-amino acids, γ-amino acids, etc.); and (iv) other amino acid analogs that do not exist in nature or are not encoded by genetic codons and are not routinely synthesized in organisms via the ribosomal pathway.

[0094] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0095] If a substituent is described as “optionally substituted by one or more…”, then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together by independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted by independently selected optional substituents.

[0096] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0097] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0098] The numerical ranges provided in this document should be understood as abbreviations of all numerical values ​​or subranges within that range. For example, the numerical range of 0-30 should be understood as including any number, combination of numbers, or subrange (e.g., 0-10 or 1-10) selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0099] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0100] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0101] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., ... 11 C 13 C and 14 C); isotopes of chlorine (e.g.) 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g. 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e.3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0102] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, nitroso-oximes can exist in equilibrium in solution in the following tautomer forms:

[0103] It should be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0104] Solid lines may be used in this article. solid wedge Or virtual wedge The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or dashed wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0105] In this invention, when a radionuclide chelates with a chelating agent, for example: Both refer to chelating agents and nuclides (such as...) 177 Coordinate bonds are formed between Lu and Lu.

[0106] In this invention, the structures obtained by chelating the compounds of this invention with non-radioactive nuclides Rn' or radioactive nuclides Rn are respectively denoted as Rn'-compounds or Rn-compounds. For example, in this invention, 175 Lu-A126-1 represents the precursor compound A126-1 and a non-radioactive nuclide. 175 The structure obtained by Lu chelation 177 Lu-A126-1 represents the precursor compound A126-1 and the radionuclide. 177 The structure obtained by Lu chelation.

[0107] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0108] Cocrystal refers to the combination of active pharmaceutical molecules and other physiologically acceptable acids, bases, salts, and nonionic compound molecules in the same crystal lattice via hydrogen bonds, π-π stacking interactions, van der Waals forces, and other non-covalent bonds.

[0109] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0110] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0111] Pharmaceutically acceptable salts of the compounds of this invention include their acid addition salts and base addition salts. Examples include hexafluorophosphates and meglumine salts. For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002).

[0112] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0113] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0114] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized to oxides. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming N-oxides. They will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including but not limited to the oxidation of heterocycles and tertiary amines using peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

[0115] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0116] This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACSSymposium Series (T. Higuchi and V. Stella). The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0117] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in T.W. Greene & P. ​​G.W. M. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0118] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0119] compound

[0120] In some embodiments, the first aspect of the invention provides a ligand compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug having the structure of formula (I02):

[0121] in:

[0122] X 1 X 3 and X 5 Each is independently selected from N and CH, preferably X. 1 and X 3Each is independently selected from N and CH, X 5 Selected from CH;

[0123] X 6 and X 7 Each is independently selected from N and CH, preferably X. 6 and X 7 Both are CH, or X 6 Selected from CH, X 7 Selected from N;

[0124] X 2 Selected from -CR t1 R t2 -, -CH2CR t1 R t2 -, -NH- and -N(CH3)-;

[0125] R 1 R 4 R 8 R 10 Each is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 The cycloalkyl groups are optionally each selected independently by one or more elements chosen from D, halogen, -OH, -CN, -CONR. 12 R 13 Substitution with -COOH substituents;

[0126] R 2 and R 6 Each is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Each cycloalkyl group is optionally surrounded by one or more elements independently selected from halogens, D, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR13 -NHCOR 14 C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0127] R 3 and R 5 Each is independently selected from H, D, halogens, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. c Replace; or R 3 and R 5 Together with the atoms it is attached to, they form 7-18 membered heterocyclic groups;

[0128] R 7 Selected from H, D, halogens, -OH, -CN, -NR 12 R13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 -OR 14 -OC(=O)R 14 -OP(=O)(OR) 13 (OR) 14 -P(=O)(OR) 13 (OR) 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -L 1 -C 3-8 cycloalkyl-, -L 1 -(3-8 membered heterocyclic group)-, -L 1 -C 6-10 Aryl- and -L 1 -(5-10 heteroaryl)-, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. d replace;

[0129] L 1 Selected from C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S-, -NH- and -N(CH3)-;

[0130] R9 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected halogens, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, -SO2R 14 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of haloalkyl groups;

[0131] R′ and R″ are each independently selected from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH;

[0132] R 11a and R 11 Each is independently selected from H, D, OH, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl groups, amino acid residues, and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C3-8 The cycloalkyl group, amino acid residue, and 3-8 membered heterocyclic group are each optionally selected independently from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substitution by haloalkoxy groups, -OH, -NH2-, -CN, -COOH, and -CONH2; or R 11a and R 11 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally composed of one or more atoms independently selected from H, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 and -OC(=O)R 14 Substituents of the substituents;

[0133] R t1 and R t2 Each independently selected from H, D, C 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 Deuterated alkyl; or R t1 and R t2 Together with the atoms it is attached to, they form C 3-6 cycloalkyl;

[0134] R 12 and R 13 Each occurrence is independently selected from H, D, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each optionally substituted by one or more substituents selected independently from D, halogen, -OH, -CN, and -COOH; or R 12 and R 13 Together with the atoms it is attached to, they form 3-8 membered heterocyclic groups;

[0135] R14 Each time it appears, it is independently selected from H, D, halogen, -OH, -NH2, -NHCH3, -N(CH3)2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0136] R 16 R 17 R 18 R 19 Each is independently selected from H, D, halogens, -OH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl;

[0137] R 20 Selected from -CONR 12 R 13 -COR 13 -OSO2R 14 -NHCOR 14 -SOR 14 -SO2R 14 -OR 14 -OC(=O)R 14 -P(=O)(OR) 13 (OR) 14 ) and -OP(=O)(OR 13 (OR) 14 );

[0138] R a Chelating groups selected from non-radioactive or radioactive nuclides;

[0139] R c and R d Each occurrence is independently selected from H, D, halogen, =O, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally surrounded by one or more independently selected from halogen, D, OH, -COOH, -CH2COOH, -CH2CH2COOH, -CONH2, -CH2CONH2, CN, -NH2, =CR′R″, -SO2R 14 and C 1-6 Alkyl substituents; preferably, R c and R d Each occurrence is independently selected from H, D, halogen, =O, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally surrounded by one or more groups independently selected from halogens, D, OH, -COOH, -CH2COOH, -CH2CH2COOH, -CONH2, -CH2CONH2, CN, -NH2, and C. 1-6 Alkyl substituents;

[0140] L is Where “*” represents the connection point with Y;

[0141] X a X b X c X d X e Xf X h and X i It does not exist, or it is selected independently from -O-, -S-, -Se-, -CR each time it appears. x R y -、-NR z -, -C(=O)-, -C(=S)-, -C(=CH2)-, -S(=O)-, -S(=O)2-, -CR x =CR y -、-C≡C-、-N=CR x -、-C(=N-OH)-、C 3-6 Cycloalkylene, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic, phenylene and 5-6 membered heteroaryl, wherein C 3-6 Cycloalkylene, C 3-6 The cycloene group, the 4-8 membered heterocyclic group, the phenylene group, and the 5-6 membered heteroaryl group are each optionally selected by one or more independently selected from halogen, D, =O, -OH, -CN, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; condition is when L is And R 1 R 4 R 8 R 10 CH3, R 9 For phenyl and pyrazolyl groups, R 11 and R 11a Let H be the integer part of the set, k1, k2, k3, k4, k5, k6, k7, k8, and k9 all be 0, k10 be 2, and R be the integer part of the set. 16 R 17 R 18 and R 19 For H, R 3 R 20 For -COOH, R 5 For -C(O)NH2, X 5 When X is -CH-, 2 Not -CH2-;

[0142] R x and R y Each is independently selected from H, halogen, D, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group may be optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH;

[0143] R z Selected from H, C 1-6 Alkyl and C 1-6 Deuterated alkyl groups;

[0144] X g Selected from CH, N and Among them, ring B is selected from C. 3-6 Cycloalkanes, 4-8 membered heterocycles, C 6-10 Aromatic rings and 5-12 membered heteroaromatic rings, wherein ring B is optionally selected by one or more elements, each independently selected from halogens, D, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0145] Each time Y appears, it is independently selected from chemical bonds, -(CR) f R g ) m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6-10 aryl groups, amino acid residues, and 5-12 heteroaryl groups; the C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6- 10 The aryl group, amino acid residue, and 5-12 heteroaryl group are each optionally substituted by one or more groups selected from: D, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O;

[0146] R f and R g Each occurrence is independently selected from H, D, halogen, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR14 -NHCO-(CH2CH2O) m -(CH2) m -NHCO-(CH2) m -C 6-10 Aryl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6- 10 The aryl group and the 5-12 heteroaryl group are each optionally surrounded by one or more elements independently selected from halogen, D, OH, -COOH, -CONH2, CN, -NH2, and C. 1-6 Alkyl substituents;

[0147] Each time m appears, it is independently selected from any integer in the range of 1-20;

[0148] n is any integer selected from the range 0 to 20;

[0149] J1, J2, J3, and J4 are each independently selected from 0, 1, 2, or 3 each time they appear;

[0150] k1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0151] k2, k3, k4, k5, k6, k7, k8, k9, and k10 are each independently selected from 0, 1, or 2 each time they appear.

[0152] In some embodiments, in the compound of formula (I02) provided by the present invention, when L is And R 1 R 4 R 8 R 10 CH3, R 9 For phenyl and pyrazolyl groups, R 11 and R 11a When H is defined, and k1, k2, k3, k4, k5, k6, k7, k8, and k9 are all 0, and k10 is 2, X 2 Not -CH2-.

[0153] In some embodiments, the compound has the structure of formula (I01):

[0154] in:

[0155] X 1 X 3 and X 5 Each is independently selected from N and CH, preferably X. 1 and X 3 Each is independently selected from N and CH, X 5 Selected from CH;

[0156] X 2 Selected from -CR t1 R t2 -, -CH2CR t1 R t2 -, -NH- and -N(CH3)-;

[0157] R 1 R 4 R 8 R 10 Each is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 The cycloalkyl groups are optionally each selected independently by one or more elements chosen from D, halogen, -OH, -CN, -CONR. 12 R 13 Substitution with -COOH substituents;

[0158] R 2 and R 6 Each is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Each cycloalkyl group is optionally surrounded by one or more elements independently selected from halogens, D, -OH, -CN, and -NR. 12R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0159] R 3 and R 5 Each is independently selected from H, D, halogens, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. c Replace; or R 3 and R 5 Together with the atoms it is attached to, they form 7-18 membered heterocyclic groups;

[0160] R 7 Selected from H, D, halogens, -OH, -CN, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 -OR 14 -OC(=O)R 14 -OP(=O)(OR) 13 (OR) 14 -P(=O)(OR) 13 (OR) 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -L 1 -C 3-8 cycloalkyl-, -L 1 -(3-8 membered heterocyclic group)-, -L 1 -C 6-10 Aryl- and -L 1 -(5-10 heteroaryl)-, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. d replace;

[0161] L 1 Selected from C 1-6 Alkylene, C 1-6Heteroalkyl, -O-, -S-, -NH- and -N(CH3)-;

[0162] R 9 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected halogens, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, -SO2R 14 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of haloalkyl groups;

[0163] R′ and R″ are each independently selected from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH;

[0164] R 11a and R 11 Each is independently selected from H, D, OH, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C3-8 Cycloalkyl groups, amino acid residues, and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl group, amino acid residue, and 3-8 membered heterocyclic group are each optionally selected independently from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substitution by haloalkoxy groups, -OH, -NH2-, -CN, -COOH, and -CONH2; or R 11a and R 11 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally composed of one or more atoms independently selected from H, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 and -OC(=O)R 14 Substituents of the substituents;

[0165] R t1 and R t2 Each independently selected from H, D, C 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 Deuterated alkyl; or R t1 and R t2 Together with the atoms it is attached to, they form C 3-6 cycloalkyl;

[0166] R 12 and R 13 Each occurrence is independently selected from H, D, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each optionally substituted by one or more substituents selected independently from D, halogen, -OH, -CN, and -COOH; or R 12 and R 13Together with the atoms it is attached to, they form 3-8 membered heterocyclic groups;

[0167] R 14 Each time it appears, it is independently selected from H, D, halogen, -OH, -NH2, -NHCH3, -N(CH3)2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0168] R 16 R 17 R 18 R 19 Each is independently selected from H, D, halogens, -OH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl;

[0169] R 20 Selected from -CONR 12 R 13 -COR 13 -OSO2R 14 -NHCOR 14 -SOR 14 -SO2R 14 -OR 14 -OC(=O)R 14 -P(=O)(OR) 13 (OR) 14 ) and -OP(=O)(OR 13 (OR) 14 );

[0170] R a Chelating groups selected from non-radioactive or radioactive nuclides;

[0171] R c and R d Each occurrence is independently selected from H, D, halogen, =O, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13-COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally surrounded by one or more groups independently selected from halogens, D, OH, -COOH, -CH2COOH, -CH2CH2COOH, -CONH2, -CH2CONH2, CN, -NH2, and C. 1-6 Alkyl substituents;

[0172] L is Where “*” represents the connection point with Y;

[0173] X a X b X c X d X e X f X h and X i It does not exist, or it is selected independently from -O-, -S-, -Se-, -CR each time it appears. x R y -、-NR z -, -C(=O)-, -C(=S)-, -C(=CH2)-, -S(=O)-, -S(=O)2-, -CR x =CR y -、-C≡C-、-N=CR x -、-C(=N-OH)-、C 3-6 Cycloalkylene, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic, phenylene and 5-6 membered heteroaryl, wherein C 3-6 Cycloalkylene, C 3-6 The cycloene group, the 4-8 membered heterocyclic group, the phenylene group, and the 5-6 membered heteroaryl group are each optionally selected by one or more independently selected from halogen, D, =O, -OH, -CN, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6Substituents of haloalkoxy groups; condition is when L is And R 1 R 4 R 8 R 10 CH3, R 9 For phenyl and pyrazolyl groups, R 11 and R 11a Let H be the integer part of the set, k1, k2, k3, k4, k5, k6, k7, k8, and k9 all be 0, k10 be 2, and R be the integer part of the set. 16 R 17 R 18 and R 19 For H, R 3 R 20 For -COOH, R 5 For -C(O)NH2, X 5 When X is -CH-, 2 Not -CH2-;

[0174] R x and R y Each is independently selected from H, halogen, D, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group may be optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH;

[0175] R z Selected from H, C 1-6 Alkyl and C 1-6 Deuterated alkyl groups;

[0176] X g Selected from CH, N and Among them, ring B is selected from C. 3-6 Cycloalkanes, 4-8 membered heterocycles, C 6-10 Aromatic rings and 5-12 membered heteroaromatic rings, wherein ring B is optionally selected by one or more elements, each independently selected from halogens, D, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0177] Each time Y appears, it is independently selected from chemical bonds, -(CR) f R g ) m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2)m -、-(CH2CH2O) m -、C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6-10 aryl groups, amino acid residues, and 5-12 heteroaryl groups; the C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6- 10 The arylene, amino acid residues, and 5-12 heteroarylene groups are optionally substituted with one or more of the following groups: D, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O;

[0178] R f and R g Each occurrence is independently selected from H, D, halogen, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -NHCO-(CH2CH2O) m -(CH2) m -NHCO-(CH2) m -C 6-10 Aryl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6- 10 The aryl group and the 5-12 heteroaryl group are each optionally surrounded by one or more elements independently selected from halogen, D, OH, -COOH, -CONH2, CN, -NH2, and C. 1-6 Alkyl substituents; for example, Rf and R g Each occurrence is independently selected from H, D, halogen, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are optionally separated by one or more elements, each independently selected from halogen, D, OH, -COOH, -CONH2, CN, -NH2, and C. 1-6 Alkyl substituents;

[0179] Each time m appears, it is independently selected from any integer in the range of 1-20;

[0180] n is any integer selected from the range 0 to 20;

[0181] J1, J2, J3, and J4 are each independently selected from 0, 1, 2, or 3 each time they appear;

[0182] k1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0183] k2, k3, k4, k5, k6, k7, k8, k9, and k10 are each independently selected from 0, 1, or 2 each time they appear.

[0184] In some embodiments, in the compound of formula (I01) provided by the present invention, when L is And R 1 R 4 R 8 R 10 CH3, R 9 For phenyl and pyrazolyl groups, R 11 and R 11aWhen H is defined, and k1, k2, k3, k4, k5, k6, k7, k8, and k9 are all 0, and k10 is 2, X 2 Not -CH2-.

[0185] In some embodiments, the compound is a compound of formula I”:

[0186] in:

[0187] X 1 X 3 and X 5 Each is independently selected from N and CH, preferably X. 1 and X 3 Each is independently selected from N and CH, X 5 Selected from CH;

[0188] X 2 Selected from -CR t1 R t2 -, -CH2CR t1 R t2 -, -NH- and -N(CH3)-;

[0189] R 1 R 4 R 8 R 10 Each is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 The cycloalkyl groups are optionally each selected independently by one or more elements chosen from D, halogen, -OH, -CN, -CONR. 12 R 13 Substitution with -COOH substituents;

[0190] R 2 and R 6 Each is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups and C 3-6 Each cycloalkyl group is optionally surrounded by one or more elements independently selected from halogens, D, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0191] R 3 and R 5 Each is independently selected from H, D, halogens, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups.c Replace; or R 3 and R 5 Together with the atoms it is attached to, they form 7-18 membered heterocyclic groups;

[0192] R 7 Selected from H, D, halogens, -OH, -CN, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 -OR 14 -OC(=O)R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -L 1 -C 3-8 cycloalkyl-, -L 1 -(3-8 membered heterocyclic group)-, -L 1 -C 6-10 Aryl- and -L 1 -(5-10 heteroaryl)-, the C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. d replace;

[0193] L 1 Selected from C 1-6 Alkylene, C 1-6Heteroalkyl, -O-, -S-, -NH- and -N(CH3)-;

[0194] R 9 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected from halogen, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of haloalkyl groups;

[0195] R′ and R″ are each independently selected from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH;

[0196] R 11a and R 11 Each is independently selected from H, D, OH, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8Cycloalkyl groups, amino acid residues, and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl group, amino acid residue, and 3-8 membered heterocyclic group are each optionally substituted by one or more substituents selected independently from halogens, -OH, -NH2-, -CN, -COOH, and -CONH2; or R 11a and R 11 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally composed of one or more atoms independently selected from H, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 and -OC(=O)R 14 Substituents of the substituents;

[0197] R t1 and R t2 Each independently selected from H, D, C 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 Deuterated alkyl; or R t1 and R t2 Together with the atoms it is attached to, they form C 3-6 cycloalkyl;

[0198] R 12 and R 13 Each occurrence is independently selected from H, D, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each optionally substituted by one or more substituents selected independently from D, halogen, -OH, -CN, and -COOH; or R 12 and R 13 Together with the atoms it is attached to, they form 3-8 membered heterocyclic groups;

[0199] R 14Each occurrence is independently selected from H, D, -OH, -NH2, -NHCH3, -N(CH3)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0200] R 16 R 17 R 18 R 19 Each is independently selected from H, D, halogens, -OH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl;

[0201] R a Chelating groups selected from non-radioactive or radioactive nuclides;

[0202] R c and R d Each occurrence is independently selected from H, D, halogen, =O, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally surrounded by one or more groups independently selected from halogens, D, OH, -COOH, -CH2COOH, -CH2CH2COOH, -CONH2, -CH2CONH2, CN, -NH2, and C. 1-6Alkyl substituents;

[0203] L is Where “*” represents the connection point with Y;

[0204] X a X b X c X d X e X f X h and X i It does not exist, or it is selected independently from -O-, -S-, -Se-, -CR each time it appears. x R y -、-NR z -, -C(=O)-, -C(=S)-, -C(=CH2)-, -S(=O)-, -S(=O)2-, -CR x =CR y -、-C≡C-、-N=CR x -、-C(=N-OH)-、C 3-6 Cycloalkylene, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic, phenylene and 5-6 membered heteroaryl, wherein C 3-6 Cycloalkylene, C 3-6 The cycloene group, the 4-8 membered heterocyclic group, the phenylene group, and the 5-6 membered heteroaryl group are optionally selected by one or more independently selected from halogen, D, =O, -OH, -CN, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; condition is when L is And R 1 R 4 R 8 R 10 CH3, R 9 For phenyl and pyrazolyl groups, R 11 and R 11a Let H be the integer part of the set, k1, k2, k3, k4, k5, k6, k7, k8, and k9 all be 0, k10 be 2, and R be the integer part of the set. 16 R 17 R 18 and R 19 For H, R 3 For -COOH, R 5 For -C(O)NH2, X 5 When X is -CH-, 2 Not -CH2-;

[0205] Rx and R y Each is independently selected from H, halogen, D, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group may be optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH;

[0206] R z Selected from H, C 1-6 Alkyl and C 1-6 Deuterated alkyl groups;

[0207] X g Selected from CH, N and Among them, ring B is selected from C. 3-6 Cycloalkanes, 4-8 membered heterocycles, C 6-10 Aromatic rings and 5-12 membered heteroaromatic rings, wherein ring B is optionally selected by one or more elements, each independently selected from halogens, D, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0208] Each time Y appears, it is independently selected from chemical bonds, -(CR) f R g ) m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6-10 aryl groups, amino acid residues, and 5-12 heteroaryl groups; the C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6- 10 The aryl group, amino acid residue, and 5-12 heteroaryl group are each optionally substituted by one or more groups selected from: D, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O;

[0209] R f and R g Each occurrence is independently selected from H, D, halogen, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each optionally surrounded by one or more elements independently selected from halogen, D, OH, -COOH, -CONH2, CN, -NH2, and C. 1-6 Alkyl substituents;

[0210] Each time m appears, it is independently selected from any integer in the range of 1-20;

[0211] n is any integer selected from the range 0 to 20;

[0212] J1, J2, J3, and J4 are each independently selected from 0, 1, 2, or 3 each time they appear;

[0213] k1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0214] k2, k3, k4, k5, k6, k7, k8, k9, and k10 are each independently selected from 0, 1, or 2 each time they appear.

[0215] In some embodiments, the compound is the compound shown in Formula I'.

[0216] Among them, X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5R 6 R 7 R 8 R 9 R 10 R 11 R 11a ,k1,k2,k3,k4,k5,k6,k7,k8,k9,k10,R a And n is as defined above.

[0217] In some embodiments, the compound is the compound shown in Formula I.

[0218] in:

[0219] X 1 and X 3 Each is independently selected from N and CH;

[0220] X 2 Selected from -CH2-, -NH- and -N(CH3)-;

[0221] R 1 R 4 R 8 R 10 Each is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Each cycloalkyl group is optionally substituted by one or more substituents selected independently from D, halogens, -OH, -CN and -COOH;

[0222] R 2 and R 6 Each is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Each cycloalkyl group is optionally surrounded by one or more elements independently selected from halogens, D, -OH, -CN, and -NR. 12 R13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0223] R 3 and R 5 Each is independently selected from H, D, halogens, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. c Replace; or R 3 and R 5 Together with the atoms it is attached to, they form 7-18 membered heterocyclic groups;

[0224] R 7 Selected from H, D, halogens, -OH, -CN, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 -OR 14 -OC(=O)R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -L 1 -C 3-8 cycloalkyl-, -L 1 -(3-8 membered heterocyclic group)-, -L 1 -C 6-10 Aryl- and -L 1 -(5-10 heteroaryl)-, the C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more R d replace;

[0225] L 1 Selected from C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S-, -NH- and -NHCH3-;

[0226] R 9 Selected from halogens, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected from halogen, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of haloalkyl groups;

[0227] R′ and R″ are each independently selected from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH;

[0228] R 11 Selected from H, D, OH, C 1-6 Alkyl and C 1-6 Deuterated alkyl groups;

[0229] R 12 and R 13 Each occurrence is independently selected from H, D, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each optionally substituted by one or more substituents selected independently from D, halogen, -OH, -CN, and -COOH; or R 12 and R 13 Together with the atoms it is attached to, they form 3-8 membered heterocyclic groups;

[0230] R 14 Each occurrence is independently selected from H, D, -OH, -NH2, -NHCH3, -N(CH3)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0231] R a Chelating agents selected from non-radioactive or radioactive nuclides;

[0232] R c and R d Each occurrence is independently selected from H, D, halogen, =O, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally surrounded by one or more groups independently selected from halogen, D, OH, -COOH, -CONH2, CN, -NH2, and C. 1-6 Alkyl substituents;

[0233] L is Where “*” represents the connection point with Y;

[0234] X a X b X c X d X e X f X h and X i It does not exist, or it is selected independently from -O-, -S-, -Se-, -CR each time it appears. x R y -、-NR z -, -C(=O)-, -C(=S)-, -C(=CH2)-, -S(=O)-, -S(=O)2-, -CR x =CR y -、-C≡C-、-N=CR x -、-C(=N-OH)-、C 3-6 Cycloalkylene, 4-8-membered heterocyclic alkylene, phenylene, and 5-6-membered heteroaryl alkylene, wherein C 3-6 The cycloalkyl group, the 4-8 membered heterocyclic group, the phenylene group, and the 5-6 membered heteroaryl group are each optionally selected by one or more independently from halogens, D, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; condition is when L is And R 1 R 4 R 8 R 10 CH3, R 9 For phenyl and pyrazolyl groups, R 11 When it is H, X 2 For -NH- and -N(CH3)-;

[0235] R x and R y Each is independently selected from H, halogen, D, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group may be optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH;

[0236] R z Selected from H, C 1-6 Alkyl and C 1-6 Deuterated alkyl groups;

[0237] X g Selected from CH, N and Among them, ring B is selected from C. 3-6 Cycloalkanes, 4-8 membered heterocycles, C 6-10 Aromatic rings and 5-12 membered heteroaromatic rings, wherein ring B is optionally selected by one or more elements, each independently selected from halogens, D, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0238] Each time Y appears, it is independently selected from chemical bonds, -(CR) f R g ) m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6-10 arylene and 5-12 heteroarylene; the C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6-10 The arylene and the 5-12-membered heteroarylene are each optionally substituted by one or more of the following groups: D, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O;

[0239] R f and R g Each occurrence is independently selected from H, D, halogen, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each optionally surrounded by one or more elements independently selected from halogen, D, OH, -COOH, -CONH2, CN, -NH2, and C. 1-6 Alkyl substituents;

[0240] Each time m appears, it is independently selected from any integer in the range of 1-20;

[0241] n is any integer selected from the range 0 to 20.

[0242] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, wherein:

[0243] X 1 and X 3 Each is independently selected from N and CH;

[0244] X 2 Selected from -CH2-, -NH- and -N(CH3)-;

[0245] R 1 R 4 R 8 R 10 Each is independently selected from H, D, CD3, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl;

[0246] R 2 and R 6 Each is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Cycloalkyl, wherein the alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, and cycloalkyl group are each optionally selected independently from one or more halogens, D, -OH, -CN, -NR. 12 R 13 -CONR 12 R13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0247] R 3 and R 5 Each is independently selected from H, D, halogens, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heteroalkyl, hydroxyalkyl, hydroxyalkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. c Replace; or R 3 and R 5 Together with the atoms it is attached to, they form 7-18 membered heterocyclic groups;

[0248] R 7 Selected from H, halogens, -OH, -CN, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 -OR 14 -OC(=O)R 14 C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -L 1 -C 3-8 cycloalkyl-, -L 1 -(3-8 membered heterocyclic group)-, -L 1 -C 6-10 Aryl- and -L 1 -(5-10-membered heteroaryl)-, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heteroalkyl, hydroxyalkyl, hydroxyalkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by one or more R d replace;

[0249] L 1 Selected from C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S-, -NH- and -N(CH3)-;

[0250] R 9 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heteroalkyl, hydroxyalkyl, hydroxyalkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are optionally selected by one or more of the following groups, each independently selected from halogen, D, OH, CN, -NH2, -COOH, -CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6Substituents of haloalkyl groups;

[0251] R 11 Selected from H, OH and C 1-6 alkyl;

[0252] R 12 and R 13 Each time it appears, it is independently selected from H, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, or R 12 and R 13 Together with the atoms it is attached to, they form 3-8 membered heterocyclic groups;

[0253] R 14 Each occurrence is independently selected from H, -OH, -NH2, -NHCH3, -N(CH3)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, cycloalkyl and heterocyclic groups are optionally selected independently by one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0254] R a Chelating agents selected from non-radioactive or radioactive nuclides;

[0255] R c and R d Each occurrence is independently selected from H, D, halogen, =O, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl and heterocyclic groups are optionally selected by one or more independently from halogen, D, OH, -COOH, -CONH2, CN, -NH2 and C. 1-6 Alkyl substituents;

[0256] L is Where “*” represents the connection point with Y;

[0257] X a X b X c X d X e X f X h and X i It does not exist, or it is selected independently from -O-, -S-, -Se-, -CR each time it appears. x R y -、-NR z -, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, -CR x =CR y -、-C≡C-、-N=CR x -、-C(=N-OH)-、C 3-6 Cycloalkyl, 4-8-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups, wherein the cycloalkyl, heterocyclic, phenyl, and heteroaryl groups are optionally selected by one or more of the radicals, each independently selected from halogens, D, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; condition is when L is And R 1 R 4 R 8 R 10 CH3, R 9 For phenyl and pyrazolyl groups, R 11 When it is H, X 2 For -NH- and -N(CH3)-;

[0258] R x and R y Each is independently selected from H, halogen, D, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0259] R z Selected from H, C 1-6 Alkyl groups and CD3;

[0260] X g Selected from CH, N, C 3-6 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl and 5-12-membered heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected independently by one or more halogens, D, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0261] Each time Y appears, it is independently selected from chemical bonds, -(CR) f R g ) m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkenyl, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12-membered heteroaryl groups; the alkenyl, ynyl, cycloalkenyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more of the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O;

[0262] R f and R g Each occurrence is independently selected from H, D, halogen, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, wherein the alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected by one or more elements, each independently selected from halogen, D, OH, -COOH, -CONH2, CN, -NH2, and C. 1-6 Alkyl substituents;

[0263] Each time m appears, it is independently selected from 1 to 20;

[0264] n is selected from 0-20.

[0265] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, X1 and X 3 Each is independently selected from N and CH, X 2 Selected from -CH2- and -NH-.

[0266] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, X 1 and X 3 Each is independently selected from N, X 2 Selected from -CH2-.

[0267] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, X 1 and X 3 Each is independently selected from N, X 2 Selected from -NH-.

[0268] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, X 1 Selected from N, X 3 Selected from CH, X 2 Selected from -CH2-.

[0269] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, X 1 Selected from N, X 3 Selected from CH, X 2 Selected from -NH-.

[0270] In some embodiments, in the compounds of formula I02, formula I01, and formula I” provided by the present invention, X 5 Selected from CH.

[0271] In some embodiments, in the compounds of formula I02, formula I01, and formula I” provided by the present invention, X 5 Selected from N.

[0272] In some implementations, R 1 R 4 R 8 R 10 Each is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C3-6 Each cycloalkyl group is optionally substituted by one or more substituents selected independently from D, halogens, -OH, -CN and -COOH.

[0273] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 1 R 4 R 8 R 10 Each is independently selected from H and C. 1-4 Deuterated alkyl and C 1-4 Alkyl, the C 1-4 The alkyl group may optionally be substituted with one or more substituents, each independently selected from D, halogen, -OH, -CN, -C(O)NH2 and -COOH.

[0274] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 1 R 4 R 8 R 10 Each of the following groups is independently selected from H, CD3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are each optionally substituted by one or more substituents independently selected from D, halogen, -OH, -CN, -C(O)NH2, and -COOH.

[0275] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 1 R 4 R 8 R 10 Each of the groups is independently selected from H, CD3, methyl, and ethyl, wherein the methyl or ethyl group is optionally substituted with one or more substituents independently selected from D, halogen, -OH, -CN, -C(O)NH2, and -COOH.

[0276] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 1 R 4 R 8 R 10 Each is independently selected from H, CD3, -CH2C(O)NH2 or -CH2CH2C(O)NH2.

[0277] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 1 R 4R 8 R 10 Each is independently selected from H and C. 1-4 Deuterated alkyl and C 1-4 alkyl.

[0278] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 1 R 4 R 8 R 10 Each is independently selected from H, -CD3, and C. 1-4 alkyl.

[0279] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 1 R 4 R 8 R 10 Each is independently selected from H, -CD3, -CH3 and -CH2CH3.

[0280] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 1 R 4 R 8 R 10 Each is independently selected from H, -CD3, and -CH3.

[0281] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 1 R 4 R 8 R 10 Each is independently selected from -CD3 and -CH3.

[0282] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 1 R 4 R 8 R 10 Selected from -CH3.

[0283] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 1 R 4 R 8 R 10 At least one of them is selected from -CD3, and the rest are selected from -CH3.

[0284] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 1 R 4 R 8 R 10 Each was independently selected from C 1-4 Deuterated alkyl and C 1-4 Alkyl, the C 1-4 The alkyl group may be optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN, -C(O)NH2 and -COOH.

[0285] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 1 R 4 R 8 R 10 Each is independently selected from CD3, methyl, ethyl and -CH2CH2C(O)NH2.

[0286] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 2 and R 6 Each was independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Each of the haloalkoxy groups is optionally surrounded by one or more elements independently selected from halogen, D, -OH, -NH2, -CONH2, -COR. 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups.

[0287] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 2 and R 6 Each was independently selected from C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 Each alkoxy group is optionally selected by one or more independently from -NH2, -CONH2, C 1-6 Alkyl and C1-6 Substitution of alkoxy groups.

[0288] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 2 and R 6 Each was independently selected from C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally selected from one or more C14 groups. 1-6 Alkyl and C 1-6 Substitution of alkoxy groups.

[0289] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 2 Selected from C 3-6 alkyl.

[0290] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 2 Selected from

[0291] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 6 Selected from C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally bounded by one or more C groups, each independently of the other. 1-3 Substitution of alkoxy groups.

[0292] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 6 Selected from

[0293] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 3 and R 5 Each is independently selected from H, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SO2R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 2-6 Heteroalkyl, the C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 2-6 Each heteroalkyl group is optionally surrounded by one or more R c Replace; or R 3 and R 5 Together with the atoms to which it is attached, they form 7-18 membered heterocyclic groups.

[0294] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 3 and R 5 Each is independently selected from H, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 2-6 Heteroalkyl, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy and heteroalkyl are optionally denoted by one or more R c Replace; or R 3 and R 5 Together with the atoms to which it is attached, they form 7-18 membered heterocyclic groups.

[0295] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 3 and R 5 Each is independently selected from H and C. 1-4 Alkyl groups, -CONH2, -COOH, -NHCONH2, and -S(O)2OH; or R 3 and R 5 Together with the atoms to which it is attached, they form 7-18 membered heterocyclic groups.

[0296] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 3 and R 5 Each is independently selected from H and C. 1-4 Alkyl, -CONH2, -COOH and -NHCONH2; or R 3 and R 5 Together with the atoms to which it is attached, they form 7-18 membered heterocyclic groups.

[0297] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 3 and R 5 Each is independently selected from H, -CONH2, -COOH, -NHCONH2, and -S(O)2OH; or R 3 and R 5 Together with the atoms to which it is attached, they form 7-18 membered heterocyclic groups.

[0298] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 3 and R 5 Each is independently selected from H, -CONH2, -COOH, and -NHCONH2; or R 3 and R 5 Together with the atoms to which it is attached, they form 7-18 membered heterocyclic groups.

[0299] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 3 and R 5 Each is independently selected from H, -CONH2, -COOH and -S(O)2OH.

[0300] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 3 and R 5 Each is independently selected from H, -CONH2, and -COOH.

[0301] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 3 Selected from -COOH and -S(O)2OH.

[0302] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 3 Selected from -COOH.

[0303] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 5 Selected from -CONH2.

[0304] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, k10 is 0 or 1, R 5 Selected from H, C 1-4 alkyl.

[0305] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, k10 is 0 or 1, R 5 Selected from H, -CH3.

[0306] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, k10 is 0 or 1, R 5 Selected from H.

[0307] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, k10 is 2, and R 5 Selected from -C(O)NH2.

[0308] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 3 Selected from -COOH and -S(O)2OH, R 5 Selected from -CONH2.

[0309] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 3 Selected from -COOH, R 5 Selected from -CONH2.

[0310] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 7 Selected from -OH, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -OR 14 -OC(=O)R 14 -SO2R 14 -OP(=O)(OR) 13 (OR) 14 -P(=O)(OR) 13 (OR) 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups, C 2-6 Heteroalkyl, C 1-6 The hydroxyalkyl group and the 3-8 membered heterocyclic group are each optionally surrounded by one or more R groups. d replace.

[0311] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 7 Selected from -OH, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -OR 14 -OC(=O)R 14 -OP(=O)(OR) 13 (OR) 14 -P(=O)(OR) 13 (OR) 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Heteroalkyl and C 1-6 hydroxyalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Heteroalkyl and C 1-6 hydroxyalkyl groups are each optionally surrounded by one or more R d replace.

[0312] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 7 Selected from -OH, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -OR 14 -OC(=O)R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Heteroalkyl and C 1-6Hydroxyalkyl, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, heteroalkyl, and hydroxyalkyl are optionally denoted by one or more R d replace.

[0313] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 7 Selected from -OH, -COOH, -OR 14 -SO2R 14 -OP(=O)(OR) 13 (OR) 14 -P(=O)(OR) 13 (OR) 14 C 1-6 Alkyl, C 1-6 Alkoxy, C 2- 6-heteroalkyl groups and 3-8-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroalkyl group and the 3-8 membered heterocyclic group are each optionally surrounded by one or more R groups. d replace.

[0314] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 7 Selected from -OH, -COOH, -OR 14 -OP(=O)(OR) 13 (OR) 14 -P(=O)(OR) 13 (OR) 14 C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Heteroalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 2-6 Each heteroalkyl group is optionally surrounded by one or more R d replace.

[0315] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 7 Selected from -OH, -COOH, -OR 14 C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Heteroalkyl, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, heteroalkyl and hydroxyalkyl are optionally separated by one or more R d replace.

[0316] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 7 Selected from -SO2R 14 -OP(=O)(OR) 13 (OR) 14 C 1-6 alkoxy groups and 3-8 membered heterocyclic groups, wherein the C 1-6 The alkoxy group and the 3-8 membered heterocyclic group are optionally separated by one or more R groups. d replace.

[0317] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 7 Selected from -OCH2COOH, -OP(=O)(OH)(OH), -S(O)2OH and

[0318] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 7 Selected from -S(O)2OH and

[0319] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 7 Selected from -OCH2COOH and -OP(=O)(OH)(OH).

[0320] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 7 Selected from -OCH2COOH.

[0321] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R d Each time it appears, it is independently selected from -OH, -COOH, and -CONH2.

[0322] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected halogens, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, -SO2R 14 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Substitution of alkyl halogens.

[0323] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3- 8-cyclic alkenyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected halogens, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, -SO2R 14 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6The substituents of the haloalkyl group are selected independently from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Haloalkyl, wherein the C 1-6 Alkyl or C 1-6 Each haloalkyl group is optionally substituted by one or more substituents selected independently from D, halogen, -OH, -CN and -COOH.

[0324] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected halogens, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, -SO2R 14 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 The substituents of the haloalkyl group are selected independently from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Haloalkyl, wherein the C 1-6 Alkyl or C 1-6 Each haloalkyl group is optionally substituted by one or more substituents selected independently from D, halogen, -OH, -CN and -COOH.

[0325] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic groups, C 6-10Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3- 8-cyclic alkenyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected from halogen, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 The substituents of the haloalkyl group are selected independently from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1- 6-alkyl or C 1-6 The haloalkyl group is optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH.

[0326] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected from halogen, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 The substituents of the haloalkyl group are selected independently from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6The haloalkyl group is optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH.

[0327] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from C 6-10 Aryl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic and 5-10 membered heteroaryl, C 6-10 Aryl, C 3-8 cycloalkyl, C 3-8 The cycloalkenyl, 3-8 membered heterocyclic and 5-10 membered heteroaryl groups are each optionally selected by one or more independently selected from halogen, D, CN, =CR′R″, -SO2R 14 C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkoxy group, R′ and R″, are each independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0328] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from C 6-10 Aryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic and 5-10 membered heteroaryl, C 6-10 Aryl, C 3-8 The cycloalkyl group, the 3-8 membered heterocyclic group, and the 5-10 membered heteroaryl group are each optionally selected independently by one or more halogens, D, CN, =CR′R″, -SO2R 14 C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkyl group are selected independently from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkoxy groups.

[0329] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from C 6-10 Aryl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic and 5-10 membered heteroaryl, wherein C 6-10 Aryl, C 3-8 cycloalkyl, C 3-8The cycloalkenyl, 3-8 membered heterocyclic and 5-10 membered heteroaryl groups are each optionally selected independently by one or more halogens, D, CN, =CR′R″, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkoxy group, R′ and R″, are each independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0330] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from C 6-10 Aryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic and 5-10 membered heteroaryl, wherein C 6-10 Aryl, C 3-8 The cycloalkyl group, the 3-8 membered heterocyclic group, and the 5-10 membered heteroaryl group are each optionally selected independently by one or more halogens, D, CN, =CR′R″, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkyl group are selected independently from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkoxy groups.

[0331] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl, piperidinyl, Cyclohexyl and cyclohexenyl, the phenyl, piperidinyl, The cyclohexyl and cyclohexenyl groups are optionally selected by one or more groups, each independently chosen from halogen, D, CN, =CR′R″, -SO2R. 14 C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkyl group are selected independently from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0332] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl, piperidinyl, and cyclohexyl, the phenyl, piperidinyl, The cyclohexyl group is optionally selected by one or more halogens, D, CN, =CR′R″, -SO2R. 14C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkoxy group, R′ and R″, are each independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0333] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl, piperidinyl, and cyclohexyl, the phenyl, piperidinyl, The cyclohexyl group is optionally selected by one or more halogens, D, CN, =CR′R″, C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkoxy group, R′ and R″, are each independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0334] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl, piperidinyl, and cyclohexyl, wherein the phenyl, piperidinyl, and cyclohexyl groups are optionally selected by one or more of the radicals, each independently selected from halogen, D, CN, =CR′R″, -SO2R. 14 C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkoxy group, R′ and R″, are each independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0335] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl, piperidinyl, and cyclohexyl, wherein the phenyl, piperidinyl, and cyclohexyl groups are optionally selected by one or more of the radicals, each independently selected from halogen, D, CN, =CR′R″, C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkoxy group, R′ and R″, are each independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0336] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R9 Selected from phenyl, piperidinyl, Cyclohexyl and cyclohexenyl, the phenyl, piperidinyl, The cyclohexyl and cyclohexenyl groups may optionally be substituted by one or more substituents selected independently from F, Cl, D, CN, =CF2, =C(CH3)2, methyl, methoxy, -CF3, -CHF2, -CH2F and -S(O)2NH2.

[0337] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl, piperidinyl, and cyclohexyl, the phenyl, piperidinyl, The cyclohexyl group may be optionally substituted with one or more substituents selected independently from F, Cl, D, CN, =CF2, =C(CH3)2, methyl, methoxy, -CF3, -CHF2, -CH2F and -S(O)2NH2.

[0338] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl, piperidinyl, and cyclohexyl, the phenyl, piperidinyl, The cyclohexyl group may be optionally substituted by one or more substituents selected independently from F, Cl, D, CN, =CF2, =C(CH3)2, methyl, methoxy, -CF3, -CHF2, -CH2F.

[0339] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 The group is selected from phenyl, piperidinyl, and cyclohexyl, wherein the phenyl, piperidinyl, and cyclohexyl groups are optionally substituted by one or more substituents, each independently selected from F, Cl, D, CN, =CF2, =C(CH3)2, methyl, methoxy, -CF3, -CHF2, -CH2F, and -S(O)2NH2.

[0340] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 The group is selected from phenyl, piperidinyl, and cyclohexyl, wherein the phenyl, piperidinyl, and cyclohexyl groups are optionally substituted by one or more substituents, each independently selected from F, Cl, D, CN, =CF2, =C(CH3)2, methyl, methoxy, -CF3, -CHF2, and -CH2F.

[0341] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl,

[0342] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl,

[0343] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl,

[0344] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl,

[0345] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl,

[0346] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, and heteroaryl groups are optionally selected by one or more elements, each independently selected from halogen, D, OH, CN, -NH2, -COOH, -CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Substitution of alkyl halogens.

[0347] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from C 6-10 Aryl and 5-10 heteroaryl groups, wherein the aryl and heteroaryl groups are optionally selected independently by one or more halogens, D, C. 1-6 Alkyl, C 1-6 Alkoxy and C1-6 Substituents of haloalkoxy groups.

[0348] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl and 5-6-membered heteroaryl groups, wherein the phenyl and heteroaryl groups are optionally selected by one or more halogens, D and C, respectively. 1-6 Alkyl substituents.

[0349] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl or phenyl substituted with one methyl group.

[0350] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 9 Selected from phenyl.

[0351] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, R′ and R″ are each independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0352] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R′ and R″ are each independently selected from H, D, F, Cl, methyl, ethyl, n-propyl, isopropyl, CF3, -CHF2 and -CH2F.

[0353] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Each is independently selected from H, D, OH, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 cycloalkyl, the C 1-6 Alkyl, C 3-8 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from halogens, -OH, -NH2-, -CN, -COOH, and -CONH2; or R 11a and R 11 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally composed of one or more atoms independently selected from H, halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4Haloalkoxy, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 and -OC(=O)R 14 Substituents are substituted.

[0354] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Each is independently selected from H, D, OH, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl and C 3-8 cycloalkyl, the C 1-6 Alkyl, C 3-8 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from -NH2-, -COOH, and -CONH2; or R 11a and R 11 Together with the atoms to which it is attached, it forms a 5-6 membered heterocyclic group, which is optionally formed by one or more atoms independently selected from H, halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Substituents of haloalkoxy groups.

[0355] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Each is independently selected from H, D, OH, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl and C 3-8 cycloalkyl, the C 1-6 Alkyl, C 3-8 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from -NH2-, -COOH, and -CONH2; or R 11a and R 11 Together with the atoms to which it is attached, it forms a 5-6 membered heterocyclic group, which is optionally formed by one or more atoms independently selected from H, halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Substituents of haloalkoxy groups.

[0356] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Each is independently selected from H, D, OH, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl and C 3-8 cycloalkyl, the C 1-6 Alkyl, C 3-8 The cycloalkyl group is optionally substituted by one or more substituents, each independently selected from -NH2-, -COOH, and -CONH2; or R 11a and R 11 Together with the atoms to which it is attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by one or more substituents selected independently from H, halogen, -OH, -CN, and -CH3.

[0357] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Each is independently selected from H, D, OH, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl groups and -CH2COOH.

[0358] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Each is independently selected from H, D, OH, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl and C 3-8 Cycloalkyl.

[0359] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Each is independently selected from H, D, OH, and C. 1-6 Alkyl and C 1-6 Deuterated alkyl groups.

[0360] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Each is independently selected from H, D, OH, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, the C 1-6 The alkyl group is optionally substituted by one or more substituents, each independently selected from -COOH and -CONH2.

[0361] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Each is independently selected from H, D, OH, methyl, ethyl, isopropyl, -CH2COOH and cyclopropyl.

[0362] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Each is independently selected from H, D, OH, methyl, ethyl, isopropyl, and cyclopropyl.

[0363] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Each is independently selected from H, D, OH and methyl.

[0364] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a Selected from H and methyl, R 11 Selected from H, D, OH and methyl.

[0365] In some embodiments, in the compound of formula I provided by the present invention, R 11 Selected from H and OH.

[0366] In some embodiments, in the compound of formula I provided by the present invention, R 11 Selected from H.

[0367] In some embodiments, in the compound of formula I provided by the present invention, R 11 Selected from OH.

[0368] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Together with the atoms to which it is attached, it forms a 5-6 membered heterocyclic group, which is optionally composed of one or more atoms independently selected from H, -OH, C. 1-6 Alkyl substituents.

[0369] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Together with the atoms to which it is attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by one or more substituents selected independently from H, -OH, and -CH3.

[0370] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Together with the atoms to which they are attached, they form piperazine, pyrrolidinyl, and morpholinyl groups, which are optionally substituted by one or more substituents, each independently selected from -OH and -CH3.

[0371] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Together with the atoms to which they are attached, they form piperazine or pyrrolidinyl groups, which are optionally substituted by one or more substituents selected independently from -OH or -CH3.

[0372] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Together with the atoms it is attached to, they form The aforementioned Optionally substituted by one or more substituents, each independently selected from H, halogen, -OH, -CN, -CH3.

[0373] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Together with the atoms it is attached to, they form the following groups: and

[0374] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Together with the atoms it is attached to, they form the following groups:

[0375] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11a and R 11 Each is independently selected from H, OH, methyl, isopropyl, cyclopropyl, -CH2COOH, or R. 11a and R 11 Together with the atoms it is attached to, they form the following groups:

[0376] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, R 11aSelected from H and methyl, R 11 Selected from H, D, OH and methyl; or R 11a and R 11 Together with the atoms it is attached to, they form the following groups:

[0377] In some embodiments, in the compounds of formula I02, formula I01, and formula I” provided by the present invention, R 16 R 17 R 18 R 19 Each is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 Cycloalkyl.

[0378] In some embodiments, in the compounds of formula I02, formula I01, and formula I” provided by the present invention, R 16 R 17 R 18 R 19 Each is independently selected from H, D, halogens and C. 1-6 alkyl.

[0379] In some embodiments, in the compounds of formula I02, formula I01, and formula I” provided by the present invention, R 16 R 17 R 18 R 19 Each is independently selected from H, halogens, and C. 1-6 alkyl.

[0380] In some embodiments, in the compounds of formula I02, formula I01, and formula I” provided by the present invention, R 16 R 17 R 18 R 19 Each is independently selected from H, D, F, Cl, methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl.

[0381] In some embodiments, in the compounds of formula I02, formula I01, and formula I” provided by the present invention, R 16 R 17 R 18 R 19 Each is independently selected from H and C. 1-6 alkyl.

[0382] In some embodiments, in the compounds of formula I02 and formula I01 provided by the present invention, R 20 Selected from -COR 13 -OSO2R 14 -SO2R14 -P(=O)(OR) 13 (OR) 14 ) and -OP(=O)(OR 13 (OR) 14 ).

[0383] In some embodiments, in the compounds of formula I02 and formula I01 provided by the present invention, R 20 Selected from -COOH, -OS(O)2F, -S(O)2F, -OP(=O)(OH)(OH), -P(=O)(OH)2, -S(O)2OH, -OS(O)2OH, -OS(O)2CH3 and -OS(O)2CH2CH3.

[0384] In some embodiments, in the compounds of formula I02 and formula I01 provided by the present invention, R 20 Selected from -COOH, -OS(O)2F, -S(O)2F, -OP(=O)(OH)(OH), -S(O)2OH.

[0385] In some embodiments, in the compounds of formula I02 and formula I01 provided by the present invention, R 20 Selected from -COOH, -OS(O)2F, -OP(=O)(OH)(OH), -S(O)2OH.

[0386] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R t1 and R t2 Selected from H.

[0387] In some embodiments, in the compounds of formula I02, formula I01, and formula I” provided by the present invention, J1, J2, J3, and J4 are each independently selected from 0, 1, 2, or 3 each time they appear.

[0388] In some embodiments, in the compounds of formula I02, formula I01, and formula I” provided by the present invention, J1, J2, J3, and J4 are each independently selected from 0 or 1 each time they appear.

[0389] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, k1 is selected from 0, 1, 2, or 3.

[0390] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, k1 is selected from 0 or 1.

[0391] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, k1 is 1.

[0392] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, k2, k3, k4, k5, k6, k7, k8, and k9 are selected from 0 or 1.

[0393] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, k2, k3, k4, k5, k6, k7, k8, and k9 are selected from O.

[0394] In some embodiments, in the compounds of formula I02, formula I01, formula I”, and formula I’ provided by the present invention, at least one of k2, k3, k4, k5, k6, k7, k8, and k9 is 1. For example, any one of k2, k3, k4, k5, k6, k7, k8, and k9 is 1, and the rest are 0.

[0395] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 12 and R 13 Each time it appears, it is independently selected from H, -OH, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl, or R 12 and R 13 Together with the atoms they are attached to, they form 3-8 membered heterocyclic groups.

[0396] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 12 and R 13 Each time it appears, it is independently selected from H, -OH, and C. 1-6 alkyl.

[0397] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R 14 Each occurrence is independently selected from -OH, -NH2, -NHCH3, -N(CH3)2, and C. 1-6 alkyl.

[0398] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, -(Y) n -Selected from: -NH-, -(CH2) m -NH-, -(CH2) m -S-(CH2) m -NH-, -(CH2) m -S-(CH2) m -CONH-(CH2) m-NH-、-N(R f )CO-(CH2) m -NH-、-N(R f )(CH2) m -NH-,-S-(CH2) m -NH-,-O-(CH2) m -NH-,-CO-(CH2) m -NH-、-(CH2) m -CONH-(CH2) m -NH-,-CONH-(CH2) m -NH-,-CO-(CH2) m -S-(CH2) m -NH-,-C(=N-OH)S-(CH2) m -NH-、-(CH2) m -O-(CH2) m -NH-、-(CH2) m -(CH2OCH2) m -(CH2) m -NH-、-N(R f )CO-(CH2) m -N(R f )-、-N(R f )CO-(CH2CH2O)m-(CH2) m -N(R f )-、-N(R f )CO-(CH2) m -CH(COOH)-N(R f )-、-N(R f )CO-(CR f R g ) m -(CH2) m -N(R f )-、-N(R f )CO-(CH2) m -N(R f )-(CH2) m -N(R f )-、-N(R f )CO-(CH2) m -N(R f )CO-(CH2) m -N(R f )-、-N(R f )-(CH2)mN(R f )-(CH2)mN(R f)-、-N(R f CO-(CH2) m -(4-12 membered heterocyclic group)-, -N(R) f CO-(CH2) m -(4-12 membered heterocyclic group)-N(R) f )-、-N(R f CO-(CH2) m –amino acid residue-, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -C 3-6 Cycloalkyl-CO-(CH2) m -、-(4-12 membered heterocyclic group)-CO-(CH2) m -、-C 6-10 Aryl-CO-(CH2) m -、-(5-12 heteroaryl)-CO-(CH2) m -、-C 3-6 Cycloalkyl-CO-, -(4-12 membered heterocyclic)-CO-, -C 6-10 aryl-CO-, -(5-12 heteroaryl)-CO-, -C 3-6 Cycloalkyl-(CH2) m -、-(4-12 membered heterocyclic group)-(CH2) m -、-C 6-10 Aryl-(CH2) m -、-(5-12 heteroaryl)-(CH2) m -、-N(R f CO-(CH2) m -N(R f -amino acid residues-、-N(R) f CO-(CH2) m -N(R f )-amino acid residue-amino acid residue-、

[0399] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, -(Y) n -Selected from: -NH-, -(CH2) m -NH-, -(CH2) m -S-(CH2) m -NH-, -(CH2) m -S-(CH2) m -CONH-(CH2) m -NH-、-N(R f)CO-(CH2) m -NH-、-N(R f )(CH2) m -NH-、-S-(CH2) m -NH-、-O-(CH2) m -NH-、-CO-(CH2) m -NH-、-(CH2) m -CONH-(CH2) m -NH-、-CONH-(CH2) m -NH-、-CO-(CH2) m -S-(CH2) m -NH-、-C(=N-OH)S-(CH2) m -NH-、-(CH2) m -O-(CH2) m -NH-、-(CH2) m -(CH2OCH2) m -(CH2) m -NH-、-N(R f )CO-(CH2) m -N(R f )-、-N(R f )CO-(CH2CH2O)m-(CH2) m -N(R f )-、-N(R f )CO-(CR f R g ) m -(CH2) m -N(R f )-、-N(R f )CO-(CH2) m -N(R f )-(CH2) m -N(R f )-、-N(R f )CO-(CH2) m -N(R f )CO-(CH2) m -N(R f )-、-N(R[[ID=7)]] f )CO-(CH2) m -(4-12 membered heterocyclic group)-、-N(R f )CO-(CH2) m -(4-12 membered heterocyclic group)-N(R f )-、-N(R f )CO-(CH2)m –amino acid residue-, C 3- 6-cycloalkyl, 4-12 membered heterocyclic, C 6-10 Aryl, 5-12 heteroaryl, -C 3-6 Cycloalkyl-CO-(CH2) m -、-(4-12 membered heterocyclic group)-CO-(CH2) m -、-C 6-10 Aryl-CO-(CH2) m -、-(5-12 heteroaryl)-CO-(CH2) m -、-C 3-6 Cycloalkyl-CO-, -(4-12 membered heterocyclic)-CO-, -C 6-10 aryl-CO-, -(5-12 heteroaryl)-CO-, -C 3-6 Cycloalkyl-(CH2) m -、-(4-12 membered heterocyclic group)-(CH2) m -、-C 6-10 Aryl-(CH2) m -、-(5-12 heteroaryl)-(CH2) m -、-N(R f CO-(CH2) m -N(R f -amino acid residues-、-N(R) f CO-(CH2) m -N(R f )-amino acid residue-amino acid residue-.

[0400] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, -(Y) n -Selected from: -NH-, -(CH2) m -NH-, -(CH2) m -S-(CH2) m -NH-, -(CH2) m -S-(CH2) m -CONH-(CH2) m -NH-、-N(R f CO-(CH2) m -NH-、-N(R f (CH2) m -NH-, -S-(CH2) m -NH-, -O-(CH2) m -NH-, -CO-(CH2) m -NH-, -(CH2) m-CONH-(CH2) m -NH-, -CONH-(CH2) m -NH-, -CO-(CH2) m -S-(CH2) m -NH-, -C(=N-OH)S-(CH2) m -NH-, -(CH2) m -O-(CH2) m -NH-, -(CH2) m -(CH2OCH2) m -(CH2) m -NH-、-N(R f CO-(CH2) m -N(R f )-、-N(R f CO-(CH2CH2O)m-(CH2) m -N(R f )-、-N(R f )CO-(CR f R g ) m -(CH2) m -N(R f )-、-N(R f CO-(CH2) m -N(R f )-(CH2) m -N(R f )-、-N(R f CO-(CH2) m -N(R f CO-(CH2) m -N(R f )-、-N(R f CO-(CH2) m -(4-12 membered heterocyclic group)-, -N(R) f CO-(CH2) m -(4-12 membered heterocyclic group)-N(R) f )-、-N(R f CO-(CH2) m –amino acid residue-, C 3- 6-cycloalkyl, 4-12 membered heterocyclic, C 6-10 Aryl, 5-12 heteroaryl, -C 3-6 Cycloalkyl-CO-(CH2) m -、-(4-12 membered heterocyclic group)-CO-(CH2) m -、-C 6-10Aryl-CO-(CH2) m -、-(5-12 heteroaryl)-CO-(CH2) m -、-C 3-6 Cycloalkyl-CO-, -(4-12 membered heterocyclic)-CO-, -C 6-10 aryl-CO-, -(5-12 heteroaryl)-CO-, -C 3-6 Cycloalkyl-(CH2) m -、-(4-12 membered heterocyclic group)-(CH2) m -、-C 6-10 Aryl-(CH2) m -、-(5-12 heteroaryl)-(CH2) m -

[0401] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, -(Y) n -Selected from:-(CH2) m -NH-, -(CH2) m -S-(CH2) m -NH-, -(CH2) m -S-(CH2) m -CONH-(CH2) m -NH-、-N(R f CO-(CH2) m -NH-、-N(R f (CH2) m -NH-, -S-(CH2) m -NH-, -O-(CH2) m -NH-, -CO-(CH2) m -NH-, -(CH2) m -CONH-(CH2) m -NH-, -CONH-(CH2) m -NH-, -CO-(CH2) m -S-(CH2) m -NH-, -C(=N-OH)S-(CH2) m -NH-, -(CH2) m -O-(CH2) m -NH-, -(CH2) m -(CH2OCH2) m -(CH2) m -NH-、-N(R f CO-(CH2) m -N(R f )-、-N(Rf CO-(CH2CH2O)m-(CH2) m -N(R f )-、C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -C 3-6 Cycloalkyl-CO-(CH2) m -、-(4-12 membered heterocyclic group)-CO-(CH2) m -、-C 6-10 Aryl-CO-(CH2) m -、-(5-12 heteroaryl)-CO-(CH2) m -、-C 3-6 Cycloalkyl-CO-, -(4-12 membered heterocyclic)-CO-, -C 6-10 aryl-CO-, -(5-12 heteroaryl)-CO-, -C 3-6 Cycloalkyl-(CH2) m -、-(4-12 membered heterocyclic group)-(CH2) m -、-C 6-10 Aryl-(CH2) m -、-(5-12 heteroaryl)-(CH2) m -

[0402] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, -(Y) n -Selected from:-(CH2) m -NH-, -(CH2) m -S-(CH2) m -NH-, -(CH2) m -S-(CH2) m -CONH-(CH2) m -NH-、-N(R f CO-(CH2) m -NH-、-N(R f (CH2) m -NH-, -S-(CH2) m -NH-, -O-(CH2) m -NH-, -CO-(CH2) m -NH-, -(CH2) m -CONH-(CH2) m -NH-, -CONH-(CH2) m -NH-, -CO-(CH2) m -S-(CH2) m-NH-, -C(=N-OH)S-(CH2) m -NH-, -(CH2) m -O-(CH2) m -NH-, -(CH2) m -(CH2OCH2) m -(CH2) m -NH-, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -C 3-6 Cycloalkyl-CO-(CH2) m -、-(4-12 membered heterocyclic group)-CO-(CH2) m -、-C 6-10 Aryl-CO-(CH2) m -、-(5-12 heteroaryl)-CO-(CH2) m -、-C 3-6 Cycloalkyl-CO-, -(4-12 membered heterocyclic)-CO-, -C 6-10 aryl-CO-, -(5-12 heteroaryl)-CO-, -C 3-6 Cycloalkyl-(CH2) m -、-(4-12 membered heterocyclic group)-(CH2) m -、-C 6-10 Aryl-(CH2) m -、-(5-12 heteroaryl)-(CH2) m -

[0403] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, -(Y) n -Selected from:-(CH2) m -NH-, -(CH2) m -S-(CH2) m -NH-, -(CH2) m -S-(CH2) m -CONH-(CH2) m -NH-、-N(R f CO-(CH2) m -NH-, -S-(CH2) m -NH-, -O-(CH2) m -NH-, -CO-(CH2) m -NH-, -(CH2) m -CONH-(CH2) m -NH-, -CONH-(CH2) m-NH-, -CO-(CH2) m -S-(CH2) m -NH-, -C(=N-OH)S-(CH2) m -NH-, -(CH2) m -O-(CH2) m -NH-, -(CH2) m -(CH2OCH2) m -(CH2) m -NH-, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -C 3-6 Cycloalkyl-CO-(CH2) m -、-(4-12 membered heterocyclic group)-CO-(CH2) m -、-C 6-10 Aryl-CO-(CH2) m -、-(5-12 heteroaryl)-CO-(CH2) m -、-C 3-6 Cycloalkyl-CO-, -(4-12 membered heterocyclic)-CO-, -C 6-10 aryl-CO-, -(5-12 heteroaryl)-CO-, -C 3-6 Cycloalkyl-(CH2) m -、-(4-12 membered heterocyclic group)-(CH2) m -、-C 6-10 Aryl-(CH2) m -、-(5-12 heteroaryl)-(CH2) m -

[0404] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, -(Y) n-Selected from: -NH-, -CH2CH2NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -CH2SCH2CONHCH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2N H-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -N(CH3)COCH2CH2NH-, -SCH2CH2NH-, -OCH2CH2NH-, -C(=O)CH2CH2NH-, -CH2C(=O)NHCH2CH2NH-, -C(=O)NHCH2 CH2NH-, -C(=O)CH2CH2SCH2CH2NH-, -C(=O)CH2SCH2CH2NH-, -CH2CH2C(=O)NHCH2CH2NH-, -C(=N-OH)SCH2CH2NH-, -CH2CH2OCH2CH2NH-, -CH2(CH2OCH2)2CH2NH-, -CH2(CH2OCH2)3CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-, -N(CH3)COCH2CH2N(CH3)-,

[0405] -N(CH3)CO(CH2CH2O)3CH2CH2NH-, -NHCO(CH2CH2O)3CH2CH2NH-, -NHCOCH2CH2-CH(COOH)-NH-, -NHCOCH2CH2NHCOCH2CH2 NH-, -NHCOCH(NH2)CH2CH2CH2CH2NH-, -NHCOCH2NHCH2CH2NH-, -NHCOCH2CH2NHCH2CH2NH-, -NHCH2CH2N(CH3)CH2CH2NH-,

[0406] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, -(Y) n-Selected from: -NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2NH-, -NHCOCH2CH2CH2NH-, -NHCOCH2 CH2CH2CH2NH-, -C(=O)CH2CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH 2NH-, -N(CH3)COCH2CH2N(CH3)-, -N(CH3)CO(CH2CH2O)3CH2CH2NH-, -NHCO(CH2CH2O)3CH2CH2NH-, -NHCOCH2CH2-CH(COOH)-NH-, -NHCOCH 2CH2NHCOCH2CH2NH-, -NHCOCH(NH2)CH2CH2CH2CH2NH-, -NHCOCH2NHCH2CH2NH-, -NHCOCH2CH2NHCH2CH2NH-, -NHCH2CH2N(CH3)CH2CH2NH-, -

[0407] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, -(Y) n-Selected from: -NH-, -CH2CH2NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -CH2SCH2CONHCH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2N H-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -N(CH3)COCH2CH2NH-, -SCH2CH2NH-, -OCH2CH2NH-, -C(=O)CH2CH2NH-, -CH2C(=O)NHCH2CH2NH-, -C(=O)NHCH2 CH2NH-, -C(=O)CH2CH2SCH2CH2NH-, -C(=O)CH2SCH2CH2NH-, -CH2CH2C(=O)NHCH2CH2NH-, -C(=N-OH)SCH2CH2NH-, -CH2CH2OCH2CH2NH-, -CH2(CH2OCH2)2CH2NH-, -CH2(CH2OCH2)3CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-, -N(CH3)COCH2CH2N(CH3)-,

[0408] -N(CH3)CO(CH2CH2O)3CH2CH2NH-, -NHCO(CH2CH2O)3CH2CH2NH-, -NHCOCH2CH2-CH(COOH)-NH-, -NHCOCH2CH2NHCOCH2CH2 NH-, -NHCOCH(NH2)CH2CH2CH2CH2NH-, -NHCOCH2NHCH2CH2NH-, -NHCOCH2CH2NHCH2CH2NH-, -NHCH2CH2N(CH3)CH2CH2NH-,

[0409] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, -(Y) n-Selected from: -NH-, -CH2CH2NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -CH2 SCH2CONHCH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2NH-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -N(CH3)C OCH2CH2NH-, -SCH2CH2NH-, -OCH2CH2NH-, -C(=O)CH2CH2NH-, -CH2C(=O)NHCH2CH2NH-, -C(=O)NHCH2CH2NH-, - C(=O)CH2CH2SCH2CH2NH-, -C(=O)CH2SCH2CH2NH-, -CH2CH2C(=O)NHCH2CH2NH-, -C(=N-OH)SCH2CH2NH-, -CH2CH 2OCH2CH2NH-, -CH2(CH2OCH2)2CH2NH-, -CH2(CH2OCH2)3CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHC H2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-, -N(CH3)COCH2CH2N(CH3)-, -N(CH3)CO(CH2CH2 O)3CH2CH2NH-, -NHCO(CH2CH2O)3CH2CH2NH-, -NHCOCH2CH2-CH(COOH)-NH-, -NHCOCH2CH2NHCOCH2CH2NH-, -NHC OCH(NH2)CH2CH2CH2CH2NH-, -NHCOCH2NHCH2CH2NH-, -NHCOCH2CH2NHCH2CH2NH-, -NHCH2CH2N(CH3)CH2CH2NH-,

[0410] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, -(Y) n-Selected from: -CH2CH2NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -CH2SCH2CONHCH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2NH-, - NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -N(CH3)COCH2CH2NH-, -SCH2CH2NH-, -OCH2CH2NH-, -C(=O)CH2CH2NH-, -CH2C(=O)NHCH2CH2NH-, -C(=O)NHCH2CH2 NH-, -C(=O)CH2CH2SCH2CH2NH-, -C(=O)CH2SCH2CH2NH-, -CH2CH2C(=O)NHCH2CH2NH-, -C(=N-OH)SCH2CH2NH-, -CH2CH2OCH2CH2NH-, -CH2(CH2OCH2)2CH2NH-, -C H2(CH2OCH2)3CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-, -N(CH3)COCH2CH2N(CH3)-,

[0411] -N(CH3)CO(CH2CH2O)3CH2CH2NH-, -NHCO(CH2CH2O)3CH2CH2NH-,

[0412] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, -(Y) n-Selected from: -CH2CH2NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -CH2SCH2CONHCH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH 2NH-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -N(CH3)COCH2CH2NH-, -SCH2CH2NH-, -OCH2CH2NH-, -C(=O)CH2CH2NH-, -CH2C(=O)NHCH2CH2NH-, -C (=O)NHCH2CH2NH-, -C(=O)CH2CH2SCH2CH2NH-, -C(=O)CH2SCH2CH2NH-, -CH2CH2C(=O)NHCH2CH2NH-, -C(=N-OH)SCH2CH2NH-, -CH2CH2OCH2CH2NH-, -CH2( CH2OCH2)2CH2NH-, -CH2(CH2OCH2)3CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-,

[0413] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, -(Y) n -Selected from: -CH2CH2CH2CH2NH-, -CH2CH2CH2NH-, CH2SCH2CH2CH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2NH-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -C (=O)CH2CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-, and -N(CH3)COCH2CH2NH-.

[0414] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0415] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0416] Y is independently selected from single bonds and -(CH2). m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl, amino acid residues, and 5-12 membered heteroaryl groups; said cycloalkyl, heterocyclic, aryl, amino acid residues, and heteroaryl groups are optionally substituted by one or more of the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O;

[0417] Ring A is a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle;

[0418] R b Each occurrence is independently selected from H, D, halogen, =O, -OH, -CN, -NH2, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0419] p is independently selected from any integer in the range of 0-3.

[0420] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0421] Y is independently selected from single bonds and -(CH2). m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 3-6Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 membered heteroaryl groups; said cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more of the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O;

[0422] Ring A is a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle;

[0423] R b Each occurrence is independently selected from H, D, halogen, =O, -OH, -CN, -NH2, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0424] p is independently selected from any integer in the range of 0-3.

[0425] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0426] Y is independently selected from single bonds and -(CH2). m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 membered heteroaryl groups; said cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more of the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O;

[0427] Ring A is a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle;

[0428] R b Each occurrence is independently selected from H, D, halogen, =O, -OH, -CN, -NH2, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0429] p is independently selected from any integer in the range of 0-3.

[0430] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0431] Y is independently selected from single bonds and -(CH2). m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 membered heteroaryl groups; said cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more of the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O;

[0432] Ring A is a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle;

[0433] R b Each occurrence is independently selected from H, D, halogen, =O, -OH, -CN, -NH2, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0434] p is independently selected from any integer in the range of 0-3.

[0435] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0436] Y is independently selected from single bonds and -(CH2). m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 3-6Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 membered heteroaryl groups; said cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more of the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O;

[0437] Ring A is a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle;

[0438] R b Each occurrence is independently selected from H, D, halogen, =O, -OH, -CN, -NH2, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0439] p is independently selected from any integer in the range of 0-3.

[0440] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0441] Y is independently selected from single bonds and -(CH2). m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl, amino acid residues, and 5-12 membered heteroaryl groups; said cycloalkyl, heterocyclic, aryl, amino acid residues, and heteroaryl groups are optionally substituted by one or more of the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O.

[0442] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0443] Y is independently selected from single bonds and -(CH2). m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CRf -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 membered heteroaryl groups; said cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more of the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O.

[0444] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0445] Y is independently selected from single bonds and -(CH2). m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 membered heteroaryl groups; said cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more of the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O.

[0446] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0447] Y is independently selected from single bonds and -(CH2). m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 3-6Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 membered heteroaryl groups; said cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more of the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O.

[0448] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0449] -(Y) n -Selected from: -NH-, -CH2CH2NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -CH2SCH2CONHCH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2N H-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -N(CH3)COCH2CH2NH-, -SCH2CH2NH-, -OCH2CH2NH-, -C(=O)CH2CH2NH-, -CH2C(=O)NHCH2CH2NH-, -C(=O)NHCH2 CH2NH-, -C(=O)CH2CH2SCH2CH2NH-, -C(=O)CH2SCH2CH2NH-, -CH2CH2C(=O)NHCH2CH2NH-, -C(=N-OH)SCH2CH2NH-, -CH2CH2OCH2CH2NH-, -CH2(CH2OCH2)2CH2NH-, -CH2(CH2OCH2)3CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-, -N(CH3)COCH2CH2N(CH3)-,

[0450] -N(CH3)CO(CH2CH2O)3CH2CH2NH-, -NHCO(CH2CH2O)3CH2CH2NH-, -NHCOCH2CH2-CH(COOH)-NH-, -NHCOCH2CH2NHCOCH2CH2NH-, -NHCOCH(N H2)CH2CH2CH2CH2NH-, -NHCOCH2NHCH2CH2NH-, -NHCOCH2CH2NHCH2CH2NH-, -NHCH2CH2N(CH3)CH2CH2NH-, -NHCOCH2CH2N(CH3)CH2CH2NH-,

[0451] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0452] -(Y) n -Selected from: -NH-, -CH2CH2NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -CH2SCH2CONHCH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2N H-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -N(CH3)COCH2CH2NH-, -SCH2CH2NH-, -OCH2CH2NH-, -C(=O)CH2CH2NH-, -CH2C(=O)NHCH2CH2NH-, -C(=O)NHCH2 CH2NH-, -C(=O)CH2CH2SCH2CH2NH-, -C(=O)CH2SCH2CH2NH-, -CH2CH2C(=O)NHCH2CH2NH-, -C(=N-OH)SCH2CH2NH-, -CH2CH2OCH2CH2NH-, -CH2(CH2OCH2)2CH2NH-, -CH2(CH2OCH2)3CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-, -N(CH3)COCH2CH2N(CH3)-,

[0453] -N(CH3)CO(CH2CH2O)3CH2CH2NH-, -NHCO(CH2CH2O)3CH2CH2NH-, -NHCOCH2CH2-CH(COOH)-NH-, -NHCOCH2CH2NHCOCH2CH2 NH-, -NHCOCH(NH2)CH2CH2CH2CH2NH-, -NHCOCH2NHCH2CH2NH-, -NHCOCH2CH2NHCH2CH2NH-, -NHCH2CH2N(CH3)CH2CH2NH-,

[0454] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0455] -(Y) n -Selected from: -NH-, -CH2CH2NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -CH2SCH2CONHCH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2N H-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -N(CH3)COCH2CH2NH-, -SCH2CH2NH-, -OCH2CH2NH-, -C(=O)CH2CH2NH-, -CH2C(=O)NHCH2CH2NH-, -C(=O)NHCH2 CH2NH-, -C(=O)CH2CH2SCH2CH2NH-, -C(=O)CH2SCH2CH2NH-, -CH2CH2C(=O)NHCH2CH2NH-, -C(=N-OH)SCH2CH2NH-, -CH2CH2OCH2CH2NH-, -CH2(CH2OCH2)2CH2NH-, -CH2(CH2OCH2)3CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-, -N(CH3)COCH2CH2N(CH3)-,

[0456] -N(CH3)CO(CH2CH2O)3CH2CH2NH-, -NHCO(CH2CH2O)3CH2CH2NH-, -NHCOCH2CH2-CH(COOH)-NH-, -NHCOCH2CH2NHCOCH2CH2 NH-, -NHCOCH(NH2)CH2CH2CH2CH2NH-, -NHCOCH2NHCH2CH2NH-, -NHCOCH2CH2NHCH2CH2NH-, -NHCH2CH2N(CH3)CH2CH2NH-,

[0457] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0458] -(Y) n -Selected from: -CH2CH2NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -CH2SCH2CONHCH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH 2NH-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -N(CH3)COCH2CH2NH-, -SCH2CH2NH-, -OCH2CH2NH-, -C(=O)CH2CH2NH-, -CH2C(=O)NHCH2CH2NH-, -C (=O)NHCH2CH2NH-, -C(=O)CH2CH2SCH2CH2NH-, -C(=O)CH2SCH2CH2NH-, -CH2CH2C(=O)NHCH2CH2NH-, -C(=N-OH)SCH2CH2NH-, -CH2CH2OCH2CH2NH-, -CH2( CH2OCH2)2CH2NH-, -CH2(CH2OCH2)3CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-,

[0459] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0460] -(Y) n -Selected from: -CH2CH2NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -CH2SCH2C ONHCH2CH2NH-, -NHCOCH2CH2NH-, -N(CH3)COCH2CH2NH-, -SCH2CH2NH-, -OCH2CH2NH-, -C(=O)CH2CH2NH-, -CH2 C(=O)NHCH2CH2NH-, -C(=O)NHCH2CH2NH-, -C(=O)CH2CH2SCH2CH2NH-, -C(=O)CH2SCH2CH2NH-, -CH2CH2C(=O)N HCH2CH2NH-, -C(=N-OH)SCH2CH2NH-, -CH2CH2OCH2CH2NH-, -CH2(CH2OCH2)2CH2NH-, -CH2(CH2OCH2)3CH2NH-,

[0461] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0462] -(Y) n-Selected from: -CH2CH2NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -CH2S CH2CONHCH2CH2NH-, -NHCOCH2CH2NH-, -N(CH3)COCH2CH2NH-, -SCH2CH2NH-, -OCH2CH2NH-, -CH2C(=O)NHC H2CH2NH-, -C(=O)NHCH2CH2NH-, -C(=O)CH2CH2SCH2CH2NH-, -C(=O)CH2SCH2CH2NH-, -CH2CH2C(=O)NHCH2 CH2NH-, -C(=N-OH)SCH2CH2NH-, -CH2CH2OCH2CH2NH-, -CH2(CH2OCH2)2CH2NH-, -CH2(CH2OCH2)3CH2NH-,

[0463] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0464] -(Y) n -Selected from: -CH2CH2CH2CH2NH-, -CH2CH2CH2NH-, CH2SCH2CH2CH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2NH-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -C (=O)CH2CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-, and -N(CH3)COCH2CH2NH-.

[0465] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0466] -(Y) n- Selected from: -CH2CH2CH2CH2NH-, -CH2CH2CH2NH-, CH2SCH2CH2CH2CH2NH-, -NHCOCH2CH2NH-, -C(=O)CH2CH2NH-, and -N(CH3)COCH2CH2NH-.

[0467] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected independently each time it appears:

[0468] -(Y) n - Selected from: -CH2CH2CH2CH2NH-, CH2SCH2CH2CH2CH2NH-, -NHCOCH2CH2NH- and -N(CH3)COCH2CH2NH-.

[0469] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected from Preferably, position 1 and Connection, position 2 is connected to -C(O)-, position 3 is connected to R a connect.

[0470] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected from

[0471] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected from Preferably, position 1 and Connection, position 2 is connected to -C(O)-, position 3 is connected to R a connect.

[0472] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected from Preferably, position 1 and Connection, position 2 is connected to -C(O)-, position 3 is connected to R a connect.

[0473] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected from

[0474] Preferably, position 1 and Connection, position 2 is connected to -C(O)-, position 3 is connected to R a connect.

[0475] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected from

[0476] In some embodiments, the compounds of formula I02, formula I01, formula I”, formula I’, or formula I provided by the present invention, Selected from

[0477] Preferably, position 1 and Connection, position 2 is connected to -C(O)-, position 3 is connected to R a connect.

[0478] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R a The chelating group is selected from radioactive nuclides.

[0479] In some embodiments, the chelating group is a group formed by a chelating agent, for example, by removing one or more atoms (e.g., removing -OH from DOTA).

[0480] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R a The chelating agent is selected from the following: chelating agent that removes one or more atoms to form a chelating group, wherein the chelating agent is selected from 99mTc(CO)3-chelating agent, CB-TE2A, CHX-A”-DTPA, DTPA, DATA, DFO, HBED, Crown, DOTA, DOTAGA, DOTAM, FSC, H4octapa, Macropa, HEHA, HOPO, Hynic, PCTA, PSC, NETA, NOA, NOOTA-MPAA, NODAGA, NOTP, NOPO, Pycup, RESCA, Sarcophagine, TETA, THP, TRAP, P-NH2-Bn-PCTA, pBn-SCN-PCTA, SCN-NOTA, H2-MACROPA-NCS, tetra-(S,S,S,S)-Et-DOTA, or maleimide-nBu-DOTA.

[0481] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R a Selected from the aforementioned chelating agents, for example, chelating groups formed by removing one or more atoms (e.g., removing -OH, etc.).

[0482] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R a Selected from:

[0483] R k Selected from halogens (e.g., iodine, bromine, chlorine, fluorine), C 1-6 Alkyl (e.g., methyl), C 1-6 Alkyl groups (e.g., methoxy), hydroxyl groups, amino groups, nitro groups, and cyano groups.

[0484] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R a Selected from:

[0485] R k Selected from halogens (e.g., iodine, bromine, chlorine, fluorine), C 1-6 Alkyl (e.g., methyl), C 1-6 Alkyl groups (e.g., methoxy), hydroxyl groups, amino groups, nitro groups, and cyano groups.

[0486] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, Ra Selected from:

[0487] In some embodiments, in the compounds of formula I02, formula I01, formula I”, formula I’ or formula I provided by the present invention, R a Selected from:

[0488] In some embodiments, m in the formula I02, formula I01, formula I”, formula I’ or formula I compound provided by the present invention is each independently selected from 1-10.

[0489] In some embodiments, n is selected from 0-10 in the formula I02, formula I01, formula I”, formula I’ or formula I compound provided by the present invention.

[0490] In some embodiments, the formula I” provided by the present invention is a compound of formula I-1, formula I-2, or formula I-3:

[0491] Where R 1 R 4 R 8 R 9 R 10 L, Y, R a And n is as defined above for the compound of formula I02;

[0492] X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a And n is as defined above for the compound of formula I02.

[0493] Where k1 is selected from 0 or 1, X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R9 R 10 R 11 R 11a R 16 R 17 R 18 R 19 R a And n is as defined above for compound 01.

[0494] In some embodiments, the compound of formula I provided by the present invention is a compound of formula I-A1:

[0495] Among them, L, Y, R a And n is as defined above for compound I.

[0496] In some embodiments, the compound of formula I provided by the present invention is a compound of formula I-A2:

[0497] Among them, R', R”, L, Y, R a and n are as defined above for compound I; X 4 Selected from N and CH. In some embodiments, the compound of formula I provided by the present invention is a compound of formula IB:

[0498] Where X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 And n is as defined above for compound (I).

[0499] In some embodiments, the compound of formula I provided by the present invention is a compound of formula I-B1:

[0500] Where L, Y, and n are as defined above for compound I.

[0501] In some embodiments, the compound of formula I provided by the present invention is a compound of formula I-B2:

[0502] Where R', R”, L, Y, and n are as defined above for compound I; X 4 Selected from N and CH.

[0503] In some embodiments, the compound of formula I02 provided by the present invention is a compound represented by formula I-2A1 or formula I-2B1:

[0504] X 1 X 2 X 3 X 5 X 6 X 7 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 10 R 11 R 11a R 16 R 17 R 18 R 19 R 20 R a , n, k2-k10, J1-J4 are as defined above for compound O2; R 21 Selected from H, -S(O)2NH2, halogens, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Halogenated alkyl groups;

[0505] X 1 X 2 X 3 X 5 X 6 X 7 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 10 R 11 R 11a R 16 R 17 R 18 R 19 R 20 Ra R', R”, n, k2-k10, J1-J4 are as defined above for compound O2; X 4 Selected from N and CH.

[0506] In some embodiments, the compound of formula I02 provided by the present invention is a compound represented by formula I-2A2 or formula I-2B2:

[0507] X 1 X 2 X 3 X 5 X 6 X 7 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 10 R 11 R 11a R a , n as defined above for compound O2; R 21 Selected from H, -S(O)2NH2, halogens, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Halogenated alkyl groups;

[0508] Formula I-2B2

[0509] X 1 X 2 X 3 X 5 X 6 X 7 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 10 R 11 R 11a 、、R a R', R”, and n are as defined above for compound O2; X 4 Selected from N and CH.

[0510] In some embodiments, the compounds of the present invention include, but are not limited to:

[0511] A second aspect of the invention provides chelates or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites, or prodrugs thereof, said chelates comprising compounds of formula I02, I01, I”, I’, or I and non-radioactive or radioactive nuclides chelated with compounds of formula I02, I01, I”, I’, or I.

[0512] In some embodiments, the radionuclides chelated with compounds of formula I02, I01, I”, I’, or I are selected from... 43 Sc、 44 Sc、 47 Sc、 55 Co、 62 Cu、 64 Cu、 67 Cu、 66 Ga、 67 Ga、 68 Ga、 86 Y、 89 Zr、 89 Sr、 90 Y、 90 Nb, 99m Tc, 111 In、 105 Rh、 140 Pr、 149 Tb,152 Tb, 153 Pm, 153 Sm、 159 Gd, 160 Tb, 161 Tb, 165 Er、 166 Dy、 166 Ho、 167 Tm、 175 Yb、 177 Lu、 186 Re、 188 Re、 212 Pb, 213 Bi、 225 Ac、 232 Th、 209 Bi、 223 Ra、 227 Th、 223 Fr、 148 Gd, 229 Th.

[0513] In some embodiments, the radionuclide chelated with a compound of formula I02, formula I01, formula I”, formula I’ or formula I is a nuclide that emits alpha particles.

[0514] In some embodiments, the nuclide emitting alpha particles chelated with a compound of formula I02, formula I01, formula I”, formula I’, or formula I is selected from... 225 Ac、 213 Bi、 209 Bi、 149 Tb, 223 Ra、 227 Th、 223 Fr、 148 Gd, 229 Th、 212 Pb or 213 Po.

[0515] In some embodiments, the nuclide chelated with a compound of formula I02, formula I01, formula I”, formula I’, or formula I is an alpha particle emitting nuclide. 225 Ac.

[0516] In some embodiments, the radionuclide chelated with a compound of formula I02, formula I01, formula I”, formula I’ or formula I is a nuclide that emits β particles.

[0517] In some embodiments, the nuclide chelating with a compound of formula I02, formula I01, formula I”, formula I’ or formula I’ that emits β particles is selected from... 67 Cu、 177 Lu、 90 Y、 105Rh、 175 Yb、 167 Tm、 153 Pm, 153 Sm or 111 In.

[0518] In some embodiments, the nuclide chelating with a compound of formula I02, formula I01, formula I”, formula I’ or formula I’ that emits β particles is selected from... 177 Lu.

[0519] In some embodiments, the radionuclides chelated with compounds of formula I02, formula I01, formula I”, formula I’ or formula I are positron-emitting nuclides.

[0520] In some embodiments, the positron-emitting nuclide chelated with a compound of formula I02, formula I01, formula I”, formula I’, or formula I is selected from... 68 Ga、 62 Cu、 64 Cu、 89 Zr or 152 Tb.

[0521] In some embodiments, the positron-emitting nuclide chelated with a compound of formula I02, formula I01, formula I”, formula I’, or formula I is selected from... 68 Ga.

[0522] In some embodiments, the radionuclides chelated with compounds of formula I02, I01, I”, I’, or I are selected from... 68 Ga、 177 Lu and 225 Ac.

[0523] In some embodiments, the chelate has the formula II02-A or II02-B:

[0524] Where X 1 X 2 X 3 X 5 X 6 X 7 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a R 16 R17 R 18 R 19 R 20 J1, J2, J3, J4, k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n are as defined above for the compound of formula I02, X M It can be a non-radioactive nuclide or a radioactive nuclide.

[0525] In some embodiments, the chelate has the formula II01-A or II01-B:

[0526] Where X 1 X 2 X 3 X 5 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a R 16 R 17 R 18 R 19 R 20 J1, J2, J3, J4, k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n are as defined above for compound I01, X M It can be a non-radioactive nuclide or a radioactive nuclide.

[0527] In some embodiments, the chelate has the following formula: II”-A or II”-B.

[0528] Where X 1 X 2 X 3 X 5 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11R 11a R 16 R 17 R 18 R 19 J1, J2, J3, J4, k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n are as defined above for compound I01, X M It can be a non-radioactive nuclide or a radioactive nuclide.

[0529] In some embodiments, the chelate has the following formula: II'-A, II'-B, II-A, or II-B.

[0530] Where X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n are as defined above for compounds of formula I”, X M It may be a non-radioactive or radioactive nuclide;

[0531] Where X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 And n is as defined above for compound I, X M It can be a non-radioactive nuclide or a radioactive nuclide.

[0532] In some embodiments, the chelate has the formula (II-1) compound:

[0533] Where R 1 R 4 R 8 R 9 R 10 L, Y, and n are as defined above for compounds of formula (I), X M It can be a non-radioactive nuclide or a radioactive nuclide.

[0534] In some embodiments, the chelate has the formula (II-A1):

[0535] Where L, Y, and n are as defined above for the compound of formula (I), X M It can be a non-radioactive nuclide or a radioactive nuclide.

[0536] In some embodiments, the chelate has the formula (II-A2):

[0537] Where R', R”, L, Y and n are as defined above for the compound of formula (I); X 4 Selected from N and CH, X M It can be a non-radioactive nuclide or a radioactive nuclide.

[0538] In some implementation schemes, X M Selected from 69 Ga、 175 Lu.

[0539] In some implementation schemes, X M Selected from 43 Sc、 44 Sc、 47 Sc、 55 Co、 62 Cu、 64 Cu、 67 Cu、 66 Ga、 67 Ga、 68 Ga、 86 Y、 89 Zr、 89 Sr、 90 Y、 90 Nb, 99m Tc, 111 In、 105 Rh、 140 Pr、 149 Tb, 152 Tb, 153 Pm, 153 Sm、 159 Gd, 160 Tb, 161 Tb,165 Er、 166 Dy、 166 Ho、 167 Tm、 175 Yb、 177 Lu、 186 Re、 188 Re、 212 Pb, 213 Bi、 225 Ac、 232 Th、 209 Bi、 223 Ra、 227 Th、 223 Fr、 148 Gd, 229 Th.

[0540] In some implementation schemes, X M Selected from 68 Ga、 177 Lu、 161 Tb and 225 Ac.

[0541] In some embodiments, the chelates of the present invention comprise chelates formed by chelating compounds A1-1 to A219-1 with non-radioactive or radioactive nuclides.

[0542] In some embodiments, the chelates of the present invention comprise compounds A1-1 to A219-1 and 175 The chelate formed by Lu chelation.

[0543] In some embodiments, the chelates of the present invention comprise compounds A1-1 to A219-1 and 68 Ga、 177 Lu、 161 Tb or 225 The chelate formed by Ac chelation.

[0544] In some embodiments, the chelates of the present invention comprise compounds A1-1 to A219-1 and 68 The chelate formed by Ga chelation.

[0545] In some embodiments, the chelates of the present invention comprise compounds A1-1 to A219-1 and 177 The chelate formed by Lu chelation.

[0546] In some embodiments, the chelates of the present invention comprise compounds A1-1 to A219-1 and 161 Chelates formed by Tb chelation.

[0547] In some embodiments, the chelates of the present invention comprise compounds A1-1 to A219-1 and 225 The chelate formed by Ac chelation.

[0548] In some embodiments, the chelates of the present invention include, but are not limited to:

[0549] In some embodiments, the chelates of the present invention include, but are not limited to:

[0550] In some embodiments, the chelates of the present invention include, but are not limited to:

[0551] In some embodiments, the chelates of the present invention include, but are not limited to:

[0552] In some embodiments, the chelates of the present invention include, but are not limited to:

[0553] A third aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, said compound having the structure shown in Formula III02:

[0554] Where X 1 X 2 X 3 X 5 X 6 X 7 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a R16 R 17 R 18 R 19 R 20 J1, J2, J3, J4, k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n are as defined above for the compound of formula I02, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3).

[0555] In some embodiments, the compound has the structure shown in Formula III01:

[0556] Where X 1 X 2 X 3 X 5 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a R 16 R 17 R 18 R 19 R 20 J1, J2, J3, J4, k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n are as defined above for compound I01, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3).

[0557] In some embodiments, the compound of formula III01 has the structure shown in formula (III”):

[0558] Where X 1 X 2 X 3 X 5 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R8 R 9 R 10 R 11 R 11a R 16 R 17 R 18 R 19 J1, J2, J3, J4, k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n are as defined above for compound I01, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3).

[0559] In some embodiments, the compound of formula (III”) has the structure shown in formula (III’) or formula (III):

[0560] Equation (III'),

[0561] Where X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n are as defined above for compound I01, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3);

[0562] Where X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 And n is as defined above for compound I01, R15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3).

[0563] In some embodiments, the compound of formula (III) of the present invention is a compound of formula (III-1):

[0564] Where R 1 R 4 R 8 R 9 R 10 L, Y, and n are as defined above for compound I01, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3).

[0565] In some embodiments, the compound of formula (III) of the present invention is a compound of formula (III-A1):

[0566] L, Y, R 15 And n is as defined above.

[0567] In some embodiments, the compound of formula (III) of the present invention is a compound of formula (III-A2):

[0568] Where R', R”, L, Y and n are as defined above for compound I01; X 4 Selected from N and CH, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3).

[0569] In some embodiments, the compounds of formula (III”) of the present invention include, but are not limited to:

[0570] The functional groups in all the embodiments of the present invention described above can be suitably selected and combined in any way to obtain different general formula ranges or specific schemes. These ranges and schemes are all within the scope of the present invention.

[0571] This invention covers compounds obtained by arbitrarily combining various embodiments.

[0572] The compounds of the present invention can be optionally substituted at suitable positions with suitable substituents, wherein the substituents are selected from D, halogens, -OH, -CN, -COOH, -NH2, C. 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably, the substituent is selected from D, F, Cl, -OH, -CN, -COOH, -NH2, methyl, ethyl, -CF3, -CHF2, -CH2F.

[0573] Preparation method and intermediates

[0574] The compounds of the present invention can be prepared by any method known in the art. Reagents and starting materials are readily available to those skilled in the art. Individual isomers, enantiomers and diastereomers can be separated or resolved at any convenient point in the synthesis by methods such as selective crystallization techniques or chiral chromatography (see, for example, selective crystallization techniques or chiral chromatography (see for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Elieland and S.H. Wilen).

[0575] In some embodiments, the present invention provides a method for preparing a compound of formula IB, comprising one or more of the following steps:

[0576] Among them, X 1 X 2 X3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 15 and n are as defined above for compounds of formula (I); L x and L y These are the organic fragments before L-cyclization;

[0577] Step 1: Synthesize fully protected peptide fragments sequentially using the Fmoc protection strategy with peptide resin IAa. In any embodiment, the blank resin used is preferably SIEBER amide resin, etc.; the amino acid coupling conditions can be selected from DIC / Oxyma. Alternatively, HATU / DIPEA, DIC / HOBt, PyBOP / HOBt / DIPEA, HBTU / HOBt / DIPEA, etc., can be used, with DMF, NMP, etc. as preferred solvents, and a reaction temperature of 20-120℃. The conditions for removing the Fmoc protecting group can be selected from piperidine / DMF (v / v 1 / 9-1 / 4).

[0578] Step 2: IAa is converted to IAb via an amino acid coupling reaction. The coupling conditions can be selected from DIC / Oxyma. Alternatively, HATU / DIPEA, etc., the solvent used can preferably be DMF, NMP, etc., and the reaction temperature is 20-120℃.

[0579] Step 3: IAb is cleaved and side-chain protecting groups are removed under the action of a cleavage solution to obtain IAc. The cleavage solution can be selected from TFA and a mixture of one or more reagents in different proportions, such as phenol, anisole, DTT, EDT, DODT, TES, TIS, and H2O. The reaction temperature is 20-120℃.

[0580] Step 4: IAc undergoes substitution or condensation cyclization to obtain IAd. The base used for the substitution reaction can be selected from DIPEA, TEA, t-BuOK, K3PO4, NaH, K2CO3, Na2CO3, NH4HCO3, Cs2CO3, or NaOH. The solvent used can preferably be DMF, NMP, water / acetonitrile, etc., and the reaction temperature is 20-120℃. The condensation conditions can be selected from DIC / Oxyma Alternatively, HATU / DIPEA, DIC / HOBt, PyBOP / HOBt / DIPEA, HBTU / HOBt / DIPEA, etc., can be used, with DMF, NMP, etc. as preferred solvents, and the reaction temperature is 20-120℃.

[0581] Step 5: IAD is condensed with a chelating agent (such as DOTA) to obtain IB. The condensation conditions can be selected from DIC / Oxyma. Alternatively, HATU / DIPEA, DIC / HOBt, PyBOP / HOBt / DIPEA, HBTU / HOBt / DIPEA, etc., can be used, with DMF, NMP, etc. as preferred solvents, and the reaction temperature is 20-120℃.

[0582] Alternatively, IAd may undergo a substitution reaction with a DOTA-active ester (such as DOTA-OSu) to obtain IB. The base used in this substitution reaction includes organic and / or inorganic bases. The organic base may be selected from DIPEA, TEA, t-BuOK, and pyridine, and the inorganic base may be selected from K3PO4, NaH, K2CO3, Na2CO3, NH4HCO3, Cs2CO3, and NaOH, with DIPEA and NH4HCO3 being preferred. In any embodiment, this step is carried out at a suitable temperature of 20-120°C, for example, 20°C, 25°C, 40°C, 50°C, 60°C, 100°C, or 120°C, preferably 25°C or 60°C.

[0583] In any embodiment, this step is carried out in a suitable organic solvent, which may be selected from acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and preferably acetonitrile.

[0584] Pharmaceutical compositions, formulations and treatments

[0585] In some embodiments, the present invention provides a pharmaceutical composition comprising a diagnostically, preventively, or therapeutically effective amount of a ligand compound of the first aspect of the present invention, a chelate of the second aspect, or a compound of the third aspect, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug, and one or more pharmaceutically acceptable carriers.

[0586] In some embodiments, the present invention provides a pharmaceutical formulation comprising a diagnostically, preventively, or therapeutically effective amount of a ligand compound of the first aspect, a chelate of the second aspect, or a compound of the third aspect of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug, and one or more pharmaceutically acceptable carriers. The pharmaceutical formulation is preferably a solid, semi-solid, liquid, or gaseous formulation.

[0587] In some embodiments, the pharmaceutical composition or pharmaceutical formulation may also contain one or more other therapeutic agents.

[0588] In some embodiments, the pharmaceutical composition or pharmaceutical preparation is preferably administered orally, intravenously, intra-arterially, subcutaneously, intraperitoneally, intramuscularly, or transdermally.

[0589] In some embodiments, the present invention provides the use of a ligand compound of the first aspect of the invention, a chelate of the second aspect, or a compound of the third aspect, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug of the invention, or a pharmaceutical composition or pharmaceutical preparation of the invention, in the preparation of a medicament for the diagnosis, prevention, or treatment of diseases or conditions associated with GPC3 activity.

[0590] In some embodiments, the present invention provides the use of a ligand compound of the first aspect of the invention, a chelate of the second aspect, or a compound of the third aspect, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug of the present invention, or a pharmaceutical composition or pharmaceutical formulation of the present invention, in the preparation of a medicament for modulating (e.g., reducing or inhibiting) GPC3 activity.

[0591] In some embodiments, the present invention provides a ligand compound of the first aspect of the invention, a chelate of the second aspect or a compound of the third aspect thereof, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention, for the diagnosis, prevention or treatment of diseases or conditions related to GPC3 activity.

[0592] In some embodiments, the present invention provides methods for diagnosing, preventing, or treating diseases or conditions associated with GPC3 activity, the methods comprising administering to an individual in need an effective amount of a ligand compound of the first aspect of the present invention, a chelate of the second aspect, or a compound of the third aspect, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug of the present invention, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention.

[0593] In some embodiments, the disease or condition associated with GPC3 activity is cancer or tumor, preferably cancer or tumor in which GPC3 is expressed or highly expressed.

[0594] In some implementations, the cancer or tumor is preferably hepatocellular carcinoma, etc.

[0595] In this invention, "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0596] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0597] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes.

[0598] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms.

[0599] As used in this article, the term "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the treated condition to some extent.

[0600] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0601] The amount of the compound of the present invention administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compound, and the judgment of the prescribing physician. Generally, the effective dose is from about 0.0001 to about 50 mg per kg of body weight per day. In some cases, dose levels not exceeding the upper limit of the foregoing range may be sufficient, while in other cases, larger doses may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

[0602] The content or amount of the compound of the present invention in a pharmaceutical composition or pharmaceutical preparation may be from about 0.01 mg to about 1000 mg.

[0603] Unless otherwise stated, as used herein, the term “treating” means to reverse, alleviate, or inhibit the progression of a disease or condition or one or more symptoms of such a disease or condition to which such term is applied, or to prevent such a disease or condition or one or more symptoms of such a disease or condition.

[0604] In this article, "diagnosis" refers to the process of identifying, studying, and determining the cause or lesion state of a living individual to arrive at a diagnosis of disease or assess health status.

[0605] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0606] In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention may further comprise one or more additional therapeutic or preventative agents (e.g., other drugs for treating cancer or tumor diseases). In some embodiments, the treatment methods of the present invention may further include administering one or more additional therapeutic or preventative agents (e.g., other drugs for treating cancer or tumor diseases).

[0607] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0608] The abbreviations used in this article have the meanings listed in Table 1-2:

[0609] Table 1

[0610] Table 2

[0611] The compounds of this invention are separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or fast column chromatography (Flash column chromatography), and their structures are determined by... 1 Confirmation was performed by ¹H NMR, HPLC, or LCMS. Reaction monitoring was conducted using TLC or LC-MS.

[0612] 1 The HNMR spectroscopy method was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACEIIIHD400MHz).

[0613] LC / MS uses Aglient1260Infinity / AglientG6125Quadrupole / AgilientPoroshellEC.

[0614] TLC uses silica gel GF254 as the stationary phase.

[0615] Column chromatography typically uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase.

[0616] The rapid column chromatography method uses the Biotage rapid column chromatograph.

[0617] Prep-HPLC was performed using a GX-281 or Phenomenex HPLC system, with a LunaPrepC column. 18 Gemin(25mm×120mm×5.0μm), PhenomenexLunaC 18 (50mm×250mm×10.0μm) or YMCActusTriartC 18 (20mm×150mm×5.0μm), column temperature 30℃, detection wavelength 220nm, 254nm or 280nm, mobile phase A is acetonitrile, mobile phase B is 0.05% formic acid aqueous solution or 0.05% ammonium bicarbonate aqueous solution or 0.075% TFA aqueous solution, the volume ratio of the mobile phase is adjusted according to the polarity of the compound; the mobile phase flow rate is 20mL / min.

[0618] The microwave reaction was carried out using the BiotageInitiator microwave reactor.

[0619] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0620] The reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, Bidepharm, or companies such as Gil Biochemical and TEB Chemical.

[0621] In the following preparation examples and embodiments, "mobile phase A / mobile phase B = ab, time X min" means that the volume ratio of mobile phase A and mobile phase B changes uniformly from a to b within a time period of 0-X min. For example, "0.05 vol% trifluoroacetic acid aqueous solution / acetonitrile = 75 / 25-25 / 75, 30 min" means that from 0 to 30 min, the volume ratio of mobile phase A (0.05 vol% trifluoroacetic acid aqueous solution) to mobile phase B (acetonitrile) changes uniformly from 75 / 25 to 25 / 75.

[0622] Preparation Example

[0623] Synthesis of intermediate Int 1:N2-(((9H-fluorene-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-N2-(methyl-d3)-L-lysine

[0624] 2-CTC

[0625] Peptide synthesis:

[0626] Synthesis of the target compound based on standard Fmoc-SPPS technology:

[0627] first step:

[0628] Resin preparation: DCM (20 mL) and DIEA (0.60 mL, 3.50 mmol, 4.00 equivalent) were added sequentially to 2-CTC resin (0.40 mmol, 0.80 g, substitution degree i.e., millimoles of active sites per gram of resin Sub = 1.08 mmol / g, 1.00 equivalent) and Fmoc-Lys(Boc)-OH (188 mg, 0.40 mmol, 1.00 equivalent). The resulting mixture was reacted at 25 °C under nitrogen bubbling conditions for 2 h. MeOH (0.8 mL) was added to the resulting reaction solution, and the reaction was continued under nitrogen bubbling conditions for 30 min. After the reaction was completed, the resulting resin was washed with DMF (50 mL).

[0629] Deprotection of Fmoc protecting group: Add DMF (20 mL) containing 20% ​​piperidine to the washed resin and react at 25°C under nitrogen bubbling conditions for 15 min to remove the Fmoc protecting group. After the reaction is complete, wash the resin with DMF (50 mL) and then wash with THF (50 mL). The reaction is complete when the resin turns blue as monitored by the ninhydrin reaction.

[0630] Step Two:

[0631] THF (20 mL) was added to the resin obtained in the first step reaction, followed by DIEA (4.00 equivalents) and 2-nitrobenzenesulfonyl chloride (NsCl, 2.00 equivalents). The resulting mixture was bubbled at 25 °C for 1 h. The resin was colorless as monitored by the ninhydrin reaction. The resin was then washed with DMF (50 mL) and THF (50 mL) in sequence.

[0632] Continue adding PPh3 (5.00 equivalents) to the resin, then add THF (20 mL) to dissolve it, then add CD3OH (5.00 equivalents), bubble with nitrogen for 5 min, then add DEAD (5.00 equivalents), and bubble the resulting mixture with nitrogen at 25 °C for 2 h. Wash the resulting resin with DMF (50 mL).

[0633] Continue adding sodium thiophene (De-Ns, 2.00 equivalents) and DMF (20 mL) to the resin, bubble with nitrogen at 25 °C for 1 h, wash the obtained resin with DMF (50 mL), and monitor the resin by the tetrachlorobenzoquinone reaction. If the resin turns green, the reaction is complete.

[0634] Continue adding DMF (20 mL), Fmoc-Cl (2.00 equivalents), and DIEA (4.00 equivalents) to the resin. Bubble the resulting reaction solution under nitrogen at 25°C for 30 min. The reaction is complete when the resin becomes colorless, as monitored by the tetrachlorobenzoquinone reaction. Wash the resulting resin with DMF (50 mL) and MeOH (50 mL), then blow-dry the resin and vacuum dry it.

[0635] Step 3:

[0636] Add the cutting fluid HFIP / DCM (volume ratio 1:4, 50 mL) to the dried resin and bubble under nitrogen for 10 min. Filter, collect the filtrate and concentrate under reduced pressure, then freeze-dry to obtain a white solid Int1 (136 mg, crude product).

[0637] Its structural characterization data are as follows:

[0638] MS(ESI, m / z): 508.2 [M+Na] + .

[0639] Synthesis of intermediate Int 2: (9H-fluorene-9-yl)methyl (3-oxopropyl)carbamate

[0640] DMP (8.55 g, 20.1 mmol, 6.25 mL, 1.20 eq) was added to a DCM (80.0 mL) solution of (9H-fluorene-9-yl)methyl(3-hydroxypropyl)carbamate (5.0 g, 16.8 mmol, 1.00 eq) at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction was confirmed to be complete by TLC (petroleum ether / ethyl acetate = 1 / 1). The reaction was quenched with 100 mL of saturated NaHCO3 solution and stirred at 25 °C for 10 min. The organic layer was separated from the resulting reaction product, extracted with CH2Cl2 (50 mL × 2), washed with brine, dried with sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain (9H-fluorene-9-yl)methyl(3-oxopropyl)carbamate (4.8 g).

[0641] Synthesis of intermediate Int 3:N-(3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propyl)-N-(tert-butoxycarbonyl)-S-triphenylmethyl-D-cysteine

[0642] Step 1: Synthesis of N-(3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propyl)-S-triphenylmethyl-D-cysteine

[0643] To a MeOH solution (100 mL) containing S-triphenylmethyl-D-cysteine ​​(2.97 g, 8.19 mmol, 1.10 eq) and (9H-fluorene-9-yl)methyl(3-oxopropyl)carbamate (2.20 g, 7.44 mmol, 1.00 eq), AcOH (134 mg, 2.23 mmol, 0.30 eq) and NaBH3CN (936 mg, 14.8 mmol, 2.00 eq) were added. The resulting mixture was stirred at 25 °C for 12 h, and the reaction was confirmed to be complete by LC-MS. The resulting reaction product was poured into 200 mL of water, extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Purification was performed by prep-HPLC and the product was lyophilized. The compound N-(3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propyl)-S-triphenylmethyl-D-cysteine ​​(2.0 g) was obtained. MS (ESI, m / z): 643.4 [M+H] + .

[0644] Step 2: Synthesis of N-(3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propyl)-N-(tert-butoxycarbonyl)-S-triphenylmethyl-D-cysteine

[0645] DIEA (884 mg, 6.84 mmol, 1.13 mL, 2.20 eq) was added to a solution of N-(3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propyl)-S-triphenylmethyl-D-cysteine ​​(2.0 g, 3.11 mmol, 1.00 eq) and Boc₂O (746 mg, 3.42 mmol, 1.10 eq) in EtOAc (40 mL). The resulting mixture was stirred at 25 °C for 12 h, and the reaction was confirmed to be complete by LC-MS. The resulting reaction product was poured into 100 mL of saturated NH₄Cl aqueous solution, extracted with ethyl acetate, and the collected organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. Purification was performed by prep-HPLC and the product was lyophilized. The compound N-(3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propyl)-N-(tert-butoxycarbonyl)-S-triphenylmethyl-D-cysteine ​​(1.4 g) was obtained. MS (ESI, m / z): 741.5 [MH] + .

[0646] Synthesis of intermediate Int 4: (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(6-phenylpyridin-3-yl)propionic acid

[0647] Step 1: Synthesis of methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(6-phenylpyridin-3-yl)propionate

[0648] Under a nitrogen atmosphere, Zn powder (64.8 g, 991 mmol) was added to DMF (1000 mL), followed by the slow dropwise addition of I2 (14.6 g, 57.7 mmol) in DMF (11.6 mL). After the addition was complete, the reaction system was stirred at 25 °C for 2 min. Then, methyl (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-iodopropionate (260 g, 576 mmol) was added to the resulting mixture at 25 °C, and the reaction was continued at 25 °C for 1 h. Next, 5-bromo-2-phenylpyridine (90.0 g, 384 mmol), SPhos (7.89 g, 19.2 mmol), and Pd2(dba)3·CHCl3 (7.96 g, 7.69 mmol) were added to the obtained intermediate product. The mixture was then heated to 60 °C and reacted for 3 h. The reaction was detected as complete by LCMS. After quenching the reaction, the reaction product was filtered. The filter cake was washed with ethyl acetate (1000 mL), and the filtrate was extracted with ethyl acetate. The organic phases were combined and washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 100 / 1-3 / 1). The concentrated product yielded methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(6-phenylpyridin-3-yl)propionate (145.0 g). MS(ESI, m / z): 479.3 [M+H] + .

[0649] Step 2: Synthesis of (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(6-phenylpyridin-3-yl)propionic acid (Fmoc-3Py6Ph-OH)

[0650] Methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(6-phenylpyridin-3-yl)propionate (56.0 g, 105 mmol) was dissolved in iPrOH (390 mL) and THF (130 mL). CaCl2 (29.2 g, 263 mmol) was added to the resulting mixture at 0 °C, followed by the slow dropwise addition of LiOH·H2O (17.7 g, 421 mmol). The mixture was prepared with 130 mL of H2O solution and then reacted at 25 °C for 16 h. The pH of the reaction product was adjusted to approximately 4 with a saturated NaH2PO4 aqueous solution. After filtration, the mother liquor was extracted with ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(6-phenylpyridin-3-yl)propionic acid (24.33 g). MS (ESI, m / z): 465.3 [M+H] + .

[0651] 1 H NMR (400MHz, DMSO-d6) δ8.57(s,1H),8.05(d,J=7.6Hz,2H),7.87(d,J=7.6Hz,3H),7.76-7.86(m,2H),7.64(dd,J=10.4,7.6Hz,2H),7. 45-7.50(m,2H),7.35-7.44(m,3H),7.25-7.29(m,2H),4.14-4.29(m,4H),3.17(dd,J=13.8,4.4Hz,1H),2.94(dd,J=13.6,10.8Hz,1H).

[0652] The intermediates in Table 3 were obtained by the preparation method and general steps of intermediate Int 4 in the reference examples. The required raw materials can be purchased commercially or synthesized by a person skilled in the art of organic synthesis using commercially available raw materials and reagents using conventional reaction methods.

[0653] Table 3

[0654] Synthesis of intermediate Int 5: (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(isoquinoline-7-yl)propionic acid (Fmoc-N-Me-Nal27N-OH)

[0655] Step 1: Synthesis of methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(isoquinoline-7-yl)propionate

[0656] The experimental procedure followed the first step of the synthesis method for intermediate Int 4 to obtain the title compound. MS (ESI, m / z): 453.2 [M+H] + .

[0657] Step 2: Synthesis of (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(isoquinoline-7-yl)propionic acid

[0658] The experimental procedure followed step two of the synthesis method for intermediate Int 4, yielding the title compound. MS (ESI, m / z): 439.3 [M+H] + .

[0659] Step 3: Synthesis of (9H-fluorene-9-yl)methyl(S)-4-(isoquinoline-7-ylmethyl)-5-oxooxazolidine-3-carboxylic acid ester

[0660] Compound (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(isoquinoline-7-yl)propionic acid (17.0 g, 38.8 mmol), PTSA (22.1 g, 116 mmol), and (HCHO)n (23.3 g, 581 mmol) were dissolved in THF (350 mL). The resulting mixture was purged with nitrogen and heated to 80 °C with stirring for 4.0 h. The reaction was completed by LCMS. The reaction product was filtered, and the filter cake was washed with ethyl acetate (300 mL). The filtrates were combined, and the pH was adjusted to 8 with NaHCO3 solution (400 mL). The mixture was washed with saturated brine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound (9H-fluorene-9-yl)methyl(S)-4-(isoquinoline-7-ylmethyl)-5-oxooxazolidine-3-carboxylic acid ester (10.7 g). MS(ESI, m / z): 451.2 [M+H] + .

[0661] Step 4: Synthesis of (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(isoquinoline-7-yl)propionic acid (Fmoc-N-Me-Nal27N-OH)

[0662] Compounds (9H-fluorene-9-yl)methyl(S)-4-(isoquinoline-7-ylmethyl)-5-oxooxazolidine-3-carboxylic acid ester (3.30 g, 7.33 mmol), Et3SiH (24.0 g, 206 mmol, 33.0 mL), and TFA (40.5 g, 355 mmol, 26.4 mL) were dissolved in CHCl3 (30 mL). The resulting mixture was purged with nitrogen, and the reaction was carried out at 70 °C for 12 h. The reaction was monitored by LCMS and TLC (DCM / MeOH = 10 / 1) to ensure its completion. The reaction product was diluted with H2O (400 mL), and the pH was adjusted to 8 with NaHCO3 aqueous solution. It was then extracted with CH2Cl2 (400 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM / MeOH = 100 / 0-95 / 5) to obtain compound (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(isoquinoline-7-yl)propionic acid (2.06 g). MS (ESI, m / z): 453.3 [M+H] + .

[0663] 1H NMR(400MHz, DMSO-d6)δ13.00(dd,J=2.8,2.0Hz,1H),9.07-9.33(m,1H),8.35-8.54(m,1H),7.74-7.94(m,5H),7.54-7.70(m,1H),7 .32-7.49(m,4H),7.11-7.31(m,2H),4.77-5.06(m,1H),4.08-4.34(m,3H),3.40-3.46(m,1H),3.01-3.28(m,1H),2.67-2.74(m,3H).

[0664] Synthesis of intermediate Int 6: (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(6-(4-(difluoromethylene)piperidin-1-yl)pyridin-3-yl)propionic acid

[0665] Step 1: Synthesis of tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate

[0666] 24.8 g (124 mmol) of tert-butyl 4-oxopiperidin-1-carboxylate was dissolved in 200 mL of DMF. The resulting solution was purged with nitrogen and cooled to -40 °C. Then, a 10 mL solution of 2-((difluoromethyl)sulfonyl)pyridine (20.0 g, 103 mmol) and tBuOK (23.2 g, 207 mmol) in DMF was slowly added dropwise while maintaining the temperature at -40 °C. After the addition was complete, the mixture was reacted at -40 °C for 0.5 h. The reaction was detected by TLC (PE / EtOAc = 3 / 1) to indicate completion. The reaction was quenched by adjusting the pH to 3-4 with 1 M HCl aqueous solution. The reaction product was extracted with water (500 mL) and ethyl acetate (450 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (PE / EtOAc = 100 / 1-3 / 1), and concentrated to obtain compound tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate (20.6 g).

[0667] 1 H NMR (400MHz, DMSO-d6) δ3.75 (t, J = 5.6Hz, 4H), 2.50 (s, 4H), 1.81 (s, 9H).

[0668] Step 2: Synthesis of 4-(difluoromethylene)piperidine

[0669] 20.0 g (85.7 mmol) of tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate was dissolved in 50 mL of 2 M HCl in ethyl acetate. The resulting solution was reacted at 25 °C for 2 h. The reaction was confirmed to be complete by TLC (PE / EtOAc = 1 / 1). The reaction product was directly concentrated to obtain 13.6 g of 4-(difluoromethylene)piperidine hydrochloride.

[0670] Step 3: Synthesis of 5-bromo-2-(4-(difluoromethylene)piperidin-1-yl)pyridine

[0671] Compound 4-(difluoromethylene)piperidine hydrochloride (6.94 g, 40.9 mmol) and 5-bromo-2-fluoropyridine (6.00 g, 34.1 mmol, 3.51 mL) were dissolved in DMF (60 mL). Cs2CO3 (33.3 g, 102 mmol) was then added to the resulting solution and mixed. The mixture was heated to 130 °C and reacted for 5 h. The reaction was detected by TLC (PE / EtOAc = 3 / 1) to indicate completion. The reaction product was concentrated and purified by silica gel column chromatography (PE / EtOAc = 100 / 1-3 / 1) to obtain compound 5-bromo-2-(4-(difluoromethylene)piperidin-1-yl)pyridine (4.60 g).

[0672] MS(ESI, m / z): 290.9 [M+H] + .

[0673] Step 4: Synthesis of methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(6-(4-(difluoromethylene)piperidin-1-yl)pyridin-3-yl)propionate

[0674] The experimental procedure followed the first step of the synthesis of intermediate Int 4, except that SPhos and Pd2(dba)3·CHCl3 were replaced with XPhos-Pd-G3 in the first step of the Int 4 synthesis, yielding the title compound. MS (ESI, m / z): 534.6 [M+H] + .

[0675] Step 5: Synthesis of (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(6-(4-(difluoromethylene)piperidin-1-yl)pyridin-3-yl)propionic acid

[0676] The experimental procedure followed step two of the synthesis method for intermediate Int 4, yielding (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(6-(4-(difluoromethylene)piperidin-1-yl)pyridin-3-yl)propionic acid, MS (ESI, m / z): 520.3 [M+H] + .

[0677] 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=2.0Hz,1H),7.88(d,J=7.6Hz,2H),7.55-7.79(m,3H),7.37-7.49(m,3H),7.31(q,J=8.0Hz,2H),6.7 7(d,J=8.8Hz,1H),4.07-4.23(m,4H),3.54(t,J=5.6Hz,4H),2.96(dd,J=13.8,4.4Hz,1H),2.74(dd,J=13.8,10.6Hz,1H),2.10(s,4H).

[0678] Synthesis of intermediate Int 7: (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(6-(4-(difluoromethylene)cyclohexyl)pyridin-3-yl)propionic acid

[0679] Step 1: Synthesis of 5-bromo-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine

[0680] Compounds 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborane (23.0 g, 86.4 mmol), 2,5-dibromopyridine (24.6 g, 104 mmol), K2CO3 (35.8 g, 259 mmol), and XPos-Pd-G3 (3.66 g, 4.32 mmol) were dissolved in a mixed solvent of 1,4-dioxane (230 mL) and H2O (46 mL). The resulting mixture was purged with nitrogen and heated to 80 °C for 12 h. The reaction was completed by LCMS and TLC (n-hexane / ethyl acetate = 3 / 1). Extracted with H2O (300 mL) and EtOAc (300 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 0-98 / 2). The purified compound was 5-bromo-2-(1,4-dioxane-spiro[4.5]dec-7-en-8-yl)pyridine (4.30 g). MS (ESI, m / z): 296.2 [M+H] + .

[0681] 1H NMR (400MHz, DMSO-d6) δ8.62(d,J=2.4Hz,1H),7.97(dd,J=8.4,2.4Hz,1H),7.52(d,J=8.4Hz,1H ), 6.53-6.73(m,1H),3.91(s,4H),2.57-2.66(m,2H),2.36-2.43(m,2H),1.80(t,J=6.4Hz,2H).

[0682] Step 2: Synthesis of 5-bromo-2-(1,4-dioxaspiro[4,5]dec-8-yl)pyridine

[0683] The reaction was carried out in a fluid chemistry apparatus. Solution 1: 3.80 g of 5-bromo-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine was dissolved in 80 mL of THF. A fixed bed (named FLR1, volume 5 mL) was completely filled with 10% Ru / SiO2 particulate catalyst (WXSC1019, 1.23 g). The H2 back pressure regulator was adjusted to 2.5 MPa, and the H2 flow rate was 30 mL / min. Solution 1 was then pumped to a fixed bed (FLR1, SS, fixed bed, 6.350 (1 / 4”) mm, 1 mL, 80 °C) using pump 1 (S1, P1, 0.3 mL / min). LCMS analysis showed the reaction was complete. The reaction product was concentrated under reduced pressure to give compound 5-bromo-2-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine (3.10 g). MS (ESI, m / z): 298.1 [M+H] + .

[0684] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.4Hz,1H),7.93(dd,J=8.4,2.4Hz,1H),7.26(d,J=8.4Hz,1H),3.87(s,4H),2.68-2.77(m,1H),1.51-1.72(m,8H).

[0685] Step 3: Synthesis of 4-(5-bromopyridin-2-yl)cyclohexane-1-one

[0686] 5-Bromo-2-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine (1.50 g, 5.03 mmol) was dissolved in acetone (25 mL), and then HCl (12 M, 2.10 mL) was added. The resulting solution was reacted at 25 °C for 1 h. The reaction was confirmed to be complete by LC-MS. The reaction product was alkalized to pH 8 with NaHCO3 aqueous solution, extracted with CH2Cl2 (60 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4-(5-bromopyridin-2-yl)cyclohexane-1-one (1.5 g). MS (ESI, m / z): 254.0 [M+H] + .

[0687] Step 4: Synthesis of 5-bromo-2-(4-difluoromethylene)cyclohexyl)pyridine

[0688] The experimental procedure followed the first step of the synthesis method for intermediate Int 6 to obtain the title compound. MS (ESI, m / z): 288.0 [M+H] + .

[0689] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.4Hz,1H),7.95(dd,J=8.4,2.4Hz,1H),7.28(d,J=8.4Hz ,1H),2.81(tt,J=12.0,3.2Hz,1H),2.42-2.49(m,2H),1.90-2.04(m,4H),1.45-1.59(m,2H).

[0690] Step 5: Synthesis of methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(6-(4-(difluoromethylene)cyclohexyl)pyridin-3-yl)propionate

[0691] The experimental procedure followed the first step of the synthesis method for intermediate Int 4, replacing SPhos and Pd2(dba)3·CHCl3 with XPhos-Pd-G3 to obtain the title compound. MS (ESI, m / z): 533.3 [M+H] + .

[0692] 1H NMR (400MHz, DMSO-d6) δ8.33-8.40(m,1H),7.90-7.93(m,1H),7.88(d,J=7.6Hz,2H),7.56 -7.66(m,3H),7.38-7.42(m,2H),7.28-7.32(m,2H),7.14(d,J=8.0Hz,1H),4.26-4.32(m, 1H),4.22(d,J=7.2Hz,2H),4.10-4.14(m,1H),3.64(s,3H),3.03-3.10(m,1H),2.83-2.88 (m,1H),2.66-2.72(m,1H),2.42(d,J=13.6Hz,2H),1.85-1.95(m,4H),1.41-1.51(m,2H).

[0693] Step 6: Synthesis of (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(6-(4-(difluoromethylene)cyclohexyl)pyridin-3-yl)propionic acid

[0694] The experimental procedure followed step two of the synthesis method for intermediate Int 4, yielding the title compound. MS (ESI, m / z): 519.3 [M+H] + .

[0695] 1 H NMR (400MHz, DMSO-d6) δ12.84(d,J=1.6Hz,1H),8.38(d,J=1.6Hz,1H),7.88(d,J=7.6Hz, 2H),7.79(d,J=8.4Hz,1H),7.47-7.66(m,3H),7.41(d,J=7.2,3.6Hz,2H),7.26-7.35(m, 2H),7.14(d,J=8.0Hz,1H),4.09-4.23(m,4H),3.04-3.18(m,1H),2.85(dd,J=13.6,10.8 Hz, 1H), 2.66-2.78 (m, 1H), 2.42 (d, J = 12.0Hz, 2H), 1.83-2.00 (m, 4H), 1.37-1.56 (m, 2H).

[0696] The intermediates in Table 4 were obtained by the preparation method and general steps of intermediate Int 7 in the reference examples. Other required raw materials can be purchased commercially or synthesized by professionals in the field of organic synthesis using commercially available raw materials and reagents through conventional reactions.

[0697] Table 4

[0698] Synthesis of intermediate Int 8: (S)-4-(tert-butoxy)-2-((2S,3S)-2-(1,3-dimethylthiourea)-3-methylpentamido)-4-oxobutyric acid

[0699] Step 1: Synthesis of 5-bromo-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine

[0700] Compounds N-(((9H-fluorene-9-yl)methoxy)carbonyl)-N-methyl-L-isoleucine (3.00 g, 8.16 mmol), HOSu (1.13 g, 9.80 mmol), and EDCI (1.88 g, 9.80 mmol) were dissolved in DMF (40 mL). The resulting mixture was purged with nitrogen and reacted at 25 °C for 3 h. The reaction was confirmed to be complete by LCMS. The reaction product was directly used in the next step of the reaction.

[0701] Step 2: Synthesis of (S)-2-((2S,3S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-methylpentamido)-4-(tert-butoxy)-4-oxobutyric acid

[0702] To a DMF (80 mL) solution of compound 5-bromo-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine (3.60 g, 7.75 mmol), (S)-2-amino-4-(tert-butoxy)-4-oxobutyric acid (1.61 g, 8.53 mmol) and DIEA (3.00 g, 23.2 mmol, 4.05 mL) were added. The resulting mixture was purged with nitrogen and reacted at 25 °C for 12 h. The reaction was then monitored by LCMS until complete. The organic phases were extracted with water (100 mL) and EtOAc (100 mL × 3), combined, dried with anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography (MeOH / DCM = 100 / 1-10 / 1). The concentrated product yielded (S)-2-((2S,3S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-methylpentamido)-4-(tert-butoxy)-4-oxobutyric acid (7.70 g).

[0703] Step 3: Synthesis of (S)-4-(tert-butoxy)-2-((2S,3S)-3-methyl-2-(methylamino)pentamido)-4-oxobutyric acid

[0704] (S)-2-((2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-methylpentamido)-4-(tert-butoxy)-4-oxobutyric acid (2.00 g, 3.71 mmol) was dissolved in DMF (40 mL), and then Et2NH (2.72 g, 37.1 mmol, 3.82 mL) was added. Under a nitrogen atmosphere, the resulting mixture was reacted at 25 °C for 1 h. The reaction was confirmed to be complete by LCMS, and the reaction product was concentrated to obtain a crude product. The crude product was ground with isopropyl ether (160 mL) at 25 °C for 5 min to obtain compound (S)-4-(tert-butoxy)-2-((2S,3S)-3-methyl-2-(methylamino)pentamido)-4-oxobutyric acid (827 mg, 2.48 mmol).

[0705] 1 H NMR (400MHz, DMSO-d6) δ4.49(br d,J=4.8Hz,1H),3.61(dt,J=12.1,6.1Hz,3H),2.90(s,2H),2.72-2.77(m,2H),2.66(br d,J=5.5Hz,2H),2.24(s,3H),1.38(s,9H),1.04(br d,J=6.0Hz,9H),0.76-0.91(m,6H).

[0706] Step 4: Synthesis of (S)-4-(tert-butoxy)-2-((2S,3S)-2-(1,3-dimethylthiourea)-3-methylpentamido)-4-oxobutyric acid

[0707] The compound (S)-4-(tert-butoxy)-2-((2S,3S)-3-methyl-2-(methylamino)pentamido)-4-oxobutyric acid (800 mg, 2.53 mmol) was dissolved in EtOH (10 mL), and isothiocyanomethane (221 mg, 3.03 mmol, 207 μL) was added. The resulting mixture was reacted at 60 °C for 12 h, and the reaction was confirmed by LC-MS. The reaction product was concentrated and purified by prep-HPLC (0.05 wt% NH4HCO3 aqueous solution / ACN), and lyophilized to obtain the compound (S)-4-(tert-butoxy)-2-((2S,3S)-2-(1,3-dimethylthioureo)-3-methylpentamido)-4-oxobutyric acid (581.81 mg). MS (ESI, m / z): 390.0 [M+H] + .

[0708] 1H NMR (400MHz, DMSO-d6) δ (ppm) 7.33-7.69 (m, 2H), 5.28-5.73 (m, 1H), 4.10 (br d, J = 5.6Hz, 1H), 2.91 (d, J = 4.0Hz, 3H), 2.87 (br s,2H),2.52-2.56(m,1H),2.37-2.46(m,1H),1.92-2.06(m,1H),1.34-1.42( m,1H),1.33(s,9H),1.14-1.25(m,1H),0.89-1.00(m,1H),0.79-0.84(m,6H).

[0709] Synthesis of intermediate Int 9: N-(((9H-fluorene-9-yl)methoxy)carbonyl)-N-(4-((tert-butoxycarbonyl)amino)butyl)-L-alanine

[0710] Step 1: Synthesis of (4-((tert-Butoxycarbonyl)amino)butyl)-L-alanine

[0711] The compound (4-bromobutyl)carbamate tert-butyl ester (2.00 g, 7.93 mmol), L-alanine (777 mg, 8.73 mmol), and K2CO3 (3.29 g, 23.8 mmol) were dissolved in DMF (20 mL). The resulting mixture was purged with nitrogen and heated to 60 °C for 4 h. The reaction was confirmed to be complete by TLC (DCM / MeOH = 10 / 1). After the reaction product was cooled to room temperature, NaH2PO4 aqueous solution (80 mL) was added to adjust the pH to 5. The product was then extracted with ethyl acetate (60 mL). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound (4-((tert-butyloxycarbonyl)amino)butyl)-L-alanine (2.10 g).

[0712] Step 2: Synthesis of N-(((9H-fluorene-9-yl)methoxy)carbonyl)-N-(4-((tert-butoxycarbonyl)amino)butyl)-L-alanine

[0713] Compound (4-((tert-Butoxycarbonyl)amino)butyl)-L-alanine (2.10 g, 8.07 mmol), FmocOSu (3.27 g, 9.68 mmol), and K2CO3 (2.23 g, 16.1 mmol) were dissolved in THF (40 mL) and H2O (40 mL). The resulting mixture was purged with nitrogen and reacted at 25 °C for 12 h. The reaction was confirmed by LCMS. The reaction product was extracted with H2O (100 mL) and EtOAc (100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (0.05 wt% NH4HCO3 aqueous solution / ACN). The purified compound was lyophilized to obtain compound N-(((9H-fluorene-9-yl)methoxy)carbonyl)-N-(4-((tert-Butoxycarbonyl)amino)butyl)-L-alanine (390 mg). MS(ESI, m / z): 483.3 [M+H] + .

[0714] 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=7.6Hz,2H),7.69-7.79(m,2H),7.37-7.46(m,2H),7.30-7.36(m,2H),6.79(t,J=5.6Hz,1H),4.26-4.35(m ,2H),4.19-4.25(m,1H),3.95-4.11(m,3H),2.90(q,J=6.4Hz,2H),1.4 9-1.58(m,2H),1.37-1.44(m,2H),1.35(s,9H),1.28(d,J=7.2Hz,3H).

[0715] Intermediate Int 10 in Table 5 was prepared by the method and general steps described in the example of intermediate Int 9. Other required raw materials can be purchased commercially or synthesized by those skilled in the art of organic synthesis using commercially available raw materials and reagents through conventional reactions.

[0716] Table 5

[0717] Synthesis of intermediate Int 11: N-(((9H-fluorene-9-yl)methoxy)carbonyl)-N-(4-((tert-butoxycarbonyl)amino)butyl)-L-alanine

[0718] Step 1: Synthesis of N-triphenylmethylacrylamide

[0719] Acrylamide (10.0 g, 140 mmol), TrtCl (39.2 g, 140 mmol), and ZnCl2 (19.1 g, 140 mmol) were dissolved in MeCN (250 mL). The resulting mixture was purged with nitrogen and stirred at 25 °C for 10 min. Then, a MeCN (100 mL) solution of Et3N (14.2 g, 140 mmol, 19.5 mL) was added to the intermediate product. The mixture was then reacted at 25 °C for 12 h. The reaction was then analyzed by TL... The reaction was detected by C(n-hexane / ethyl acetate = 3 / 1). The reaction was quenched by adding 2% citric acid solution. The pH of the reaction product was then adjusted to 7. After extraction with H2O (150 mL), the residual organic phase in the aqueous phase was extracted with EtOAc (150 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 1-2 / 1). The concentrated product yielded N-triphenylmethylacrylamide (13.7 g).

[0720] 1 H NMR (400MHz, CDCl3) δ7.13-7.29 (m, 15H), 6.63 (s, 1H), 6.11-6.20 (m, 2H), 5.57 (dd, J = 8.4, 3.3Hz, 1H).

[0721] Step 2: Synthesis of (3-oxo-3-(triphenylmethylamino)propyl)glycine

[0722] Glycine (958 mg, 12.7 mmol) and KOH (1.07 g, 19.1 mmol) were dissolved in MeOH (80 mL). After purging the mixture with nitrogen, the mixture was stirred at 25 °C for 10 min. Then, N-triphenylmethylacrylamide (5.00 g, 15.9 mmol) was slowly added dropwise to the intermediate product. After the addition was complete, the reaction system was heated to 60 °C and reacted for 12 h. The reaction was confirmed to be complete by LCMS. After the reaction system was cooled to 25 °C, AcOH (2 mL) was added to quench the reaction. The pH of the reaction product was then adjusted to 5-6. After stirring at 25 °C for 20 min, the crude product was ground with MeOH (100 mL) at 25 °C for 30 min to obtain compound (3-oxo-3-(triphenylmethylamino)propyl)glycine (7.70 g).

[0723] Step 3: Synthesis of N-(((9H-fluorene-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(triphenylmethylamino)propyl)glycine

[0724] Compound (3-oxo-3-(triphenylmethylamino)propyl)glycine (7.40 g, 19.0 mmol), FmocOSu (7.71 g, 22.8 mmol), and Na2CO3 (3.48 g, 32.8 mmol) were dissolved in acetone (111 mL) and H2O (111 mL). The resulting mixture was purged with nitrogen and reacted at 25 °C for 2 h. The reaction was confirmed to be complete by LCMS. The reaction product was directly concentrated, and the pH was adjusted to approximately 7 with NaH2PO4 aqueous solution. Then, H2O (400 mL) and EtOAc (400 mL x 3) Extraction, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, filtration, concentration, and purification by silica gel column chromatography (MeOH / DCM = 100 / 1-20 / 1), followed by further purification by prep-HPLC (0.05 VT% HCl aqueous solution / ACN). Lyophilization yielded compound N-(((9H-fluorene-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(triphenylmethylamino)propyl)glycine (1390.19 mg). MS (ESI, m / z): 611.0 [M+H] + .

[0725] 1 H NMR (400MHz, DMSO-d6) δ12.48-12.93(m,1H),8.54-8.78(m,1H),7.88(t,J=7.5Hz,2H),7 .56-7.72(m,2H),7.41(q,J=6.6Hz,2H),7.15-7.32(m,17H),4.18-4.32(m,3H),3.83(br d,J=11.8Hz,2H),3.36-3.45(m,2H),2.52(br s,2H).

[0726] Intermediate Int 12 in Table 6 was prepared by referring to the method and general steps described in the example of intermediate Int 11. Other required raw materials can be purchased commercially or synthesized by a person skilled in the art of organic synthesis using commercially available raw materials and reagents using conventional reactions.

[0727] Table 6

[0728] Synthesis of intermediate Int 13:(2S,4S)-1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(triphenylmethylthio)pyrrolidine-2-carboxylic acid

[0729] Step 1: Synthesis of methyl (2S,4R)-1-(3-((tert-butoxycarbonyl)amino)propyl)-4-hydroxypyrrolidine-2-carboxylate

[0730] (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (14.0 g, 96.4 mmol) was dissolved in DMF (300 mL), and TEA (29.2 g, 289 mmol) and DMAP (1.18 g, 9.64 mmol) were added. The resulting mixture was stirred at 20 °C for 0.5 h. Then, a DMF (100 mL) solution of 3-bromopropylcarbamate tert-butyl ester (23.0 g, 96.4 mmol) was slowly added dropwise to the resulting intermediate. The mixture was heated to 70 °C and the reaction was continued. The reaction was monitored by TLC (hexane / ethyl acetate = 1 / 1, R...). f =0.4) The reaction was detected as complete. The reaction product was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with water and CH2Cl2, the organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 1-1 / 1). The product was concentrated to obtain methyl (2S,4R)-1-(3-((tert-butoxycarbonyl)amino)propyl)-4-hydroxypyrrolidine-2-carboxylate (12.5 g).

[0731] Step 2: Synthesis of methyl (2S,4R)-1-(3-((tert-butoxycarbonyl)amino)propyl)-4-hydroxypyrrolidine-2-carboxylate

[0732] Methyl (2S,4R)-1-(3-((tert-Butoxycarbonyl)amino)propyl)-4-hydroxypyrrolidine-2-carboxylate (12.5 g, 41.3 mmol) was dissolved in CH2Cl2 (200 mL), followed by the addition of TEA (20.9 g, 206 mmol). The mixture was cooled to 0 °C, and MsCl (14.2 g, 124 mmol, 9.60 mL) was slowly added dropwise while the mixture was stirred at 0 °C. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 1 / 1, R...). f =0.50) to detect the completion of the reaction. Water and CH2Cl2 were added to the reaction product for extraction. The organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated to give methyl (2S,4R)-1-(3-((tert-butoxycarbonyl)amino)propyl)-4-((methanesulfonyl)oxy)pyrrolidine-2-carboxylate (15.3 g).

[0733] 1H NMR (400MHz, CDCl3) δ5.20-5.30(m,1H),5.12(s,1H),3.74(s,3H),3.50-3.57(m,2H),3.15-3.25(m,2H ),3.03(s,3H),75-2.77(m,2H),2.50-2.61(m,1H),2.37-2.39(m,2H),1.64-1.66(m,2H),1.44(s,9H).

[0734] Step 3: Synthesis of (2S,4S)-1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(triphenylmethylthio)pyrrolidine-2-carboxylic acid

[0735] The compound triphenylmethanethiol (330 mg, 1.20 mmol) was dissolved in THF (5 mL), and NaH (55.1 mg, 1.38 mmol, 60% purity) was added under ice bath conditions. The resulting mixture was stirred continuously at 0 °C for 1 h. A solution of (2S,4R)-1-(3-((tert-butoxycarbonyl)amino)propyl)-4-((methanesulfonyl)oxy)pyrrolidine-2-carboxylate (350 mg, 919 μmol) in THF (5 mL) was added to the intermediate product. The resulting mixture was then heated to 25 °C and the reaction was continued. The reaction was monitored by TLC (CH2Cl2 / MeOH = 10 / 1, R...). f =0.30) to detect the completion of the reaction, quenched the reaction with water in an ice bath, and then extracted the reaction product with EtOAc. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 100 / 1-10 / 1). The concentrated product yielded (2S,4S)-1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(triphenylmethylthio)pyrrolidine-2-carboxylic acid (137.13 mg). MS (ESI, m / z): 547.5 [M+H] + .

[0736] 1 H NMR(400MHz,DMSO-d6)δ7.23-7.37(m,15H),6.77(s,1H),8.23(s,1H),2.85-3.19(s,5H), 2.60-2.65(m,2H),2.11-2.25(m,1H),2.08-2.10(m,2H),1.58-1.65(m,1H),1.36(s,10H).

[0737] Synthesis of intermediate Int 17:(S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methylisoquinoline-7-yl)propionic acid

[0738] Step 1: Synthesis of methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-chloroisoquinoline-7-yl)propionate

[0739] Zinc powder (1.78 g, 27.2 mmol) was added to DMF (20 mL), followed by I2 (313 mg, 1.24 mmol). The resulting mixture was stirred at 25 °C for 5 min. Methyl (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-iodopropionate (7.24 g, 8.25 mmol) was added to intermediate 1 at 25 °C. The mixture was further reacted at 25 °C for 1 h. Then, 7-bromo-3-chloroisoquinoline (2.00 g, 8.25 mmol) and SPhos (169.2 mg, 412 μmol) were added to intermediate 2. The mixture of 173 mg (189 μmol) and Pd2(dba)3·CHCl3 was heated to 60 °C and the reaction was continued. The reaction was detected by LCMS and the reaction was completed. After the reaction system was cooled to room temperature, H2O was added to quench the reaction. The reaction product was extracted with EtOAc, the organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated, and separated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 1-3 / 1). The compound (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-chloroisoquinoline-7-yl)propionate methyl ester (5.00 g) was obtained.

[0740] 1 H NMR (400MHz, DMSO-d6) δ7.05-8.11(m,13H),4.52-5.07(m,1H),4.08-4.47(m,3H),3.48-3.75(m,3H),2.58-2.80(m,3H).

[0741] Step 2: Synthesis of methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methylisoquinoline-7-yl)propionate

[0742] The compounds (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-chloroisoquinoline-7-yl)propionate (3.70 g, 7.39 mmol), methylboronic acid (2.21 g, 36.9 mmol), Xphos-Pd-G3 (625 mg, 738 μmol), and K3PO4 (4.70 g, 22.1 mmol) were dissolved in 1,4-dioxane (37 mL). The resulting mixture was then purged with nitrogen and heated to 10 °C. The reaction was carried out at 0℃ and the reaction was detected as complete by LCMS. After the reaction system was cooled to room temperature, H2O was added to quench the reaction. The reaction product was extracted with EtOAc, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and separated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 1-2 / 1). The compound (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methylisoquinoline-7-yl)propionate methyl ester (600 mg) was obtained by concentration.

[0743] Step 3: Synthesis of (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methylisoquinoline-7-yl)propionic acid

[0744] The compound (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methylisoquinoline-7-yl)propionate (711 mg, 1.48 mmol) and CaCl2 (410 mg, 3.70 mmol) were dissolved in a mixed solvent of iPrOH (53.1 mL) and THF (17.7 mL). A solution of LiOH·H2O (74.5 mg, 1.78 mmol) in H2O (17.7 mL) was slowly added dropwise to the resulting solution under ice bath conditions. After the addition was complete, the mixture was incubated at 25 °C. The reaction was stirred for 12 h, and the reaction was confirmed to be complete by LCMS. NaH₂PO₄ aqueous solution was added to the reaction product to adjust the pH to 5. The mixture was filtered, and the filtrate was extracted with EtOAc (50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 1-25 / 1). The purified compound (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-methylisoquinoline-7-yl)propionic acid (331 mg) was obtained. MS (ESI, m / z): 467.1 [M+H] + .

[0745] 1H NMR(400MHz,DMSO-d6)δ12.98(br s,1H),8.95-9.19(m,1H),7.69-7.91(m,4H),7.51-7.65(m,2H),7.32-7.46(m,4H),7.09-7.30(m,2H),4.72- 5.02(m,1H),4.05-4.37(m,3H),3.35-3.46(m,1H),3.19-3.29(m,1H),2.66-2.74(m,3H),2.54-2.61(m,3H).

[0746] The intermediates in Table 7 were prepared by referring to the method and general steps described in the intermediate Int 17 example. Other required raw materials can be purchased commercially or synthesized by a person skilled in the art of organic synthesis using commercially available raw materials and reagents using conventional reactions.

[0747] Table 7

[0748] Synthesis of intermediate Int 18:(S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-ethylisoquinoline-7-yl)propionic acid

[0749] Step 1: The synthesis of methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-vinylisoquinoline-7-yl)propionate was performed following Step 2 of the synthesis method for intermediate Int 17, yielding the title compound. MS(ESI, m / z): 493.1 [M+H] + .

[0750] Step 2: Synthesis of methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-ethylisoquinoline-7-yl)propionate

[0751] Methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-vinylisoquinoline-7-yl)propionate (1.60 g, 3.25 mmol) was dissolved in MeOH (16.0 mL). Pd / C (345 mg, 324 μmol, 10% purity) was then added to the resulting solution under a nitrogen atmosphere. After purging with hydrogen, the mixture was reacted in an ice bath under a hydrogen (15 Psi) atmosphere. The reaction was confirmed to be complete by LC-MS. The reaction product was directly filtered and concentrated to obtain methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-ethylisoquinoline-7-yl)propionate (1.70 g). MS (ESI, m / z): 495.2 [M+H] + .

[0752] Step 3: The synthesis of (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-3-(3-ethylisoquinoline-7-yl)propionic acid was performed following step 3 of the synthesis method for intermediate Int 17, yielding the title compound. MS(ESI, m / z): 481.1 [M+H] + .

[0753] 1 H NMR (400MHz, DMSO-d6) δ9.06-9.15(m,1H),7.73-7.89(m,4H),7.44-7.65(m,3H),7.26-7.44(m,4H),7.10-7.15(m,1H),4.90(br s,1H),3.97-4.21(m,3H),3.40-3.46(m,1H),3.12-3.22(m,1H),2.80-2.89(m,2H),2.68-2.79(m,3H),1.28(q,J=7.6Hz,3H).

[0754] Synthesis of intermediate Int 25:(S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(5-(4-(difluoromethylene)cyclohexyl)pyridin-2-yl)propionic acid

[0755] Step 1: Synthesis of 2-bromo-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine

[0756] Compound 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborane (20.0 g, 75.1 mmol) and compound 2-bromo-5-iodopyridine (21.3 g, 75.1 mmol) were dissolved in a mixed solvent of MeCN (400 mL), MeOH (100 mL), and H2O (100 mL). Then, Pd(OAc)2 (1.69 g, 7.51 mmol) and PPh3 ( 3.94 g (15.0 mmol) and K2CO3 (31.1 g, 225 mmol) were mixed, and the resulting mixture was purged with nitrogen and heated to 80 °C. The reaction was detected by TLC (n-hexane / ethyl acetate = 3 / 1, Rf = 0.4) to indicate completion. The reaction product was filtered, and the filtrate was concentrated and then purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 0-1 / 1). The purified compound was 2-bromo-5-(1,4-dioxane-spiro[4.5]dec-7-en-8-yl)pyridine (20.2 g). MS (ESI, m / z): 296.0, 298.0 [M+H] + .

[0757] Step 2: Synthesis of methyl (S)-3-(5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridin-2-yl)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propionate

[0758] The experimental procedure followed step five of the synthesis method for intermediate Int 7, yielding methyl (S)-3-(5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridin-2-yl)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propionate (4.87 g). MS (ESI, m / z): 541.2 [M+H] + .

[0759] Step 3: Synthesis of methyl (S)-3-(5-(1,4-dioxaspiro[4.5]dec-8-yl)pyridin-2-yl)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propionate

[0760] Methyl (S)-3-(5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridin-2-yl)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propionate (4.87 g, 9.01 mmol) was dissolved in MeOH (100 mL). Pd / C (958 mg, 901 μmol, 10% purity) was added to the resulting solution under a nitrogen atmosphere. The resulting mixture was then purged with hydrogen under a hydrogen (15 psi) atmosphere. The reaction was carried out at 25°C. The reaction was completed by TLC (n-hexane / ethyl acetate = 1 / 1, Rf = 0.4). The reaction product was directly filtered, and the filtrate was concentrated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 1-1 / 1). The concentrate yielded methyl (S)-3-(5-(1,4-dioxaspiro[4.5]dec-8-yl)pyridin-2-yl)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propionate (4.87 g). MS (ESI, m / z): 543.2 [M+H] + .

[0761] Step 4: Synthesis of methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(5-(4-oxocyclohexyl)pyridin-2-yl)propionate

[0762] Methyl (S)-3-(5-(1,4-dioxaspiro[4.5]dec-8-yl)pyridin-2-yl)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)propionate (4.00 g, 7.37 mmol) was dissolved in CH2Cl2 (40 mL), followed by the addition of TFA (40 mL). The mixture was reacted at 25 °C, and the reaction was confirmed to be complete by LCMS. The pH of the reaction product was adjusted to 7 by adding NaHCO3, and the mixture was extracted with CH2Cl2. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain methyl (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(5-(4-oxocyclohexyl)pyridin-2-yl)propionate (3.50 g). MS (ESI, m / z): 499.5 [M+H] + .

[0763] Step 5: Synthesis of (S)-2-amino-3-(5-(4-(difluoromethylene)cyclohexyl)pyridin-2-yl)propionic acid

[0764] The experimental procedure followed step four of the synthesis method for intermediate Int 7, yielding compound (S)-2-amino-3-(5-(4-(difluoromethylene)cyclohexyl)pyridin-2-yl)propionic acid (0.7 g). MS (ESI, m / z): 297.0 [M+H] + .

[0765] Step 6: Synthesis of (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(5-(4-(difluoromethylene)cyclohexyl)pyridin-2-yl)propionic acid

[0766] The compound (S)-2-amino-3-(5-(4-(difluoromethylene)cyclohexyl)pyridin-2-yl)propionic acid (700 mg, 2.36 mmol) was dissolved in a mixed solvent of MeCN (10 mL) and H2O (10 mL). Then, NaHCO3 (793 mg, 9.45 mmol) and FmocOSu (796 mg, 2.36 mmol) were added to the resulting solution. The mixture was reacted at 25 °C, and the reaction was monitored by TLC (CH2Cl2 / MeOH = 10 / 1, R0). f =0.40) to detect the completion of the reaction. Water (100 mL) was added to the reaction system to quench the reaction. The reaction product was extracted with EtOAc, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography (CH2Cl2 / MeOH = 100 / 1-10 / 1). After concentration, the compound (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(5-(4-(difluoromethylene)cyclohexyl)pyridin-2-yl)propionic acid (205 mg) was obtained. MS (ESI, m / z): 519.3 [M+H] + .

[0767] 1 H NMR (400MHz, DMSO-d6) δ8.29 (s, 1H), 7.86 (d, J = 8.0Hz, 2H), 7.60 (s, 2H), 7. 37-7.43(m,3H),7.24-7.31(m,2H),7.15-7.19(m,2H),4.18-4.28(m,2H),4 .02-4.15(m,2H),3.23-3.37(m,1H),2.96-3.07(m,1H),2.54-2.60(m,1H), 2.38-2.41(m,2H),1.87-1.93(m,2H),1.73-1.76(m,2H),1.31-1.37(m,2H).

[0768] Intermediate Int 26: 2,2',2”-(10-(1-carboxy-4-(4-nitrophenoxy)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid

[0769] Step 1: Synthesis of 1-(tert-butyl)5-(4-nitrophenyl)2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutarate

[0770] 5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecano-1-yl)valeric acid (800 mg, 1.141 mmol) and 4-nitrophenol (476.331 mg, 3.424 mmol) were dissolved in DMF (10 mL). Then, EDCI (1.094 g, 5.707 mmol) was added to the resulting solution. The mixture was reacted at room temperature for 16 h. After the reaction was complete as monitored by LCMS, the reaction product was filtered. The filtrate was concentrated and then passed through a preparative high-performance liquid chromatograph (mobile phase A: H₂O (0.075%)). (TFA), mobile phase B:ACN, mobile phase A:B volume ratio = 75 / 25-25 / 75) purification, yielded compound 1-(tert-butyl)5-(4-nitrophenyl)2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutarate (397 mg). MS (ESI, m / z): 822.7 [M+H) + .

[0771] Step 2: Synthesis of 2,2',2”-(10-(1-carboxy-4-(4-nitrophenoxy)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid

[0772] 1-(tert-butyl)5-(4-nitrophenyl)2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutarate (397 mg, 482.972 μmol) was dissolved in a mixed solvent of DCM (50 mL) and TFA (50 mL). The resulting mixture was reacted at 25 °C for 12 h. After the reaction was complete as monitored by LCMS, the solvent was removed by rotary evaporation, and the product was dissolved in H2O (25 mL) and ACN (25 mL) and then lyophilized to give compound 2,2',2”-(10-(1-carboxy-4-(4-nitrophenoxy)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid. MS (ESI, m / z): 598.4 [M+H] + .

[0773] Example 1: 2,2',2”-(10-(2-((4-(((5R,8S,14S,17S,20S,23S,26S,29S,32S,35S,38S))-29-(3-amino-3-oxopropyl)-20,35-bis((S)-sec-butyl)-5-carbamoyl-26-(4-carboxybenzyl)-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline-7-ylmethyl)-23-((R)-1-methoxyethyl)- 6,15,30,36-Tetramethyl-7,10,13,16,19,22,25,28,31,34,37-Undecano-8-((6-phenylpyridin-3-yl)methyl)-1,3-dithio-6,9,12,15,18,21,24,27,30,33,36-Undecano-38-yl)amino)-4-oxobutyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (A42-1)

[0774] Step 1: 4-((2R,5S,11S,14S,17S,20S,23S)-1-amino-23-((2S,5S,8S,11S)-16-amino-2-(3-amino-3-oxopropyl)-8-((S)-sec-butyl)-5-(carboxymethyl)-11-(mercaptomethyl)-3,9-dimethyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazahexadecanoyl)-17-((S)-sec-butyl)-14-(4 Synthesis of -(carboxymethoxy)benzyl)-11-(isoquinoline-7-ylmethyl)-2-(mercaptomethyl)-20-((R)-1-methoxyethyl)-3,12-dimethyl-1,4,7,10,13,16,19,22-octaoxo-5-((6-phenylpyridin-3-yl)methyl)-3,6,9,12,15,18,21-heptaazatetracosane-24-yl)benzoic acid 1. The target compound was synthesized using the standard Fmoc-SPPS technique:

[0775] 1) Resin preparation: Weigh 0.3 g of Sieber Resin (substituent degree Sub = 0.50 mmol / g, 1.00 equivalent), add 10 mL of DMF for soaking, and drain the liquid. Then add 10 mL of 20% piperidine / DMF to the soaked resin, bubble with nitrogen, and drain the liquid. Wash the obtained resin with 10 mL of DMF and drain the liquid. Ninhydrin test: the resin is red, and the solution is light blue.

[0776] 2) Amino acid condensation: Weigh 3.00 equivalents of Fmoc-N-Me-Cys(Trt)-OH and add it to the above resin. Add 6.00 equivalents of DIEA and 3.0 mL of DMF to the reaction column. Purge the resulting mixture with nitrogen. After the amino acids dissolve, add 2.85 equivalents of HATU and adjust the nitrogen pressure to ensure uniform bubbling of the resin. The reaction system is then incubated at 25°C for 40 min. Ninhydrin detection shows the resin is colorless and transparent, while the solution is pale yellow. Remove the reaction solution, wash the resin with DMF, and drain the liquid completely.

[0777] 3) Deprotection of Fmoc: Add 20% piperidine / DMF (10 mL) to the resin, puff with nitrogen for 10 min, and then drain the liquid. Wash the resulting resin with DMF (10 mL) and drain the liquid. The resin turns green when tested with tetrachlorobenzoquinone.

[0778] 4) Replace Fmoc-N-Me-Cys(Trt)-OH in step 2) with reagents 2 to 13 in Table 1-1 in turn, and replace HATU and DIEA in step 2) with coupling conditions 2 to 13 in Table 1-1 in turn. Repeat steps 2) and 3) in turn, and proceed to the next step with the final resin.

[0779] 5) After condensation, the resin was washed sequentially with DMF (20 mL), MeOH (20 mL) and isopropyl ether (20 mL), and then vacuum dried.

[0780] Table 1-1: List of amino acids used in SPPS and corresponding reagents

[0781] 2. Peptide cleavage: Add cleavage buffer (TFA / 3-MPA / Tis / H2O, v / v / v / v, 92.5 / 2.5 / 2.5 / 2.5, 10 mL) to the dried resin. Shake the resulting mixture on a shaker for 1 h, filter, add 100 mL of ice-cold isopropyl ether to the filtrate, centrifuge, wash the precipitate with isopropyl ether, and dry to obtain 4-((2R,5S,11S,14S,17S,20S,23S)-1-amino-23-((2S,5S,8S,11S)-16-amino-2-(3-amino-3-oxopropyl)-8-((S)-sec-butyl)-5-(ca Carboxymethyl)-11-(mercaptomethyl)-3,9-dimethyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazahexadecanoyl)-17-((S)-sec-butyl)-14-(4-(carboxymethoxy)benzyl)-11-(isoquinoline-7-ylmethyl)-2-(mercaptomethyl)-20-((R)-1-methoxyethyl)-3,12-dimethyl-1,4,7,10,13,16,19,22-octaoxo-5-((6-phenylpyridin-3-yl)methyl)-3,6,9,12,15,18,21-heptaazaeicosano-24-yl)benzoic acid (0.31 g).

[0782] Its structural characterization data are as follows:

[0783] MS(ESI, m / z): 921.1 [M / 2+H] + .

[0784] Step 2: 4-(((5R,8S,14S,17S,20S,23S,26S,29S,32S,35S,38S)-29-(3-amino-3-oxopropyl)-38-(4-aminobutamido)-20,35-bis((S)-sec-butyl)-5-carbamoyl-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline-7-ylmethyl)-23 Synthesis of -((R)-1-methoxyethyl)-6,15,30,36-tetramethyl-7,10,13,16,19,22,25,28,31,34,37-undecoxo-8-((6-phenylpyridin)-3-yl)methyl)-1,3-dithio-6,9,12,15,18,21,24,27,30,33,36-undecazacyclononadecan-26-yl)methyl)benzoic acid

[0785] Take compound 4-((2R,5S,11S,14S,17S,20S,23S)-1-amino-23-((2S,5S,8S,11S)-16-amino-2-(3-amino-3-oxopropyl)-8-((S)-sec-butyl)-5-(ca-carboxymethyl)-11-(mercaptomethyl)-3,9-dimethyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazahexadecanoyl)-17-((S)-sec-butyl)-14-(4-(carboxymethoxy)benzyl)-11-(isoquinoline-7-ylmethyl)-2-(mercaptomethyl)-20-((R)-1-methoxyethyl)-3 1,2-Dimethyl-1,4,7,10,13,16,19,22-octaoxo-5-((6-phenylpyridin-3-yl)methyl)-3,6,9,12,15,18,21-heptaazatetracosane-24-yl)benzoic acid (150.0 mg, 81.47 μmol) was dissolved in 50% ACN / H2O (150 mL). CH2I2 (326.8 mg, 1.22 mmol) and TCEP (20.36 mg, 81.47 μmol) were added to the resulting solution at 25 °C. The pH of the resulting mixture was adjusted to 9-10 with NaHCO3, and the reaction was stirred at 25 °C for 16 h. The reaction product was analyzed using 1M... The pH was adjusted to 6-7 with HCl, and the mixture was purified by preparative high-performance liquid chromatography (HPLC). Lyophilization yielded 4-(((5R,8S,14S,17S,20S,23S,26S,29S,32S,35S,38S)-29-(3-amino-3-oxopropyl)-38-(4-aminobutamido)-20,35-bis((S)-sec-butyl)-5-carbamoyl-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline- 7-ylmethyl)-23-((R)-1-methoxyethyl)-6,15,30,36-tetramethyl-7,10,13,16,19,22,25,28,31,34,37-undecoxo-8-((6-phenylpyridin)n-3-yl)methyl)-1,3-dithio-6,9,12,15,18,21,24,27,30,33,36-undecazacyclononadecano-26-yl)methyl)benzoic acid (49.0 mg).

[0786] Its structural characterization data are as follows:

[0787] MS(ESI, m / z): 927.2 [M / 2+H] + .

[0788] The operating conditions for preparing high performance liquid chromatography are as follows:

[0789] Column: Gemini, C18 (5μm, )+Luna,C18(10μm, (in series);

[0790] Mobile phase A: 0.075 wt% trifluoroacetic acid aqueous solution; Mobile phase B: acetonitrile; The mobile phase elution program is shown in Table 1-2.

[0791] Table 1-2: Mobile Phase Elution Procedure

[0792] Step 3: 2,2',2”-(10-(2-((4-(((5R,8S,14S,17S,20S,23S,26S,29S,32S,35S,38S))-29-(3-amino-3-oxopropyl)-20,35-di((S)-sec-butyl)-5-carbamoyl-26-(4-carboxybenzyl)-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline-7-ylmethyl)-23-((R)-1-methoxyethyl)-6,15,3 Synthesis of 0,36-tetramethyl-7,10,13,16,19,22,25,28,31,34,37-undecano-8-((6-phenylpyridin-3-yl)methyl)-1,3-dithio-6,9,12,15,18,21,24,27,30,33,36-undecano-38-yl)amino)-4-oxobutyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid: 4-(((5R,8S,1) 4S,17S,20S,23S,26S,29S,32S,35S,38S)-29-(3-amino-3-oxopropyl)-38-(4-aminobutamido)-20,35-bis((S)-sec-butyl)-5-carbamoyl-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline-7-ylmethyl)-23-((R)-1-methoxyethyl)-6,15,30,36-tetramethyl-7,10,13,16,19,22,25,28, 31,34,37-Undecano-8-((6-phenylpyridin)n-3-yl)methyl)-1,3-dithio-6,9,12,15,18,21,24,27,30,33,36-Undecano-3-nonacontane-26-yl)methyl)benzoic acid (25.00 mg, 13.49 μmol) was dissolved in DMF (1.50 mL), and the pH of the resulting solution was adjusted to 9-10 with DIEA. Then, DOTA-OSu (40.59 mg, 13.49 μmol) was added to the resulting solution at 25 °C.49 μmol) was reacted, and after the reaction was confirmed to be complete by LCMS, the pH of the reaction product was adjusted to 6-7 with 1M HCl, and then purified by preparative high performance liquid chromatography. The product was then lyophilized to obtain 2,2',2”-(10-(2-((4-(((5R,8S,14S,17S,20S,23S,26S,29S,32S,35S,38S))-29-(3-amino-3-oxopropyl)-20,35-di((S)-sec-butyl)-5-carbamoyl-26-(4-carboxybenzyl)-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline-7-ylmethyl)-23-((R) -1-Methoxyethyl)-6,15,30,36-tetramethyl-7,10,13,16,19,22,25,28,31,34,37-undecano-8-((6-phenylpyridin-3-yl)methyl)-1,3-dithio-6,9,12,15,18,21,24,27,30,33,36-undecazatenechos-38-yl)amino)-4-oxobutyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (7.6 mg).

[0793] Its structural characterization data are as follows:

[0794] MS(ESI, m / z): 1120.5 [M / 2+H] + .

[0795] The operating conditions for preparing high performance liquid chromatography are as follows:

[0796] Column: Gemini, C18 (5μm*30mm*150mm);

[0797] Mobile phase A: 0.075 wt% trifluoroacetic acid aqueous solution; Mobile phase B: acetonitrile; The mobile phase elution program is shown in Table 1-3.

[0798] Table 1-3: Mobile Phase Elution Procedure

[0799] Example 2: 2,2',2”-(10-(2-((4-((5S,8S,11S,14S,17S,20S,23S,26S,29S,35S,38R)-14-(3-amino-3-oxopropyl)-8,23-di((S)-sec-butyl)-38-carbamoyl-17-(4-carboxybenzyl)-26-(4-(carboxymethoxy)benzyl)-11-(carboxymethyl)-29-(isoquinoline-7-ylmethyl)-20-((R)-1-methoxyethyl)-7,13 28,37-Tetramethyl-4-(methyl-d3)-3,6,9,12,15,18,21,24,27,30,33,36-Dodecoxo-35-((6-phenylpyridin-3-yl)methyl)-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-Dodecazacyclononacontane-5-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound A26-1)

[0800] Step 1: 4-((2R,5S,11S,14S,17S,20S,23S)-1-amino-23-((2S,5S,8S,11S)-2-(3-amino-3-oxopropyl)-11-(4-aminobutyl)-8-((S)-sec-butyl)-5-(carboxymethyl)-14-chloro-3,9-dimethyl-12-(methyl-d3)-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecanoamide Synthesis of 17-((S)-sec-butyl)-14-(4-(carboxymethoxy)benzyl)-11-(isoquinoline-7-ylmethyl)-2-(mercaptomethyl)-20-((R)-1-methoxyethyl)-3,12-dimethyl-1,4,7,10,13,16,19,22-octaoxo-5-((6-phenylpyridin-3-yl)methyl)-3,6,9,12,15,18,21-heptaazatetracosane-24-yl)benzoic acid

[0801] 1. Peptide synthesis: Targeted synthesis was achieved using standard Fmoc-SPPS technology.

[0802] Synthesis of compounds:

[0803] 1) Resin Preparation: Add 10 mL of DMF to RinkMBHA-AmideResin (0.690 g, Substitution Rate Sub = 0.290 mmol / g, 1.00 equivalent), and bubble under nitrogen for 30 min to allow the resin to swell. Wash the swollen resin with 20 mL of DMF, then add 10 mL of 20% piperidine / DMF to the washed resin and bubble under nitrogen at 20°C for 15 min to remove the Fmoc protecting group. After the reaction is complete, wash the resin with 20 mL of DMF; the resin turns blue when monitored by the ninhydrin reaction.

[0804] 2) Amino acid condensation: Fmoc-N-Me-Cys(Trt)-OH (360 mg, 3.00 equivalent) and Oxyma (85 mg, 3.00 equivalent) were dissolved in a mixed solvent of NMP / DCE (10 mL, v / v, 1:1). DIC (3.30 equivalent) was then added to the resulting solution, and the mixture was shaken for 3 min to activate the amino acids. The resulting mixture was added to the resin described above, and the reaction system was bubbled under nitrogen at 20 °C for 1 h. The ninhydrin reaction was complete when the resin became colorless. The resin was then washed with DMF (20 mL).

[0805] 3) Removal of Fmoc protecting group: Add 20% piperidine / DMF (10 mL) to the resin. Bubble the resulting mixture under nitrogen at 20 °C for 15 min to remove the Fmoc protecting group. After the reaction is complete, wash the resin with DMF (20 mL). The resin turns green when monitored by the tetrachlorobenzoquinone reaction.

[0806] 4) Replace Fmoc-N-Me-Cys(Trt)-OH in step 2) with reagents numbered 2 to 13 in Table 2-1 in turn, and replace DIC and Oxyma in step 2) with coupling conditions numbered 2 to 13 in Table 2-1 in turn. Repeat steps 2) and 3) in a cycle, and proceed to the next step with the resin obtained.

[0807] 5) After condensation, the resin is washed with DMF (20 mL), MeOH (20 mL) and isopropyl ether (20 mL) in sequence, and then vacuum dried.

[0808] Table 2-1: List of amino acids and corresponding reagents used in SPPS

[0809] 2. Peptide cleavage:

[0810] Cutting fluid (TFA / 3-MPA / Tis / H2O, v / v / v / v, 92.5 / 2.5 / 2.5 / 2.5, 10 mL) was added to the dried resin. The resulting mixture was shaken on a shaker at room temperature for 2 h, filtered, and cooled isopropyl ether was added to the filtrate. The solid was collected by centrifugation, washed with isopropyl ether, and dried to obtain compound 4-((2R,5S,11S,14S,17S,20S,23S)-1-amino-23-((2S,5S,8S,11S)-2-(3-amino-3-oxopropyl)-11-(4-aminobutyl)-8-((S)-sec-butyl)-5-(carboxymethyl) (138 mg)-14-chloro-3,9-dimethyl-12-(methyl-d3)-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecanoamide-17-((S)-sec-butyl)-14-(4-(carboxymethoxy)benzyl)-11-(isoquinoline-7-ylmethyl)-2-(mercaptomethyl)-20-((R)-1-methoxyethyl)-3,12-dimethyl-1,4,7,10,13,16,19,22-octaoxo-5-((6-phenylpyridin-3-yl)methyl)-3,6,9,12,15,18,21-heptaazatetracosan-24-yl)benzoic acid.

[0811] Its structural characterization data are as follows:

[0812] MS(ESI, m / z): 1875.0 [M+H] + .

[0813] Step 2: 4-(((5S,8S,11S,14S,17S,20S,23S,26S,29S,35S,38R)-14-(3-amino-3-oxopropyl)-5-(4-aminobutyl)-8,23-bis((S)-sec-butyl)-38-carbamoyl-26-(4-(carboxymethoxy)benzyl)-11-(carboxymethyl)-29-(isoquinoline-7-ylmethyl)-20-((R)-1 Synthesis of (-methylethoxyethyl)-7,13,28,37-tetramethyl-4-(methyl-d3)-3,6,9,12,15,18,21,24,27,30,33,36-dodecoxo-35-((6-phenylpyridin-3-yl)methyl)-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononadecan-17-yl)methyl)benzoic acid

[0814] The compound 4-((2R,5S,11S,14S,17S,20S,23S)-1-amino-23-((2S,5S,8S,11S)-2-(3-amino-3-oxopropyl)-11-(4-aminobutyl)-8-((S)-sec-butyl)-5-(carboxymethyl)-14-chloro-3,9-dimethyl-12-(methyl-d3)-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecanoamide)-17-((S)-sec-butyl)-14-(4-( Carboxymethoxy)benzyl)-11-(isoquinoline-7-ylmethyl)-2-(mercaptomethyl)-20-((R)-1-methoxyethyl)-3,12-dimethyl-1,4,7,10,13,16,19,22-octaoxo-5-((6-phenylpyridin-3-yl)methyl)-3,6,9,12,15,18,21-heptaazatetracosane-24-yl)benzoic acid (0.138 g, 1.00 equivalent) was dissolved in a mixed solvent of ACN / H2O (74 mL, v / v, 1:1) under nitrogen protection. The pH of the resulting solution was adjusted to 8-9 with saturated NaHCO3 solution, and the reaction was carried out at 25℃ for 1 h. The reaction product was lyophilized and purified by preparative high performance liquid chromatography to obtain compound 4-(((5S,8S,11S,14S,17S,20S,23S,26S,29S,35S,38R)-14-(3-amino-3-oxopropyl)-5-(4-aminobutyl)-8,23-bis((S)-sec-butyl)-38-carbamoyl-26-(4-(carboxymethoxy)benzyl)-11-(carboxymethyl) )-29-(isoquinoline-7-ylmethyl)-20-((R)-1-methylethoxyethyl)-7,13,28,37-tetramethyl-4-(methyl-d3)-3,6,9,12,15,18,21,24,27,30,33,36-dodecoxo-35-((6-phenylpyridin-3-yl)methyl)-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononadecan-17-yl)methyl)benzoic acid (70mg).

[0815] Its structural characterization data are as follows:

[0816] MS(ESI, m / z): 1839.1 [M+H] + .

[0817] The operating conditions for preparing high performance liquid chromatography are as follows:

[0818] Column: BP-C18 (30×250mm, 5μm);

[0819] Mobile phase A: 0.1 wt% trifluoroacetic acid aqueous solution; Mobile phase B: acetonitrile; The mobile phase elution program is shown in Table 2-2.

[0820] Table 2-2: Mobile Phase Elution Procedure

[0821] Step 3: 2,2',2”-(10-(2-((4-((5S,8S,11S,14S,17S,20S,23S,26S,29S,35S,38R)-14-(3-amino-3-oxopropyl)-8,23-di((S)-sec-butyl)-38-carbamoyl-17-(4-carboxybenzyl)-26-(4-(carboxymethoxy)benzyl)-11-(carboxymethyl)-29-(isoquinoline-7-ylmethyl)-20-((R)-1-methoxyethyl)-7 Synthesis of 13,28,37-Tetramethyl-4-(methyl-d3)-3,6,9,12,15,18,21,24,27,30,33,36-Dodecoxo-35-((6-phenylpyridin-3-yl)methyl)-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-Dodecazacyclononacontane-5-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-Tetraazacyclododecane-1,4,7-triyl)triacetic acid

[0822] The compound 4-(((5S,8S,11S,14S,17S,20S,23S,26S,29S,35S,38R)-14-(3-amino-3-oxopropyl)-5-(4-aminobutyl)-8,23-di((S)-sec-butyl)-38-carbamoyl-26-(4-(carboxymethoxy)benzyl)-11-(carboxymethyl)-29-(isoquinoline-7-ylmethyl)-20-((R)-1-methylethoxyethyl)-7,13,28,37-tetramethyl-4-(methyl-d3)-3,6,9,12,15,18,21, 24,27,30,33,36-Dodecoxo-35-((6-phenylpyridin-3-yl)methyl)-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononadecano-17-yl)methyl)benzoic acid (70.00 mg, 38.08 μmol, 1.00 equivalent) was dissolved in anhydrous DMF (1 mL). DOTA-NHS ester (38.20 mg, 76.17 μmol, 2.00 equivalent) and DIEA (19.69 mg, 152.3 μmol, ) were added sequentially to the resulting solution. The mixture was reacted at 25°C for 30 min, and the reaction product was purified by preparative high performance liquid chromatography to obtain the target product 2,2',2”-(10-(2-((4-((5S,8S,11S,14S,17S,20S,23S,26S,29S,35S,38R)-14-(3-amino-3-oxopropyl)-8,23-di((S)-sec-butyl)-38-carbamoyl-17-(4-carboxybenzyl)-26-(4-(carboxymethoxy)benzyl)-11-(carboxymethyl)-29-(isoquinoline-7-ylmethyl)-20 -((R)-1-methoxyethyl)-7,13,28,37-tetramethyl-4-(methyl-d3)-3,6,9,12,15,18,21,24,27,30,33,36-dodecano-35-((6-phenylpyridin-3-yl)methyl)-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecano-5-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecano-1,4,7-triyl)triacetic acid (white solid, 39.7 mg).

[0823] Its structural characterization data are as follows:

[0824] MS(ESI, m / z): 1112.9 [M / 2+H] + .

[0825] The operating conditions for preparing high performance liquid chromatography are as follows:

[0826] Chromatographic column: YMC-ActusC18 (30×150mm, 5μm) + YMC-ActusC18 (30×150mm, 5μm) (tandem);

[0827] Mobile phase A: 0.1 wt% trifluoroacetic acid aqueous solution; Mobile phase B: acetonitrile; The mobile phase elution program is shown in Table 2-3.

[0828] Table 2-3: Mobile Phase Elution Procedure

[0829] Example 3: 2,2',2”-(10-(2-((3-((1S,5R,8S,14S,17S,20S,23S,26S,29S,32S,35S,38S)-29-(3-amino-3-oxopropyl)-20,35-di((S)-sec-butyl)-5-carbamoyl-26-(4-carboxybenzyl)-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline-7-ylmethyl)-23-((R)-1-methoxyethyl)-6,15,3 0,36-Tetramethyl-7,10,13,16,19,22,25,28,31,34,37-Undecano-8-((6-phenylpyridin-3-yl)methyl)-2,3-dithia-6,9,12,15,18,21,24,27,30,33,36,39-Dodecazabicyclo[36.2.1]tetradecane-39-yl)-3-oxopropyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (compound A36-1)

[0830] Step 1: 4-((2R,5S,11S,14S,17S,20S,23S)-1-amino-23-((S)-5-amino-2-((S)-2-((2S,3S)-2-((2S,4S)-1-(3-aminopropionyl)-4-mercapto-N-methylpyrrolidine-2-carboxamido)-3-methylpentamido)-3-carboxy-N-methylpropionamido)-5-oxopentamido)-17-((S)-sec-butyl)-14-(4- Synthesis of (carboxymethoxy)benzyl)-11-(isoquinoline-7-ylmethyl)-2-(mercaptomethyl)-20-((R)-1-methoxyethyl)-3,12-dimethyl-1,4,7,10,13,16,19,22-octaoxo-5-((6-phenylpyridin-3-yl)methyl)-3,6,9,12,15,18,21-heptaazatetracosane-24-yl)benzoic acid 1. Synthesis of the target compound was performed using the standard Fmoc-SPPS technique:

[0831] 1) Resin preparation: Weigh 0.3 g of Sieber Resin (substituent degree Sub = 0.50 mmol / g, 1.00 equivalent), add 10 mL of DMF for soaking, and drain the liquid. Then add 10 mL of 20% piperidine / DMF to the soaked resin, bubble with nitrogen, and drain the liquid. Wash the obtained resin with 10 mL of DMF and drain the liquid. Ninhydrin test: the resin is red, and the solution is light blue.

[0832] 2) Amino acid condensation: Weigh 3.00 equivalents of Fmoc-N-Me-Cys(Trt)-OH and add it to the above resin. Add 6.00 equivalents of DIEA and then add 3.0 mL of DMF to the reaction column. Purge the resulting mixture with nitrogen gas until the amino acids dissolve. Then add 2.85 equivalents of HATU and adjust the nitrogen gas level to ensure uniform bubbling of the resin. The reaction system is then incubated at 25°C for 40 min. Ninhydrin detection shows that the resin is colorless and transparent, while the solution is pale yellow. The reaction solution is removed, the resin is washed with DMF, and the liquid is drained.

[0833] 3) Deprotection of Fmoc: Add 20% piperidine / DMF (10 mL) to the resin, puff with nitrogen for 10 min, and then drain the liquid. Wash the resulting resin with DMF (10 mL) and drain the liquid. The resin turns green when tested with tetrachlorobenzoquinone.

[0834] 4) Replace Fmoc-N-Me-Cys(Trt)-OH in step 2) sequentially with reagents 2 to 13 in Table 3-1, and replace HATU and DIEA in step 2) sequentially with coupling conditions 2 to 13 in Table 3-1. Repeat steps 2) and 3) in a cyclical manner. The resulting resin is then used for the next step. Specifically, after the coupling of Fmoc-4-(tert-butoxycarbonylmethoxy)-L-Phe-OH is completed, the reaction product is subjected to nitrogen purging for 20 min in a DMF solution containing (Boc)₂O (3.00 equivalents) and DIEA (6.00 equivalents). The mixture is then filtered, the solid is collected, washed with DMF, and the liquid is drained. The Fmoc protection is then removed to proceed with the next amino acid coupling.

[0835] 5) After condensation, the resin was washed sequentially with DMF (20 mL), MeOH (20 mL) and isopropyl ether (20 mL), and then vacuum dried.

[0836] Table 3-1: List of amino acids used in SPPS and corresponding reagents

[0837] 2. Peptide cleavage: Add cleavage solution (TFA / 3-MPA / Tis / H2O, v / v / v / v, 92.5 / 2.5 / 2.5 / 2.5, 8 mL) to the dried resin. Shake the resulting mixture on a shaker for 1 h, filter, add 42 mL of ice-cold isopropyl ether to the filtrate, centrifuge, wash the precipitate with isopropyl ether, and dry to obtain 4-((2R,5S,11S,14S,17S,20S,23S)-1-amino-23-((S)-5-amino-2-((S)-2-((2S,3S)-2-((2S,4S)-1-(3-aminopropionyl)-4-mercapto -N-methylpyrrolidine-2-carboxamido)-3-methylpentamido)-3-carboxy-N-methylpropamido)-5-oxopentamido)-17-((S)-sec-butyl)-14-(4-(carboxymethoxy)benzyl)-11-(isoquinoline-7-ylmethyl)-2-(mercaptomethyl)-20-((R)-1-methoxyethyl)-3,12-dimethyl-1,4,7,10,13,16,19,22-octaoxo-5-((6-phenylpyridin-3-yl)methyl)-3,6,9,12,15,18,21-heptaazatetracosane-24-yl)benzoic acid (0.30 g).

[0838] Its structural characterization data are as follows:

[0839] MS(ESI, m / z): 927.2 [M / 2+H] + .

[0840] Step 2: 4-(((1S,5R,8S,14S,17S,20S,23S,26S,29S,32S,35S,38S)-29-(3-amino-3-oxopropyl)-39-(3-aminopropionyl)-20,35-di((S)-sec-butyl)-5-carbamoyl-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline-7-ylmethyl)-23-((R)-1-methoxyethyl)-6,15,30,36-tetra- Synthesis of methyl-7,10,13,16,19,22,25,28,31,34,37-undecano-8-((6-phenylpyridin-3-yl)methyl)-2,3-dithia-6,9,12,15,18,21,24,27,30,33,36,39-dodecazabicyclo[36.2.1]tetradecano-26-yl)methyl)benzoic acid. The compound 4-((2R,5S,11S,14S,17S,20S,23S)-1-amino-23-(( S)-5-amino-2-((S)-2-((2S,3S)-2-((2S,4S)-1-(3-aminopropionyl)-4-mercapto-N-methylpyrrolidine-2-carboxamido)-3-methylpentamido)-3-carboxy-N-methylpropionamido)-5-oxopentamido)-17-((S)-sec-butyl)-14-(4-(carboxymethoxy)benzyl)-11-(isoquinoline-7-ylmethyl)-2-(mercaptomethyl)-20-((R)-1-methoxyethyl)-3,12 Dimethyl-1,4,7,10,13,16,19,22-octaoxo-5-((6-phenylpyridin-3-yl)methyl)-3,6,9,12,15,18,21-heptaazatetracosane-24-yl)benzoic acid (150.0 mg) was dissolved in DMF (150 mL). I2 / MeOH (0.2 M) was added to the resulting solution at 25 °C until the solution turned yellow. The resulting mixture was stirred at 25 °C for 2 min. Na2S2O3 (0.2 M) was slowly added dropwise to the resulting intermediate product.(1M) until the yellow color disappears, the reaction product is concentrated by rotary evaporation, purified by preparative high performance liquid chromatography, and lyophilized to obtain 4-(((1S,5R,8S,14S,17S,20S,23S,26S,29S,32S,35S,38S)-29-(3-amino-3-oxopropyl)-39-(3-aminopropionyl)-20,35-bis((S)-sec-butyl)-5-carbamoyl-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline- 7-ylmethyl)-23-((R)-1-methoxyethyl)-6,15,30,36-tetramethyl-7,10,13,16,19,22,25,28,31,34,37-undecoxo-8-((6-phenylpyridin-3-yl)methyl)-2,3-dithia-6,9,12,15,18,21,24,27,30,33,36,39-dodecazabicyclo[36.2.1]tetradecane-26-yl)methyl)benzoic acid (39.0 mg).

[0841] Its structural characterization data are as follows:

[0842] MS(ESI, m / z): 926.1 [M / 2+H] + .

[0843] The operating conditions for preparing high performance liquid chromatography are as follows:

[0844] Column: Gemini, C18 (5μm, )+Luna,C18(10μm, (in series);

[0845] Mobile phase A: 0.075 wt% trifluoroacetic acid aqueous solution; Mobile phase B: acetonitrile; The mobile phase elution program is shown in Table 3-2.

[0846] Table 3-2: Mobile Phase Elution Procedure

[0847] Step 3: 2,2',2”-(10-(2-((3-((1S,5R,8S,14S,17S,20S,23S,26S,29S,32S,35S,38S)-29-(3-amino-3-oxopropyl)-20,35-bis((S)-sec-butyl)-5-carbamoyl-26-(4-carboxybenzyl)-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline-7-ylmethyl)-23-((R) -1-Methoxyethyl)-6,15,30,36-Tetramethyl-7,10,13,16,19,22,25,28,31,34,37-Undecano-8-((6-phenylpyridin-3-yl)methyl)-2,3-dithia-6,9,12,15,18,21,24,27,30,33,36,39-Dodecazabicyclo[36.2.1]tetradecano-39-yl)-3-oxopropyl)amino)-2-oxoethyl)-1,4,7, Synthesis of 10-tetraazacyclododecane-1,4,7-triyl)triacetic acid: 4-(((1S,5R,8S,14S,17S,20S,23S,26S,29S,32S,35S,38S)-29-(3-amino-3-oxopropyl)-39-(3-aminopropionyl)-20,35-bis((S)-sec-butyl)-5-carbamoyl-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline-7-ylmethyl)- 23-((R)-1-methoxyethyl)-6,15,30,36-tetramethyl-7,10,13,16,19,22,25,28,31,34,37-undecoxo-8-((6-phenylpyridin-3-yl)methyl)-2,3-dithia-6,9,12,15,18,21,24,27,30,33,36,39-dodecazabicyclo[36.2.1]tetradecane-26-yl)methyl)benzoic acid (20 mg) with DMF (1.After dissolving (50 mL), the pH of the resulting solution was adjusted to 9-10 using DIEA. Then, DOTA-OSu (6 equivalents) was added to the resulting solution at 25 °C and the reaction was carried out. After the reaction was confirmed to be complete by LCMS, the reaction product was analyzed with 1 M... The pH was adjusted to 6-7 with HCl, and then purified by preparative high-performance liquid chromatography (HPLC). The resulting product was lyophilized to obtain 2,2',2”-(10-(2-((3-((1S,5R,8S,14S,17S,20S,23S,26S,29S,32S,35S,38S)-29-(3-amino-3-oxopropyl)-20,35-di((S)-sec-butyl)-5-carbamoyl-26-(4-carboxybenzyl)-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline-7-ylmethyl)-23-((R)-1-methyl (13.4 mg)-6,15,30,36-tetramethyl-7,10,13,16,19,22,25,28,31,34,37-undecano-8-((6-phenylpyridin-3-yl)methyl)-2,3-dithia-6,9,12,15,18,21,24,27,30,33,36,39-dodecazabicyclo[36.2.1]tetradecane-39-yl)-3-oxopropyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid.

[0848] Its structural characterization data are as follows:

[0849] MS(ESI,m / z):2237.1[M+H] + .

[0850] The operating conditions for preparing high performance liquid chromatography are as follows:

[0851] Column: Gemini, C18 (5μm*30mm*150mm);

[0852] Mobile phase A: 0.075 wt% trifluoroacetic acid aqueous solution; Mobile phase B: acetonitrile; The mobile phase elution program is shown in Table 3-3.

[0853] Table 3-3: Mobile Phase Elution Procedure

[0854] Example 4: 2,2',2”-(10-(2-((3-(((5R,8S,14S,17S,20S,23S,26S,29S,32S,35S,38R)-29-(3-amino-3-oxopropyl)-20,35-bis((S)-sec-butyl)-5-carbamoyl-26-(4-carboxybenzyl)-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline-7-ylmethyl)-23-((R)-1-methoxyethyl)-6, 15,30,36-Tetramethyl-7,10,13,16,19,22,25,28,31,34,37-Undecano-8-((6-phenylpyridin-3-yl)methyl)-1,3-dithia-6,9,12,15,18,21,24,27,30,33,36-Undecano-38-yl)amino)-3-oxopropyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound A48-1)

[0855] The synthesis method is the same as in Example 1. Only the substitution of Boc-GABA-OH in Table 1-1 with N-Boc-beta-Ala is required to prepare compound 2,2',2”-(10-(2-((3-(((5R,8S,14S,17S,20S,23S,26S,29S,32S,35S,38R)-29-(3-amino-3-oxopropyl)-20,35-bis((S)-sec-butyl)-5-carbamoyl-26-(4-carboxybenzyl)-17-(4-(carboxymethoxy)benzyl)-32-(carboxymethyl)-14-(isoquinoline- 7-ylmethyl)-23-((R)-1-methoxyethyl)-6,15,30,36-tetramethyl-7,10,13,16,19,22,25,28,31,34,37-undecano-8-((6-phenylpyridin-3-yl)methyl)-1,3-dithia-6,9,12,15,18,21,24,27,30,33,36-undecazateneco-38-yl)amino)-3-oxopropyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (7.4 mg).

[0856] Its structural characterization data are as follows:

[0857] MS(ESI, m / z): 1113.4 [M / 2+H] + .

[0858] In the third step, the operating conditions for preparing high-performance liquid chromatography are as follows:

[0859] Column: Gemini, C18 (5μm*30mm*150mm)

[0860] Mobile phase A: 0.075 wt% trifluoroacetic acid aqueous solution; Mobile phase B: acetonitrile; The mobile phase elution program is shown in Table 4-1.

[0861] Table 4-1: Mobile Phase Elution Procedure

[0862] Example 5: 2,2',2”-(10-(2-((4-((5S,8S,11S,14S,17S,20S,23S,26S,29S,35S,38R)-38-(2-amino-2-oxoethyl)-14-(3-amino-3-oxopropyl)-8,23-di((S)-sec-butyl)-17-(4-carboxybenzyl)-26-(4-(carboxymethoxy)benzyl)-11-(carboxymethyl)-29-(isoquinoline-7-ylmethyl)-20-((R)-1-methoxy) (Ethyl)-4,7,13,28,37-pentamethyl-3,6,9,12,15,18,21,24,27,30,33,36-dodecano-35-((6-phenylpyridin-3-yl)methyl)-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononadecano-5-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound A59-1)

[0863] Step 1: 4-((2S,5S,8S,11S,14S,20S,23R)-25-amino-2-((2S,5S,8S,11S)-2-(3-amino-3-oxopropyl)-11-(4-aminobutyl)-8-((S)-sec-butyl)-5-(carboxymethyl)-14-chloro-3,9,12-trimethyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecanoamide)-8 Synthesis of -((S)-sec-butyl)-11-(4-(carboxymethoxy)benzyl)-14-(isoquinoline-7-ylmethyl)-23-(mercaptomethyl)-5-((R)-1-methoxyethyl)-13,22-dimethyl-3,6,9,12,15,18,21,25-octaoxo-20-((6-phenylpyridin-3-yl)methyl)-4,7,10,13,16,19,22-heptaazapentaalkyl)benzoic acid

[0864] 1. Synthesis of the target compound based on standard Fmoc-SPPS technology:

[0865] 1) Resin preparation: RinkAmideMBHAresin (0.61 g, Substitution rate Sub = 0.33 mmol / g, 1.00 equivalent) was soaked in DMF (10 mL) for 30 min, and the liquid was drained. Then, 20% piperidine / DMF (10 mL) was added to the soaked resin, and nitrogen was bubbled for 10 min, and the liquid was drained. The obtained resin was washed with DMF (10 mL), and the liquid was drained. Ninhydrin detection showed that the resin was red and the solution was light blue.

[0866] 2) Amino acid condensation: Weigh 2.00 equivalents of Fmoc-N-Me-β-hCys(Trt)-OH and add it to the above resin. Add 4.00 eq of DIEA and then add 3.0 mL of DMF to the reaction column. Purge the resulting mixture with nitrogen gas until the amino acids dissolve. Then add 1.95 eq of HATU and adjust the nitrogen gas level to ensure uniform bubbling of the resin. The reaction system was incubated at 25°C for 40 min. Ninhydrin detection showed that the resin was colorless and transparent, while the solution was pale yellow. The reaction solution was removed, the resin was washed with DMF, and the liquid was drained.

[0867] 3) Deprotection of Fmoc: Add 20% piperidine / DMF (10 mL) to the resin, puff with nitrogen for 10 min, and then drain the liquid. Wash the resulting resin with DMF (10 mL) and drain the liquid. The resin turns green when tested with tetrachlorobenzoquinone.

[0868] 4) Replace Fmoc-N-Me-β-hCys(Trt)-OH in step 2) sequentially with reagents 2 to 13 in Table 5-1, and replace HATU and DIEA in step 2) sequentially with coupling conditions 2 to 13 in Table 5-1. Repeat steps 2) and 3) in a cyclical manner. The resulting resin is then used for the next step. Specifically, after the coupling of Fmoc-3Py6Ph-OH is completed, the reaction product is subjected to nitrogen purging in acetic anhydride / DIEA / DMF (v / v / v, 10 / 5 / 85, 20 mL), filtered, and the solid is collected. The solid is washed with DMF, and the liquid is drained. Then, the Fmoc protection is removed to proceed with the next amino acid coupling.

[0869] 5) After condensation, the resin was washed sequentially with DMF (20 mL), MeOH (20 mL) and isopropyl ether (20 mL), and then vacuum dried.

[0870] Table 5-1: List of amino acids used in SPPS and corresponding reagents

[0871] 2. Peptide cleavage: Cleavage solution (TFA / 3-MPA / Tis / H2O, v / v / v / v, 92.5 / 2.5 / 2.5 / 2.5, 8 mL) was added to the dried resin. The resulting mixture was shaken on a shaker for 1 h, filtered, and 42 mL of ice-cold isopropyl ether was added to the filtrate. The mixture was centrifuged, and the precipitate was washed with isopropyl ether and dried to obtain 4-((2S,5S,8S,11S,14S,20S,23R)-25-amino-2-((2S,5S,8S,11S)-2-(3-amino-3-oxopropyl)-11-(4-aminobutyl)-8-((S)-sec-butyl)-5- (Carboxymethyl)-14-chloro-3,9,12-trimethyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecanoamide)-8-((S)-sec-butyl)-11-(4-(carboxymethoxy)benzyl)-14-(isoquinoline-7-ylmethyl)-23-(mercaptomethyl)-5-((R)-1-methoxyethyl)-13,22-dimethyl-3,6,9,12,15,18,21,25-octaoxo-20-((6-phenylpyridin-3-yl)methyl)-4,7,10,13,16,19,22-heptaazapentaalkyl)benzoic acid (0.23 g).

[0872] Its structural characterization data are as follows:

[0873] MS(ESI, m / z): 943.2 [M / 2+H] + .

[0874] Step 2: 4-(((5S,8S,11S,14S,17S,20S,23S,26S,29S,35S,38R)-38-(2-amino-2-oxoethyl)-14-(3-amino-3-oxopropyl)-5-(4-aminobutyl)-8,23-bis((S)-sec-butyl)-26-(4-(carboxymethoxy)benzyl)-11-(carboxymethyl)-29-(isoquinoline-7-ylmethyl)-2 Synthesis of 0-((R)-1-methoxyethyl)-4,7,13,28,37-pentamethyl-3,6,9,12,15,18,21,24,27,30,33,36-dodecano-35-((6-phenylpyridin-3-yl)methyl)-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononadecan-17-yl)methyl)benzoic acid

[0875] Take compound 4-((2S,5S,8S,11S,14S,20S,23R)-25-amino-2-((2S,5S,8S,11S)-2-(3-amino-3-oxopropyl)-11-(4-aminobutyl)-8-((S)-sec-butyl)-5-(carboxymethyl)-14-chloro-3,9,12-trimethyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecanoamide)-8-((S)-sec-butyl)-11-(4-(carboxymethoxy)benzyl)-14-(isoquinoline-7-ylmethyl) -23-(mercaptomethyl)-5-((R)-1-methoxyethyl)-13,22-dimethyl-3,6,9,12,15,18,21,25-octaoxo-20-((6-phenylpyridin-3-yl)methyl)-4,7,10,13,16,19,22-heptaazapentaalkyl)benzoic acid (100.0 mg) was dissolved in H2O (80 mL) and ACN (20 mL). The pH of the resulting solution was adjusted to 8-9 with saturated NH4HCO3 at 25 °C, and then the reaction was stirred at 25 °C for 1 h. The reaction product was then analyzed with 1 M... The pH was adjusted to 6 with HCl, and after lyophilization, the product was purified by preparative high-performance liquid chromatography (HPLC). The lyophilized product yielded 4-(((5S,8S,11S,14S,17S,20S,23S,26S,29S,35S,38R)-38-(2-amino-2-oxoethyl)-14-(3-amino-3-oxopropyl)-5-(4-aminobutyl)-8,23-di((S)-sec-butyl)-26-(4-(carboxymethoxy)benzyl)-11-(carboxymethyl)-29-(isobutyl) Quinoline-7-ylmethyl)-20-((R)-1-methoxyethyl)-4,7,13,28,37-pentamethyl-3,6,9,12,15,18,21,24,27,30,33,36-dodecoxo-35-((6-phenylpyridin-3-yl)methyl)-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononadecan-17-yl)methyl)benzoic acid (35.0 mg).

[0876] Its structural characterization data are as follows:

[0877] MS(ESI, m / z): 925.2 [M / 2+H] + .

[0878] The operating conditions for preparing high performance liquid chromatography are as follows:

[0879] Column: Gemini, C18 (5μm, )+Luna,C18(10μm, (in series);

[0880] Mobile phase A: 0.075 wt% trifluoroacetic acid aqueous solution; Mobile phase B: acetonitrile; The mobile phase elution program is shown in Table 5-2.

[0881] Table 5-2: Mobile Phase Elution Procedure

[0882] Step 3: 2,2',2”-(10-(2-((4-((5S,8S,11S,14S,17S,20S,23S,26S,29S,35S,38R)-38-(2-amino-2-oxoethyl)-14-(3-amino-3-oxopropyl)-8,23-di((S)-sec-butyl)-17-(4-carboxybenzyl)-26-(4-(carboxymethoxy)benzyl)-11-(carboxymethyl)-29-(isoquinoline-7-ylmethyl)-20-((R)-1-methyl Synthesis of oxyethyl(l)-4,7,13,28,37-pentamethyl-3,6,9,12,15,18,21,24,27,30,33,36-dodecoxo-35-((6-phenylpyridin-3-yl)methyl)-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononadecano-5-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid

[0883] Take 4-(((5S,8S,11S,14S,17S,20S,23S,26S,29S,35S,38R)-38-(2-amino-2-oxoethyl)-14-(3-amino-3-oxopropyl)-5-(4-aminobutyl)-8,23-bis((S)-sec-butyl)-26-(4-(carboxymethox...

Claims

1. A ligand compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, said compound having the structure of formula (I02): in: X 1 X 3 and X 5 Each is independently selected from N and CH; X 6 and X 7 Each is independently selected from N and CH; X 2 Selected from -CR t1 R t2 -, -CH2CR t1 R t2 -, -NH- and -N(CH3)-; R 1 R 4 R 8 R 10 Each is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 The cycloalkyl groups are optionally each selected independently by one or more elements chosen from D, halogen, -OH, -CN, -CONR. 12 R 13 Substitution with -COOH substituents; R 2 and R 6 Each is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Each cycloalkyl group is optionally surrounded by one or more elements independently selected from halogens, D, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups; R 3 and R 5 Each is independently selected from H, D, halogens, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. c Replace; or R 3 and R 5 Together with the atoms it is attached to, they form 7-18 membered heterocyclic groups; R 7 Selected from H, D, halogens, -OH, -CN, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 -OR 14 -OC(=O)R 14 -OP(=O)(OR) 13 (OR) 14 -P(=O)(OR) 13 (OR) 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -L 1 -C 3-8 cycloalkyl-, -L 1 -(3-8 membered heterocyclic group)-, -L 1 -C 6-10 Aryl- and -L 1 -(5-10 heteroaryl)-, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. d replace; L 1 Selected from C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S-, -NH- and -N(CH3)-; R 9 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected halogens, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, -SO2R 14 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of haloalkyl groups; R′ and R″ are each independently selected from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH; R 11a and R 11 Each is independently selected from H, D, OH, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl groups, amino acid residues, and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl group, amino acid residue, and 3-8 membered heterocyclic group are each optionally selected independently from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substitution by haloalkoxy groups, -OH, -NH2-, -CN, -COOH, and -CONH2; or R 11a and R 11 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally composed of one or more atoms independently selected from H, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 and -OC(=O)R 14 Substituents of the substituents; R t1 and R t2 Each independently selected from H, D, C 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 Deuterated alkyl; or R t1 and R t2 Together with the atoms it is attached to, they form C 3-6 cycloalkyl; R 12 and R 13 Each occurrence is independently selected from H, D, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each optionally substituted by one or more substituents selected independently from D, halogen, -OH, -CN, and -COOH; or R 12 and R 13 Together with the atoms it is attached to, they form 3-8 membered heterocyclic groups; R 14 Each time it appears, it is independently selected from H, D, halogen, -OH, -NH2, -NHCH3, -N(CH3)2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents; R 16 R 17 R 18 R 19 Each is independently selected from H, D, halogens, -OH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl; R 20 selected from -CONR 12 R 13 、 -COR 13 、 -OSO2R 14 、 -NHCOR 14 、 -SOR 14 、 -SO2R 14 、 -OR 14 、 -OC(=O)R 14 、 -P(=O)(OR 13 )(OR 14 ) and -O-P(=O)(OR 13 )(OR 14 ); R a Chelating groups selected from non-radioactive or radioactive nuclides; R c and R d Each occurrence is independently selected from H, D, halogen, =O, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally surrounded by one or more independently selected from halogen, D, OH, -COOH, -CH2COOH, -CH2CH2COOH, -CONH2, -CH2CONH2, CN, -NH2, =CR′R″, -SO2R 14 and C 1-6 Alkyl substituents; preferably, R c and R d Each occurrence is independently selected from H, D, halogen, =O, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally surrounded by one or more groups independently selected from halogens, D, OH, -COOH, -CH2COOH, -CH2CH2COOH, -CONH2, -CH2CONH2, CN, -NH2, and C. 1-6 Alkyl substituents; L is Where "*" represents the connection point with Y; X a X b X c X d X e X f X h and X i It does not exist, or it is selected independently from -O-, -S-, -Se-, -CR each time it appears. x R y -、-NR z -, -C(=O)-, -C(=S)-, -C(=CH2)-, -S(=O)-, -S(=O)2-, -CR x =CR y -、-C≡C-、-N=CR x -、-C(=N-OH)-、C 3-6 Cycloalkylene, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic, phenylene and 5-6 membered heteroaryl, wherein C 3-6 Cycloalkylene, C 3-6 The cycloene group, the 4-8 membered heterocyclic group, the phenylene group, and the 5-6 membered heteroaryl group are each optionally selected by one or more independently from halogen, D, =O, -OH, -CN, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; condition is when L is And R 1 R 4 R 8 R 10 CH3, R 9 For phenyl and pyrazolyl groups, R 11 and R 11a Let H be the integer part of the set, k1, k2, k3, k4, k5, k6, k7, k8, and k9 all be 0, k10 be 2, and R be the integer part of the set. 16 R 17 R 18 and R 19 For H, R 3 R 20 For -COOH, R 5 For -C(O)NH2, X 5 When X is -CH-, 2 Not -CH2-; R x and R y Each is independently selected from H, halogen, D, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group may be optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH; R z Selected from H, C 1-6 Alkyl and C 1-6 Deuterated alkyl groups; X g Selected from CH, N and Among them, ring B is selected from C. 3-6 Cycloalkanes, 4-8 membered heterocycles, C 6-10 Aromatic rings and 5-12 membered heteroaromatic rings, wherein ring B is optionally selected by one or more elements, each independently selected from halogens, D, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; Each time Y appears, it is independently selected from chemical bonds, -(CR) f R g ) m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6-10 aryl groups, amino acid residues, and 5-12 heteroaryl groups; the C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6- 10 The aryl group, amino acid residue, and 5-12 heteroaryl group are each optionally substituted by one or more groups selected from: D, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O; R f and R g Each occurrence is independently selected from H, D, halogen, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -NHCO-(CH2CH2O) m -(CH2) m -NHCO-(CH2) m -C 6-10 Aryl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6- 10 The aryl group and the 5-12 heteroaryl group are each optionally surrounded by one or more elements independently selected from halogen, D, OH, -COOH, -CONH2, CN, -NH2, and C. 1-6 Alkyl substituents; Each time m appears, it is independently selected from any integer in the range of 1-20; n is any integer selected from the range 0 to 20; J1, J2, J3, and J4 are each independently selected from 0, 1, 2, or 3 each time they appear; k1 is selected from 0, 1, 2, 3, 4, 5 or 6; k2, k3, k4, k5, k6, k7, k8, k9, and k10 are each independently selected from 0, 1, or 2 each time they appear; Preferably, the compound has the structure of formula (I01): in: X 1 X 3 and X 5 Each is independently selected from N and CH; X 2 Selected from -CR t1 R t2 -, -CH2CR t1 R t2 -, -NH- and -N(CH3)-; R 1 R 4 R 8 R 10 Each is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 The cycloalkyl groups are optionally each selected independently by one or more elements chosen from D, halogen, -OH, -CN, -CONR. 12 R 13 Substitution with -COOH substituents; R 2 and R 6 Each is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Each cycloalkyl group is optionally surrounded by one or more elements independently selected from halogens, D, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups; R 3 and R 5 Each is independently selected from H, D, halogens, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. c Replace; or R 3 and R 5 Together with the atoms it is attached to, they form 7-18 membered heterocyclic groups; R 7 Selected from H, D, halogens, -OH, -CN, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 -OR 14 -OC(=O)R 14 -OP(=O)(OR) 13 (OR) 14 -P(=O)(OR) 13 (OR) 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -L 1 -C 3-8 cycloalkyl-, -L 1 -(3-8 membered heterocyclic group)-, -L 1 -C 6-10 Aryl- and -L 1 -(5-10 heteroaryl)-, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. d replace; L 1 Selected from C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S-, -NH- and -N(CH3)-; R 9 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected halogens, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, -SO2R 14 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of haloalkyl groups; R′ and R″ are each independently selected from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH; R 11a and R 11 Each is independently selected from H, D, OH, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl groups, amino acid residues, and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl group, amino acid residue, and 3-8 membered heterocyclic group are each optionally selected independently from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substitution by haloalkoxy groups, -OH, -NH2-, -CN, -COOH, and -CONH2; or R 11a and R 11 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally composed of one or more atoms independently selected from H, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 and -OC(=O)R 14 Substituents of the substituents; R t1 and R t2 Each independently selected from H, D, C 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 Deuterated alkyl; or R t1 and R t2 Together with the atoms it is attached to, they form C 3-6 cycloalkyl; R 12 and R 13 Each occurrence is independently selected from H, D, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each optionally substituted by one or more substituents selected independently from D, halogen, -OH, -CN, and -COOH; or R 12 and R 13 Together with the atoms it is attached to, they form 3-8 membered heterocyclic groups; R 14 Each time it appears, it is independently selected from H, D, halogen, -OH, -NH2, -NHCH3, -N(CH3)2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents; R 16 R 17 R 18 R 19 Each is independently selected from H, D, halogens, -OH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl; R 20 selected from -CONR 12 R 13 、-COR 13 、-OSO2R 14 、-NHCOR 14 、-SOR 14 、-SO2R 14 、-OR 14 、-OC(=O)R 14 、-P(=O)(OR 13 )(OR 14 ) and -O-P(=O)(OR 13 )(OR 14 ); R a Chelating groups selected from non-radioactive or radioactive nuclides; R c and R d Each occurrence is independently selected from H, D, halogen, =O, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally surrounded by one or more groups independently selected from halogens, D, OH, -COOH, -CH2COOH, -CH2CH2COOH, -CONH2, -CH2CONH2, CN, -NH2, and C. 1-6 Alkyl substituents; L is Where "*" represents the connection point with Y; X a X b X c X d X e X f X h and X i It does not exist, or it is selected independently from -O-, -S-, -Se-, -CR each time it appears. x R y -、-NR z -, -C(=O)-, -C(=S)-, -C(=CH2)-, -S(=O)-, -S(=O)2-, -CR x =CR y -、-C≡C-、-N=CR x -、-C(=N-OH)-、C 3-6 Cycloalkylene, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic, phenylene and 5-6 membered heteroaryl, wherein C 3-6 Cycloalkylene, C 3-6 The cycloene group, the 4-8 membered heterocyclic group, the phenylene group, and the 5-6 membered heteroaryl group are each optionally selected by one or more independently from halogen, D, =O, -OH, -CN, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; condition is when L is And R 1 R 4 R 8 R 10 CH3, R 9 For phenyl and pyrazolyl groups, R 11 and R 11a Let H be the integer part of the set, k1, k2, k3, k4, k5, k6, k7, k8, and k9 all be 0, k10 be 2, and R be the integer part of the set. 16 R 17 R 18 and R 19 For H, R 3 R 20 For -COOH, R 5 For -C(O)NH2, X 5 When X is -CH-, 2 Not -CH2-; R x and R y Each is independently selected from H, halogen, D, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group may be optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH; R z Selected from H, C 1-6 Alkyl and C 1-6 Deuterated alkyl groups; X g Selected from CH, N and Among them, ring B is selected from C. 3-6 Cycloalkanes, 4-8 membered heterocycles, C 6-10 Aromatic rings and 5-12 membered heteroaromatic rings, wherein ring B is optionally selected by one or more elements, each independently selected from halogens, D, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; Each time Y appears, it is independently selected from chemical bonds, -(CR) f R g ) m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6-10 aryl groups, amino acid residues, and 5-12 heteroaryl groups; the C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6- 10 The aryl group, amino acid residue, and 5-12 heteroaryl group are optionally substituted with one or more of the following groups: D, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O; R f and R g Each occurrence is independently selected from H, D, halogen, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -NHCO-(CH2CH2O) m -(CH2) m -NHCO-(CH2) m -C 6-10 Aryl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6- 10 The aryl group and the 5-12 heteroaryl group are each optionally surrounded by one or more elements independently selected from halogen, D, OH, -COOH, -CONH2, CN, -NH2, and C. 1-6 Alkyl substituents; Each time m appears, it is independently selected from any integer in the range of 1-20; n is any integer selected from the range 0 to 20; J1, J2, J3, and J4 are each independently selected from 0, 1, 2, or 3 each time they appear; k1 is selected from 0, 1, 2, 3, 4, 5 or 6; k2, k3, k4, k5, k6, k7, k8, k9, and k10 are each independently selected from 0, 1, or 2 each time they appear; Preferably, the compound has the structure of formula (I”): in: X 1 X 3 and X 5 Each is independently selected from N and CH; X 2 Selected from -CR t1 R t2 -, -CH2CR t1 R t2 -, -NH- and -N(CH3)-; R 1 R 4 R 8 R 10 Each is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 The cycloalkyl groups are optionally each selected independently by one or more elements chosen from D, halogen, -OH, -CN, -CONR. 12 R 13 Substitution with -COOH substituents; R 2 and R 6 Each is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Each cycloalkyl group is optionally surrounded by one or more elements independently selected from halogens, D, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups; R 3 and R 5 Each is independently selected from H, D, halogens, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. c Replace; or R 3 and R 5 Together with the atoms it is attached to, they form 7-18 membered heterocyclic groups; R 7 Selected from H, D, halogens, -OH, -CN, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 -OR 14 -OC(=O)R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -L 1 -C 3-8 cycloalkyl-, -L 1 -(3-8 membered heterocyclic group)-, -L 1 -C 6-10 Aryl- and -L 1 -(5-10 heteroaryl)-, the C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. d replace; L 1 Selected from C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S-, -NH- and -N(CH3)-; R 9 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected from halogen, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of haloalkyl groups; R′ and R″ are each independently selected from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH; R 11a and R 11 Each is independently selected from H, D, OH, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl groups, amino acid residues, and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl group, amino acid residue, and 3-8 membered heterocyclic group are each optionally substituted by one or more substituents selected independently from halogens, -OH, -NH2-, -CN, -COOH, and -CONH2; or R 11a and R 11 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally composed of one or more atoms independently selected from H, halogen, -OH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 and -OC(=O)R 14 Substituents of the substituents; R t1 and R t2 Each independently selected from H, D, C 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 Deuterated alkyl; or R t1 and R t2 Together with the atoms it is attached to, they form C 3-6 cycloalkyl; R 12 and R 13 Each occurrence is independently selected from H, D, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each optionally substituted by one or more substituents selected independently from D, halogen, -OH, -CN, and -COOH; or R 12 and R 13 Together with the atoms it is attached to, they form 3-8 membered heterocyclic groups; R 14 Each occurrence is independently selected from H, D, -OH, -NH2, -NHCH3, -N(CH3)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents; R 16 R 17 R 18 R 19 Each is independently selected from H, D, halogens, -OH, -CN, -COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl; R a Chelating groups selected from non-radioactive or radioactive nuclides; R c and R d Each occurrence is independently selected from H, D, halogen, =O, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally surrounded by one or more groups independently selected from halogens, D, OH, -COOH, -CH2COOH, -CH2CH2COOH, -CONH2, -CH2CONH2, CN, -NH2, and C. 1-6 Alkyl substituents; L is Where "*" represents the connection point with Y; X a X b X c X d X e X f X h and X i It does not exist, or it is selected independently from -O-, -S-, -Se-, -CR each time it appears. x R y -、-NR z -, -C(=O)-, -C(=S)-, -C(=CH2)-, -S(=O)-, -S(=O)2-, -CR x =CR y -、-C≡C-、-N=CR x -、-C(=N-OH)-、C 3-6 Cycloalkylene, C 3-6 Cycloalkenyl, 4-8 membered heterocyclic, phenylene and 5-6 membered heteroaryl, wherein C 3-6 Cycloalkylene, C 3-6 The cycloene group, the 4-8 membered heterocyclic group, the phenylene group, and the 5-6 membered heteroaryl group are optionally selected by one or more independently selected from halogen, D, =O, -OH, -CN, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; condition is when L is And R 1 R 4 R 8 R 10 CH3, R 9 For phenyl and pyrazolyl groups, R 11 and R 11a When H is defined, and k1, k2, k3, k4, k5, k6, k7, k8, and k9 are all 0, then k10 is 2, and R is defined. 16 R 17 R 18 and R 19 For H, R 3 For -COOH, R 5 For -C(O)NH2, X 5 For -CH-, X 2 Not -CH2-; R x and R y Each is independently selected from H, halogen, D, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group may be optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH; R z Selected from H, C 1-6 Alkyl and C 1-6 Deuterated alkyl groups; X g Selected from CH, N and Among them, ring B is selected from C. 3-6 Cycloalkanes, 4-8 membered heterocycles, C 6-10 Aromatic rings and 5-12 membered heteroaromatic rings, wherein ring B is optionally selected by one or more elements, each independently selected from halogens, D, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; Each time Y appears, it is independently selected from chemical bonds, -(CR) f R g ) m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6-10 aryl groups, amino acid residues, and 5-12 heteroaryl groups; the C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6- 10 The aryl group, amino acid residue, and 5-12 heteroaryl group are each optionally substituted by one or more groups selected from: D, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O; R f and R g Each occurrence is independently selected from H, D, halogen, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each optionally surrounded by one or more elements independently selected from halogen, D, OH, -COOH, -CONH2, CN, -NH2, and C. 1-6 Alkyl substituents; Each time m appears, it is independently selected from any integer in the range of 1-20; n is any integer selected from the range 0 to 20; J1, J2, J3, and J4 are each independently selected from 0, 1, 2, or 3 each time they appear; k1 is selected from 0, 1, 2, 3, 4, 5 or 6; k2, k3, k4, k5, k6, k7, k8, k9, and k10 are each independently selected from 0, 1, or 2 each time they appear; Preferably, the compound has the structure shown in Formula I' or Formula I: Among them, X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a ,k1,k2,k3,k4,k5,k6,k7,k8,k9,k10,R a and n are as defined above; in: X 1 and X 3 Each is independently selected from N and CH; X 2 Selected from -CH2-, -NH- and -N(CH3)-; R 1 R 4 R 8 R 10 Each is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Each cycloalkyl group is optionally substituted by one or more substituents selected independently from D, halogens, -OH, -CN and -COOH; R 2 and R 6 Each is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Each cycloalkyl group is optionally surrounded by one or more elements independently selected from halogens, D, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups; R 3 and R 5 Each is independently selected from H, D, halogens, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bounded by one or more R groups. c Replace; or R 3 and R 5 Together with the atoms it is attached to, they form 7-18 membered heterocyclic groups; R 7 Selected from H, D, halogens, -OH, -CN, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SOR 14 -SO2R 14 -OR 14 -OC(=O)R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -L 1 -C 3-8 cycloalkyl-, -L 1 -(3-8 membered heterocyclic group)-, -L 1 -C 6-10 Aryl- and -L 1 -(5-10 heteroaryl)-, the C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally separated by one or more R d replace; L 1 Selected from C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S-, -NH- and -NHCH3-; R 9 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2- 6 heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected from halogen, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of haloalkyl groups; R′ and R″ are each independently selected from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH; R 11 Selected from H, D, OH, C 1-6 Alkyl and C 1-6 Deuterated alkyl groups; R 12 and R 13 Each occurrence is independently selected from H, D, -OH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each optionally substituted by one or more substituents selected independently from D, halogen, -OH, -CN, and -COOH; or R 12 and R 13 Together with the atoms it is attached to, they form 3-8 membered heterocyclic groups; R 14 Each occurrence is independently selected from H, D, -OH, -NH2, -NHCH3, -N(CH3)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents; R a Chelating agents selected from non-radioactive or radioactive nuclides; R c and R d Each occurrence is independently selected from H, D, halogen, =O, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally surrounded by one or more groups independently selected from halogen, D, OH, -COOH, -CONH2, CN, -NH2, and C. 1-6 Alkyl substituents; L is Where "*" represents the connection point with Y; X a X b X c X d X e X f X h and X i It does not exist, or it is selected independently from -O-, -S-, -Se-, -CR each time it appears. x R y -、-NR z -, -C(=O)-, -C(=S)-, -C(=CH2)-, -S(=O)-, -S(=O)2-, -CR x =CR y -、-C≡C-、-N=CR x -、-C(=N-OH)-、C 3-6 Cycloalkylene, 4-8-membered heterocyclic alkylene, phenylene, and 5-6-membered heteroaryl alkylene, wherein C 3-6 The cycloalkyl group, the 4-8 membered heterocyclic group, the phenyl group, and the 5-6 membered heteroaryl group are each optionally selected independently by one or more halogens, D, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; condition is when L is And R 1 R 4 R 8 R 10 CH3, R 9 For phenyl and pyrazolyl groups, R 11 When it is H, X 2 For -NH- and -N(CH3)-; R x and R y Each is independently selected from H, halogen, D, and C. 1-6 Alkyl and C 1-6 Haloalkyl, the C 1-6 Alkyl or C 1-6 The haloalkyl group may be optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN and -COOH; R z Selected from H, C 1-6 Alkyl and C 1-6 Deuterated alkyl groups; X g Selected from CH, N and Among them, ring B is selected from C. 3-6 Cycloalkanes, 4-8 membered heterocycles, C 6-10 Aromatic rings and 5-12 membered heteroaromatic rings, wherein ring B is optionally selected by one or more elements, each independently selected from halogens, D, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; Each time Y appears, it is independently selected from chemical bonds, -(CR) f R g ) m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6-10 arylene and 5-12 heteroarylene; the C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 6-10 The arylene and the 5-12-membered heteroarylene are each optionally substituted by one or more of the following groups: D, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O; R f and R g Each occurrence is independently selected from H, D, halogen, -OH, -COOH, -CN, -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each optionally surrounded by one or more elements independently selected from halogen, D, OH, -COOH, -CONH2, CN, -NH2, and C. 1-6 Alkyl substituents; Each time m appears, it is independently selected from any integer in the range of 1-20; n is any integer selected from the range 0 to 20.

2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: X 1 and X 3 Each is independently selected from N and CH, X 5 Selected from CH; and / or, X 6 and X 7 Both are CH, or X 6 Selected from CH and X 7 Selected from N; and / or, X 2 Selected from -CH2- and -NH-.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: R 1 R 4 R 8 R 10 Each is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Each cycloalkyl group is optionally substituted by one or more substituents selected independently from D, halogens, -OH, -CN and -COOH; Preferably, R 1 R 4 R 8 R 10 Each of the following groups is independently selected from H, CD3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are each optionally substituted by one or more substituents independently selected from D, halogen, -OH, -CN, -C(O)NH2, and -COOH; Preferably, R 1 R 4 R 8 R 10 Each is independently selected from H and C. 1-4 Deuterated alkyl and C 1-4 Alkyl, the C 1-4 The alkyl group may be optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN, -C(O)NH2 and -COOH; Preferably, R 1 R 4 R 8 R 10 Each of the substituents is independently selected from H, CD3 and CH3, wherein the CH3 is optionally substituted by one or more substituents independently selected from -C(O)NH2 and -COOH; Preferably, R 1 R 4 R 8 R 10 Each is independently selected from H, CD3, -CH2C(O)NH2 or -CH2CH2C(O)NH2; Preferably, R 1 R 4 R 8 R 10 Each is independently selected from C 1-4 Deuterated alkyl and C 1-4 Alkyl, the C 1-4 The alkyl group may be optionally substituted by one or more substituents, each independently selected from D, halogen, -OH, -CN, -C(O)NH2 and -COOH; Preferably, R 1 R 4 R 8 R 10 Each is independently selected from CD3, methyl, ethyl and -CH2CH2C(O)NH2; More preferably, R 1 R 4 R 8 R 10 Each is independently selected from CH3.

4. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: R 2 and R 6 Each is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Each of the haloalkoxy groups is optionally surrounded by one or more elements independently selected from halogen, D, -OH, -NH2, -CONH2, -COR. 13 -NHCOR 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; Preferably, R 2 and R 6 Each is independently selected from C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 Each alkoxy group is optionally selected by one or more independently from -NH2, -CONH2, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; More preferably, R 2 and R 6 Each is independently selected from C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally selected from one or more C14 groups. 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; More preferably, R 2 Selected from C 3-6 alkyl; More preferably, R 2 Selected from Preferably, R 6 Selected from C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally bounded by one or more C groups, each independently of the other. 1-3 Substitution of alkoxy groups; More preferably, R 6 Selected from 5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: R 3 and R 5 Each is independently selected from H, -OH, -CN, and -NR. 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -SO2R 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 2-6 Heteroalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 2-6 Each of the heteroalkyl groups is optionally surrounded by one or more R c Replace; or R 3 and R 5 Together with the atoms it is attached to, they form 7-18 membered heterocyclic groups; Preferably, R 3 and R 5 Each is independently selected from H and C. 1-4 Alkyl groups, -CONH2, -COOH, -NHCONH2, and -S(O)2OH; or R 3 and R 5 Together with the atoms it is attached to, they form 7-18 membered heterocyclic groups; More preferably, R 3 and R 5 Each is independently selected from H and C. 1-4 Alkyl groups, -CONH2, -COOH, and -S(O)2OH; More preferably, R 3 Selected from -COOH and -S(O)2OH, R 5 Selected from -CONH2; or k10 is 0 or 1, R 5 Selected from H, C 1-4 Alkyl; or k10 is 2, R 5 Selected from -C(O)NH2.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: R 7 Selected from -OH, -NR 12 R 13 -CONR 12 R 13 -COR 13 -NHCOR 14 -OR 14 -OC(=O)R 14 -SO2R 14 -OP(=O)(OR) 13 (OR) 14 -P(=O)(OR) 13 (OR) 14 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Heteroalkyl, C 1-6 The hydroxyalkyl group and the 3-8 membered heterocyclic group are each optionally surrounded by one or more R groups. d replace; Preferably, R 7 Selected from -OH, -COOH, -OR 14 -SO2R 14 -OP(=O)(OR) 13 (OR) 14 -P(=O)(OR) 13 (OR) 14 C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl groups and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroalkyl group and the 3-8 membered heterocyclic group are each optionally surrounded by one or more R d replace; More preferably, R 7 Selected from -OCH2COOH, -OP(=O)(OH)(OH), -S(O)2OH and 7. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: R 9 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally selected by one or more independently selected halogens, D, OH, CN, -NH2, -COOH, -CONH2, =CR′R″, -SO2R 14 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 The substituents of the haloalkyl group are selected independently from H, D, halogen, and C. 1-6 Alkyl and C 1- 6-Hydroalkyl group, wherein the C 1-6 Alkyl or C 1-6 Each haloalkyl group is optionally substituted by one or more substituents selected independently from D, halogen, -OH, -CN and -COOH; Preferably, R 9 Selected from C 6-10 Aryl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic and 5-10 membered heteroaryl, wherein C 6- 10 Aryl, C 3-8 cycloalkyl, C 3-8 The cycloalkenyl, 3-8 membered heterocyclic and 5-10 membered heteroaryl groups are each optionally selected by one or more independently selected from halogen, CN, D, =CR′R″, -SO2R 14 C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkyl group are selected independently from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; More preferably, R 9 Selected from phenyl, piperidinyl, Cyclohexyl and cyclohexenyl, the phenyl, piperidinyl, The cyclohexyl and cyclohexenyl groups are optionally selected by one or more independently chosen from halogens, CN, D, =CR′R″, -SO2R 14 C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkyl group are selected independently from H, D, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; More preferably, R 9 Selected from phenyl, piperidinyl, Cyclohexyl and cyclohexenyl, the phenyl, piperidinyl, The cyclohexyl and cyclohexenyl groups may be optionally substituted by one or more substituents, each independently selected from F, CN, Cl, D, =CF2, =C(CH3)2, methyl, methoxy, -CF3, -CHF2, -CH2F and -S(O)2NH2; More preferably, R 9 Selected from phenyl, 8. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: R 11a and R 11 Each is independently selected from H, D, OH, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 cycloalkyl groups and -CH2COOH; or R 11a and R 11 Together with the atoms to which it is attached, it forms a 5-6 membered heterocyclic group, which is optionally formed by one or more atoms independently selected from H, -OH, C. 1-6 Alkyl substituents; Preferably, R 11a and R 11 Each is independently selected from H, D, OH, methyl, ethyl, isopropyl, cyclopropyl, and -CH2COOH, or R. 11a and R 11 Together with the atoms to which they are attached, they form piperazine, pyrrolidinyl and morpholinyl groups, which are optionally substituted by one or more substituents, each independently selected from -OH and -CH3. Preferably, R 11a and R 11 Each is independently selected from H, OH, methyl, isopropyl, cyclopropyl, -CH2COOH, or R. 11a and R 11 Together with the atoms it is attached to, they form the following groups: More preferably, R 11a Selected from H and methyl, R 11 Selected from H, D, OH and methyl; or R 11a and R 11 Together with the atoms it is attached to, they form the following groups:

9. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: Meets one or more of the following criteria: 1)R 16 R 17 R 18 R 19 Each is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl; 2)R 16 R 17 R 18 R 19 Each is independently selected from H, D, halogens and C. 1-6 alkyl; 3)R 16 R 17 R 18 R 19 Each is independently selected from H, halogens, and C. 1-6 alkyl; 4)R 16 R 17 R 18 R 19 Each is independently selected from H, D, F, Cl, methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl; 5)R 20 selected from -COR 13 、-OSO2R 14 、-SO2R 14 、-P(=O)(OR 13 )(OR 14 ) and -O-P(=O)(OR 13 )(OR 14 ); 6)R 20 Selected from -COOH, -OS(O)2F, -S(O)2F, -S(O)2OH, -OS(O)2OH, -OP(=O)(OH)(OH), -P(=O)(OH)2, -OS(O)2CH3 and -OS(O)2CH2CH3.

10. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: Meets one or more of the following criteria: 1) k1 is selected from 0, 1, 2, or 3; 2) k1 is selected from 0 or 1; 3) k2, k3, k4, k5, k6, k7, k8, and k9 are selected from 0 or 1; 4) k2, k3, k4, k5, k6, k7, k8, and k9 are selected from 0; 5) At least one of k2, k3, k4, k5, k6, k7, k8, and k9 is 1; 6) J1, J2, J3, and J4 are selected from 0 or 1.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: -(Y) n -Selected from: -NH-, -(CH2) m -NH-, -(CH2) m -S-(CH2) m -NH-, -(CH2) m -S-(CH2) m -CONH-(CH2) m -NH-, -N(R f )CO-(CH2) m -NH-, -N(R f )(CH2) m -NH-, -S-(CH2) m -NH-, -O-(CH2) m -NH-, -CO-(CH2) m -NH-, -(CH2) m -CONH-(CH2) m -NH-, -CONH-(CH2) m -NH-, -CO-(CH2) m -S-(CH2) m -NH-, -C(=N-OH)S-(CH2) m -NH-, -(CH2) m -O-(CH2) m -NH-, -(CH2) m -(CH2OCH2) m -(CH2) m -NH-, -N(R f )CO-(CH2) m -N(R f )-, -N(R f )CO-(CH2CH2O)m-(CH2) m -N(R f )-, -N(R f )CO-(CH2) m -CH(COOH)-N(R f )-, -N(R f )CO-(CR f R g )m-(CH2)m-N(R f )-, -N(R f )CO-(CH2)m-N(R f )-(CH2)m-N(R f )-, -N(R f )CO-(CH2)m-N(R f )CO-(CH2)mN(R f )-、-N(R f )-(CH2)mN(R f )-(CH2)mN(R f )-、-N(R f )CO-(CH2)m-(4-12 membered heterocyclic group)-、-N(R f )CO-(CH2)m-(4-12 membered heterocyclic group)-N(R f )-、-N(R f )CO-(CH2)m– amino acid residues-, C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -C 3-6 Cycloalkyl-CO-(CH2) m -、-(4-12 membered heterocyclic group)-CO-(CH2) m -、-C 6-10 Aryl-CO-(CH2) m -、-(5-12 heteroaryl)-CO-(CH2) m -、-C 3-6 Cycloalkyl-CO-, -(4-12 membered heterocyclic)-CO-, -C 6-10 aryl-CO-, -(5-12 heteroaryl)-CO-, -C 3-6 Cycloalkyl-(CH2) m -、-(4-12 membered heterocyclic group)-(CH2) m -、-C 6- 10 Aryl-(CH2) m -、-(5-12 heteroaryl)-(CH2) m -、-N(R f CO-(CH2) m -N(R f -amino acid residues-、-N(R) f CO-(CH2) m -N(R f )-amino acid residue-amino acid residue-、 Preferably, -(Y) n - is selected from: -NH-, -CH2CH2NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -CH2SCH2CONHCH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2NH-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -N(CH3)COCH2CH2NH-, -SCH2CH2NH-, -OCH2CH2NH-, -C(=O)CH2CH2NH-, -CH2C(=O)NHCH2CH2NH-, -C(=O)NHCH2CH2NH-, -C(=O)CH2CH2SCH2CH2NH-, -C(=O)CH2SCH2CH2NH-, -CH2CH2C(=O)NHCH2CH2NH-, -C(=N-OH)SCH2CH2NH-, -CH2CH2OCH2CH2NH-, -CH2(CH2OCH2)2CH2NH-, -CH2(CH2OCH2)3CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-, -N(CH3)COCH2CH2N(CH3)- -N(CH3)CO(CH2CH2O)3CH2CH2NH-、-NHCO(CH2CH2O)3CH2CH2NH-、-NHCOCH2CH2-CH(COOH)-NH-、-NHCOCH2CH2NHCOCH2CH2NH-、-NHCOCH(NH2)CH2CH2CH2CH2NH-、-NHCOCH2NHCH2CH2NH-、-NHCOCH2CH2NHCH2CH2NH-、-NHCH2CH2N(CH3)CH2CH2NH-、 More preferably, -(Y) n - selected from: -NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2NH-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -C(=O)CH2CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-, -N(CH3)COCH2CH2N(CH3)-, -N(CH3)CO(CH2CH2O)3CH2CH2NH-, -NHCO(CH2CH2O)3CH2CH2NH-, -NHCOCH2CH2-CH(COOH)-NH-, -NHCOCH2CH2NHCOCH2CH2NH-, -NHCOCH(NH2)CH2CH2CH2CH2NH-, -NHCOCH2NHCH2CH2NH-, -NHCOCH2CH2NHCH2CH2NH-, -NHCH2CH2N(CH3)CH2CH2NH- More preferably, -(Y) n -Selected from: -CH2CH2CH2CH2NH-, -CH2CH2CH2NH-, CH2SCH2CH2CH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2NH-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -C (=O)CH2CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-, and -N(CH3)COCH2CH2NH-.

12. The compound of any one of claims 1-11 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: Selected independently each time it appears: Y is independently selected from single bonds and -(CH2). m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl, amino acid residues, and 5-12 membered heteroaryl groups; said cycloalkyl, heterocyclic, aryl, amino acid residues, and heteroaryl groups are optionally substituted by one or more of the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O; Ring A is a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle; R b Each occurrence is independently selected from H, D, halogen, =O, -OH, -CN, -NH2, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; p is independently selected from any integer in the range of 0-3; Preferably, Selected independently each time it appears: Y is independently selected from single bonds and -(CH2). m -, -C(=O)-, -C(=S)-, -S-, -S(=O)-, -S(=O)2-, =CH-, -N=CR f -、-NR f -, -O-, -C(=N-OH)-, -(CH2CH2OCH2CH2) m -、-(CH2CH2O) m -、C 3-6 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-10 Aryl, amino acid residues, and 5-12 membered heteroaryl groups; said cycloalkyl, heterocyclic, aryl, amino acid residues, and heteroaryl groups are optionally substituted by one or more of the following groups: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =O; More preferably, Selected independently each time it appears: -(Y) n -Selected from: -NH-, -CH2CH2NH-, -CH2CH2CH2NH-, -CH2CH2CH2CH2NH-, -CH2SCH2CH2NH-, -CH2SCH2CH2CH2CH2NH-, -CH2SCH2CONHCH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2NH-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2CH2NH-, -N(CH3)COCH2CH2NH-, -SCH2CH2NH-, -OCH2CH2NH-, -C(=O)CH2CH2NH-, -CH2C(=O)NHCH2CH2NH-, -C(=O)NHCH2CH2NH-, -C(=O)CH2CH2SCH2CH2NH-, -C(=O)CH2SCH2CH2NH-, -CH2CH2C(=O)NHCH2CH2NH-, -C(=N-OH)SCH2CH2NH-, -CH2CH2OCH2CH2NH-, -CH2(CH2OCH2)2CH2NH-, -CH2(CH2OCH2)3CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2CH2NH-, -N(CH3)COCH2CH2N(CH3)- -N(CH3)CO(CH2CH2O)3CH2CH2NH-、-NHCO(CH2CH2O)3CH2CH2NH-、-NHCOCH2CH2-CH(COOH)-NH-、-NHCOCH2CH2NHCOCH2CH2NH-、-NHCOCH(NH2)CH2CH2CH2CH2NH-、-NHCOCH2NHCH2CH2NH-、-NHCOCH2CH2NHCH2CH2NH-、-NHCH2CH2N(CH3)CH2CH2NH-、-NHCOCH2CH2N(CH3)CH2CH2NH-、 More preferably, Selected independently each time it appears: -(Y) n - Select from: -CH2CH2CH2CH2NH-, -CH2CH2CH2NH-, CH2SCH2CH2CH2CH2NH-, -NHCOCH2NH-, -NHCOCH2CH2NH-, -NHCOCH2CH2CH2NH-, -NHCOCH2CH2CH2NH-, -C(=O)CH2CH2NH-, -N(CH3)CH2CH2CH2NH-, -NHCH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, -NHCH2CH2CH2CH2NH-, and -N(CH3)COCH2CH2NH-; Preferably, Selected from Preferably, position 1 and Connection, position 2 is connected to -C(O)-, position 3 is connected to R a connect.

13. The compound of any one of claims 1-12 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: R a Chelating groups selected from radioactive nuclides; Preferably, R a The chelating agent is selected from the following: chelating agent that removes one or more atoms to form a chelating group, wherein the chelating agent is selected from 99mTc(CO)3-chelating agent, CB-TE2A, CHX-A”-DTPA, DTPA, DATA, DFO, HBED, Crown, DOTA, DOTAGA, DOTAM, FSC, H4octapa, Macropa, HEHA, HOPO, Hynic, PCTA, PSC, NETA, Nota, Nota-MPAA, NODAGA, NOTP, NOPO, Pycup, RESCA, Sarcophagine, TETA, THP, TRAP, P-NH2-Bn-PCTA, pBn-SCN-PCTA, SCN-NOTA, H2-MACROPA-NCS, tetra-(S,S,S,S)-Et-DOTA, or maleimide-nBu-DOTA; More preferably, R a Selected from: R k Selected from halogens (e.g., iodine, bromine, chlorine, fluorine), C 1-6 Alkyl (e.g., methyl), C 1-6 Alkyl groups (e.g., methoxy), hydroxyl groups, amino groups, nitro groups, and cyano groups; More preferably, R a Selected from: More preferably, R a Selected from:

14. The compound of any one of claims 1-13 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: Compounds of formula (I) are compounds of formula (I-1), formula (I-2), formula (I-3), formula (I-A1), formula (I-A2), formula (IB), formula (I-B1), or formula (I-B2): Where R 1 R 4 R 8 R 9 R 10 L, Y, R a and n as defined in any one of claims 1-13; X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a and n as defined in claims 1-13; Where k1 is selected from 0 or 1, X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a R 16 R 17 R 18 R 19 R a and n as defined in any one of claims 1-13; Among them, L, Y, and R a and n as defined in any one of claims 1-13; Among them, R', R”, L, Y, R a and n as defined in any one of claims 1-13; X 4 Selected from N and CH; Where X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and n as defined in any one of claims 1-13; Wherein L, Y and n are defined as in any one of claims 1-13; Wherein R', R”, L, Y and n are as defined in any one of claims 1-13; X 4 Selected from N and CH.

15. The compound of any one of claims 1-14 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: The compounds mentioned are selected from:

16. A chelate or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein the chelate comprises a compound of formula I02, formula I01, formula I”, formula I’ or formula I as described in any one of claims 1-15 and a non-radioactive or radioactive nuclide chelated with a compound of formula I02, formula I01, formula I”, formula I’ or formula I; Preferably, the radionuclide chelated with the compound of formula (I) is selected from... 43 Sc、 44 Sc、 47 Sc、 55 Co、 62 Cu、 64 Cu、 67 Cu、 66 Ga、 67 Ga、 68 Ga、 86 Y、 89 Zr、 89 Sr、 90 Y、 90 Nb, 99m Tc, 111 In、 105 Rh、 140 Pr、 149 Tb, 152 Tb, 153 Pm, 153 Sm、 159 Gd, 160 Tb, 161 Tb, 165 Er、 166 Dy、 166 Ho、 167 Tm、 175 Yb、 177 Lu、 186 Re、 188 Re、 212 Pb, 213 Bi、 225 Ac、 232 Th、 209 Bi、 223 Ra、 227 Th、 223 Fr、 148 Gd, 229 Th.

17. The chelate of claim 16 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein the chelate has a structure shown in formula II02-A, II02-B, II01-A, II01-B, II”-A, II”-B, II'-A, II'-B, II-A, II-B, II-1, II-A1, or II-A2: Where X 1 X 2 X 3 X 5 X 6 X 7 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a R 16 R 17 R 18 R 19 R 20 J1, J2, J3, J4, k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n as defined in any one of claims 1-15, X M It may be a non-radioactive or radioactive nuclide; Where X 1 X 2 X 3 X 5 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a R 16 R 17 R 18 R 19 R 20 J1, J2, J3, J4, k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n as defined in any one of claims 1-15, X M It may be a non-radioactive or radioactive nuclide; Where X 1 X 2 X 3 X 5 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a R 16 R 17 R 18 R 19 J1, J2, J3, J4, k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n as defined in any one of claims 1-15, X M It may be a non-radioactive or radioactive nuclide; Where X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n are as defined in any one of claims 1-15, X M It may be a non-radioactive or radioactive nuclide; Where X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 And n as defined in any one of claims 1-15, X M It may be a non-radioactive or radioactive nuclide; Where R 1 R 4 R 8 R 9 R 10 L, Y, and n are as defined in any one of claims 1-15, X M It may be a non-radioactive or radioactive nuclide; Wherein L, Y, and n are defined as in any one of claims 1-15, X M It may be a non-radioactive or radioactive nuclide; Wherein R', R”, L, Y and n are as defined in any one of claims 1-15; X 4 Selected from N and CH, X M It can be a non-radioactive nuclide or a radioactive nuclide.

18. The chelate of claim 16 or 17 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein the chelate is selected from:

19. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein the compound has the structure shown in Formula III02: Where X 1 X 2 X 3 X 5 X 6 X 7 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a R 16 R 17 R 18 R 19 R 20 J1, J2, J3, J4, k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n as defined in claims 1-15, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3); Preferably, the compound has the structure shown in Formula III01: Where X 1 X 2 X 3 X 5 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a R 16 R 17 R 18 R 19 R 20 J1, J2, J3, J4, k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n as defined in claims 1-15, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3); Preferably, the compound has the structure shown in formula (III”): Where X 1 X 2 X 3 X 5 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a R 16 R 17 R 18 R 19 J1, J2, J3, J4, k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n as defined in any one of claims 1-15, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3); Preferably, the compound has the structure shown in formula (III) or formula (III'): Where X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 11a k1, k2, k3, k4, k5, k6, k7, k8, k9, k10 and n are as defined in any one of claims 1-15, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3); Where X 1 X 2 X 3 L, Y, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 And n as defined in any one of claims 1-15, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3); Preferably, the compound of formula (III) is a compound of formula (III-1), formula (III-A1), or formula (III-A2): Where R 1 R 4 R 8 R 9 R 10 L, Y, and n are as defined in any one of claims 1-15, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3); L, Y, and n are as defined in any one of claims 1-15, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3); Wherein R', R”, L, Y and n are as defined in any one of claims 1-15; X 4 Selected from N and CH, R 15 Selected from H, OH, halogens, CN, -CO-C 1-6 Alkyl groups (e.g., COCH3).

20. The compound of claim 19 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein the compound is selected from:

21. A pharmaceutical composition comprising a diagnostically, preventively, or therapeutically effective amount of the ligand compound of any one of claims 1-15, the chelate of any one of claims 16-18, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug, and one or more pharmaceutically acceptable carriers.

22. Use of the ligand compound of any one of claims 1-15, the chelate of any one of claims 16-18, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug of the present invention or the pharmaceutical composition of claim 21 in the preparation of a medicament for the diagnosis, prevention, or treatment of diseases or conditions associated with GPC3 activity.

23. The ligand compound of any one of claims 1-15, the chelate of any one of claims 16-18, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug of the present invention, or the pharmaceutical composition of claim 21, for the diagnosis, prevention, or treatment of diseases or conditions associated with GPC3 activity.

24. A method for diagnosing, preventing, or treating a disease or condition associated with GPC3 activity, the method comprising administering to a subject in need an effective amount of the ligand compound of any one of claims 1-15, the chelate of any one of claims 16-18, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug, or the pharmaceutical composition of claim 21.

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