Polypeptide compounds and uses thereof

Abstract

Polypeptide compounds and uses thereof are disclosed. A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is provided, wherein the polypeptide compound is a compound represented by formula (I): wherein A1, A2, A3, A4, A5, A6, and A7 are sequentially linked via peptide bonds (-CO-NH-). The polypeptide compounds of the present invention have relatively good inhibitory activity against FAP proteins. TIFF2026506387000283.tif50149

Description

[Technical Field]

[0001] The present disclosure relates to polypeptide compounds and uses thereof. [Background technology]

[0002] Tumor tissue contains a tumor microenvironment formed by tumor cells, stromal cells, immune cells, and other types of cells. Cancer-associated fibroblasts (CAFs) are one of the major cell types in the tumor microenvironment in solid tumors and typically exhibit stromal cell characteristics. CAFs can be derived from various types of cells, such as fibroblasts, mesenchymal stem cells, and smooth muscle cells (Kalluri, Nat Rev Cancer, 2016, 16:582; Gascard et al., Genes Dev, 2016, 30:1002). CAFs play an important role in tumor formation, progression, and metastasis and have attracted increasing attention in antitumor therapy.

[0003] Fibroblast activation protein alpha (FAP) is a type II transmembrane serine protease consisting of 760 amino acids that is highly expressed in tumor-associated fibroblasts. Furthermore, FAP is also highly expressed in various tumor cells, including oral squamous cell carcinoma, esophageal cancer, gastric cancer, mesothelioma, and fibrosarcoma (Busek et al., Front Biosci (Landmark Ed) 2018, 23:1933).

[0004] FAP is a marker protein of tumor-associated fibroblasts, present in tumor stromal cells and tumor-associated fibroblasts. In recent years, FAP has been considered a marker protein for tumor radiodiagnosis and an important target protein for tumor radiotherapy (Siveke, J Nucl Med 2018;59:1412). In 2018, Haberkorn's team reported a class of small molecule quinoline-based FAP inhibitors and developed them as FAP-targeting radiodiagnostic agents. However, these compounds only accumulate in tumor tissue for a short time and have only recently entered clinical studies as diagnostic agents (Thomas Lindner et al., J Nucl Med 2018;59(9):1415-1422). In 2022, Frank Osterkamp's team reported a cyclic peptide-based FAP inhibitor as a ligand for the development of FAP-targeting radiodiagnostic or therapeutic agents. In animal experiments, these inhibitors showed higher tumor tissue concentration, longer retention time, and better efficacy. However, clinical data from phase 1 clinical trials have shown that the radiation doses of these inhibitors that are safe for patients' tumor tissue are still relatively low, resulting in poor therapeutic efficacy (Dirk Zboralski et al., Eur J Nucl Med Mol Imaging. 2022;49(11):3651-3667; Richard P Baum et al., J Nucl Med. 2022 Mar;63(3):415-423).

[0005] Furthermore, FAP not only plays an important role in tumor formation and development, but also in rheumatoid arthritis, wound healing (Dienus et al., Arch Dermatol Res, 2010, 302:725), fibrotic diseases (including liver fibrosis, pulmonary fibrosis, etc.), and atherosclerosis. Therefore, radiopharmaceuticals for FAP can be developed for the treatment or diagnosis of rheumatoid arthritis, scar repair agents (Dienus et al., Arch Dermatol Res, 2010, 302:725), the treatment or diagnosis of various fibrotic diseases, and as a radiotracer for the imaging of atherosclerosis (Meletta et al., Molecules, 2015, 20:2081).

[0006] Although FAP-targeted radiopharmaceuticals for tumor diagnosis and treatment have entered clinical studies, the development of radiotherapeutic agents with better target selectivity, higher tissue specificity, and higher enrichment and longer retention time in tumor tissues remains of great clinical value. Summary of the Invention [Problem to be solved by the invention]

[0007] The technical problem that the present disclosure aims to solve is that existing compounds targeting FAP proteins have a single structure. To this end, the present invention provides polypeptide compounds and uses thereof. The compounds of the present disclosure have a novel structure and relatively good inhibitory activity against FAP proteins. [Means for solving the problem]

[0008] In a first aspect, the present disclosure provides a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is a compound represented by Formula I; wherein A1, A2, A3, A4, A5, A6, and A7 are linked sequentially via peptide bonds (—CO—NH—); [ka] A7 has a structure represented by formula a-7, [ka] "&" indicates that the carbon atom is a chiral carbon, i.e., [ka] teeth [ka] Show that; The "*" end indicates the bond to B; R 1 is -(CH2) m M; m is 1, 2, 3, 4, 5 or 6; M-COR 1-1 or -NR 1-2 R 1-3 and; R 1-1 -OH, -NR a R b , -OC 1~12 Alkyl, -OC 3~12 Cycloalkyl, -OC 6~10 Aryl, -O-5 to 10-membered heteroaryl, a group formed by the loss of an H atom from an amino group on an amino acid, a group formed by the loss of an H atom from an amino group on a peptide formed by two or more amino acids, one, two or three R e -OC substituted with 1~12 alkyl, 1, 2 or 3 R f -OC substituted with 3~12 cycloalkyl, 1, 2 or 3 R e-1 -OC substituted with 6~10 aryl, or one, two or three R f-1 -O-5 to 10 membered heteroaryl substituted with; R a and R b are independently H, C 1~12Alkyl, C 3~12 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R b-1 C replaced with 1~12 alkyl, 1, 2 or 3 R b-2 C replaced with 3~12 cycloalkyl, 1, 2 or 3 R b-3 C replaced with 6~10 aryl, or one, two or three R b-4 is a 5-10 membered heteroaryl substituted with; R b-1 , R b-2 , R b-3 and R b-4 are independently deuterium, -OH, -NH2, -COOH, -CONH2, -CN, halogen, C 1~12 Alkyl, C 3~12 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R b-1-1 C replaced with 6~10 aryl, 1, 2 or 3 R b-1-2 5-10 membered heteroaryl substituted with 1, 2 or 3 R b-1-3 C replaced with 3~12 cycloalkyl, or one, two, or three R b-1-4 C replaced with 1~12 is alkyl; R b-1-1 , R b-1-2 , R b-1-3 and R b-1-4 independently, C 1~12 C substituted with alkyl, halogen, or 1, 2, or 3 halogens 1~12 is alkyl; R e , R f , R e-1 and R f-1 are independently halogen, —OH, or —NH; R 1-2 and R 1-3 are independently H, C 1~12 Alkyl, C 3~12 Cycloalkyl, C 6~10Aryl, 5-10 membered heteroaryl, -COR g a group formed by the loss of an -OH group from a carboxyl group on an amino acid; a group formed by the loss of an -OH group from a carboxyl group on a peptide formed by two or more amino acids; one, two or three R h C replaced with 1~12 alkyl, 1, 2 or 3 R h-1 C replaced with 3~12 cycloalkyl, 1, 2 or 3 R h-2 C replaced with 6~10 aryl, or one, two or three R h-3 is a 5-10 membered heteroaryl substituted with; R g independently, C 1~12 Alkyl, C 3~12 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R g-1 C replaced with 1~12 alkyl, 1, 2 or 3 R g-2 C replaced with 3~12 cycloalkyl, 1, 2 or 3 R g-3 C replaced with 6~10 aryl, or one, two or three R g-4 is a 5-10 membered heteroaryl substituted with; R g-1 , R g-2 , R g-3 and R g-4 are independently deuterium, -OH, -NH2, -COOH, -CN, halogen, C 1~12 Alkyl, C 3~12 Cycloalkyl, C 6~10 aryl, or one, two or three R g-1-1 C replaced with 6~10 is aryl; R g-1-1 are independently -OH, -NH2, -COOH, -CN, halogen, C 1~12 Alkyl or C substituted with 1, 2 or 3 halogens 1~12 is alkyl; R h , R h-1, R h-2 and R h-3 are independently deuterium, —COOH, —CN, halogen, —OH, or —NH; B is [ka] and; B1, B2 and B3 are independently N or C; a is 1, 2 or 3; R 2 are independently H, C 1~12 alkyl, or halogen; "**" ends indicate bond to A7; "##" ends indicate bond to A1; A1 has a structure represented by formula a-1, [ka] "&" indicates that the carbon atom is a chiral carbon, i.e., [ka] teeth [ka] the "#" end indicates the bond to B; In the formula, R 3 -COC 1~12 Alkyl, -COOC 1~12 alkyl, 1, 2 or 3 R 3-1 -COC substituted with 1~12 alkyl, 1, 2 or 3 R 3-2 -COOC substituted with 1~12 alkyl, a group formed by the loss of an -OH group from a carboxyl group on an amino acid, or a group formed by the loss of an -OH group from a carboxyl group on a peptide formed by two or more amino acids; R 3-1 and R 3-2are independently deuterium, -NH2, -COOH, -CN, halogen, -OH, -NR 3-1-1 R 3-1-2 , or -OC 1~12 is alkyl; R 3-1-1 and R 3-1-2 are independently H or C 1~12 is alkyl; A2 has a structure represented by formula a-2 or a-2-2, and its nitrogen end is bonded to A1 and its carbonyl end is bonded to A3; [ka] R 4 and R 5 are independently H, C 1~12 alkyl, or one, two, or three R 4-1 C replaced with 1~12 is alkyl; R 4-1 are independently deuterium, —OH, halogen, —NH, or —COOH; R A2 are independently H, deuterium, —CH, —OH, —NH, or F; R A2 is 1, 2, 3 or 4; A3 has a structure represented by formula a-3, and its nitrogen end is bonded to A2 and its carbonyl end is bonded to A4; [ka] ;R A3 is 1, 2, 3 or 4; optionally, A3 is [ka] and; R A3 is H, deuterium, -CH3, -OH, -NH2 or F; A4 has a structure represented by formula a-4, and its nitrogen end is bonded to A3 and its carbonyl end is bonded to A5; [ka] Optionally, A4 [ka] and; A5 has a structure represented by formula a-5, and its nitrogen end is bonded to A4 and its carbonyl end is bonded to A6; [ka] Optionally, A5 [ka] and; In the formula, R 6 is -(CH2) x COR 6-1 where x is 1, 2 or 3; R 6-1 is -OH or -NH; A6 has a structure represented by formula a-6, and its nitrogen terminus is bonded to A5 and its carbonyl terminus is bonded to A7; [ka] Optionally, A6 is [ka] and; In the formula, R 7 is -CH2C 6~10 Aryl, -CH2- 5-10 membered heteroaryl, -CH2C 3~12 cycloalkyl, 1, 2 or 3 R 7-1 -CH2C substituted with 6~10 aryl, 1, 2 or 3 R 7-2 -CH2- 5-10 membered heteroaryl substituted with 1, 2 or 3 R 7-3-CH2C substituted with 3~12 is cycloalkyl; R 7-1 , R 7-2 and R 7-3 are independently deuterium, -OH, -NH2, halogen, -CN, C 1~12 Alkyl or C substituted with 1, 2 or 3 halogens 1~12 is alkyl; In the 5- to 10-membered heteroaryl, the heteroatoms in each 5- to 10-membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, or 3.

[0009] In one embodiment, in a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, some groups may be defined as follows, and other groups may be defined as described in any embodiment of the present disclosure (hereinafter referred to as "in one embodiment"): [ka] teeth [ka] is.

[0010] In one embodiment, m is 1 or 2.

[0011] In one embodiment, R 1-1 -OH, -NR a R b , -OC 1~12 Alkyl, -OC 3~12 Cycloalkyl, -OC 6~10 aryl, a group formed by the loss of an H atom from the amino group on an amino acid, or a group formed by the loss of an H atom from the amino group on a peptide formed by two or more amino acids. For example, R 1-1 -OH, -NR a R b , -OC1~12 Alkyl (e.g., -OC 1~7 Alkyl, -OC 1~6 Alkyl, -OC 1~5 alkyl), -OC 3~12 Cycloalkyl (e.g., -OC 3~5 Cycloalkyl, -OC 3~6 Cycloalkyl, -OC 3~7 cycloalkyl), a group formed by the loss of an H atom from an amino group on an amino acid, or a group formed by the loss of an H atom from an amino group on a peptide formed by two or more amino acids.

[0012] In one embodiment, R a and R b are independently H, C 1~12 Alkyl, (e.g., C 1~7 alkyl), C 3~12 Cycloalkyl (e.g., C 3~7 cycloalkyl), C 6~10 aryl, 5- to 10-membered heteroaryl, or 1, 2, or 3 R b-1 C replaced with 1~12 alkyl, 1, 2 or 3 R b-3 C replaced with 6~10 It is aryl.

[0013] In one embodiment, R b-1 and R b-3 are independently deuterium, -OH, -NH2, -COOH, -CONH2, -CN, halogen, C 3~12 Cycloalkyl (e.g., C 3~7 cycloalkyl), C 6~10 aryl, 5- to 10-membered heteroaryl, or 1, 2, or 3 R b-1-1 C replaced with 6~10 aryl; for example, R b-1 independently, C 3~12 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 1, 2, or 3 R b-1-1 C replaced with 6~10 It is aryl.

[0014] In one embodiment, R b-1-1 is independently a C substituted with 1, 2 or 3 halogens; 1~12 Alkyl (e.g., C 1~6 alkyl).

[0015] In one embodiment, R 1-2 and R 1-3 are independently H, C 1~12 Alkyl, (e.g., C 1~7 Alkyl, C 1~6 alkyl), -COR g , a group formed by the loss of an -OH group from a carboxyl group on an amino acid, or a group formed by the loss of an -OH group from a carboxyl group on a peptide formed by two or more amino acids.

[0016] In one embodiment, R g independently, C 1~12 Alkyl, (e.g., C 1~7 Alkyl, C 1~6 alkyl), C 3~12 Cycloalkyl (e.g., C 3~7 cycloalkyl), C 6~10 aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R g-1 C replaced with 1~12 alkyl, 1, 2, or 3 R g-3 C replaced with 6~10 aryl, or one, two, or three R g-4 5-10 membered heteroaryl substituted with; for example, R g independently, C 1~12 Alkyl, C 3~12 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R g-1 C replaced with 1~12 alkyl, or one, two, or three R g-3 C replaced with 6~10 It is aryl.

[0017] In one embodiment, R g-1 , R g-3 and R g-4are independently -OH, -NH2, halogen, C 1~12 Alkyl, (e.g., C 1~7 Alkyl, C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 alkyl), C 6~10 aryl, or one, two or three R g-1-1 C replaced with 6~10 aryl; for example, R g-1 and R g-3 are independently halogen, C 6~10 aryl, or one, two or three R g-1-1 C replaced with 6~10 It is aryl.

[0018] In one embodiment, R g-1-1 is independently a C substituted with 1, 2 or 3 halogens; 1~12 Alkyl (C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 alkyl).

[0019] In one embodiment, R 3 -COC 1~12 Alkyl (e.g., -CO(CH2) 1~4 CH3), 1, 2 or 3 R 3-1 -COC substituted with 1~12 alkyl, a group formed by the loss of an -OH group from a carboxyl group on an amino acid, or a group formed by the loss of an -OH group from a carboxyl group on a peptide formed by two or more amino acids.

[0020] In one embodiment, R 3-1 are independently -NH2 or -OC 1~12 Alkyl (e.g., -OC 1~5 alkyl).

[0021] In one embodiment, R 4 and R 5 independently, C 1~12 Alkyl (e.g., C 1~8 Alkyl, C 1~5 Alkyl, C1~3 In one embodiment, the nitrogen-containing heterocycle in the structure represented by formula a-2-2 is a 5-membered ring.

[0022] In one embodiment, x is 2 or 3.

[0023] In one embodiment, R 7 is -CH2C 6~10 Aryl, -CH2C 6~10 Heteroaryl, -CH2C 3~12 Cycloalkyl (e.g., -CHC 3~7 Cycloalkyl, -CH2C 3~6 cycloalkyl), one, two or three R 7-1 -CH2C substituted with 6~10 aryl, or one, two or three R 7-2 -CH2- is a 5-10 membered heteroaryl substituted with; for example, R 7 is -CH2C 6~10 Aryl, -CH2C 3~12 cycloalkyl, or one, two, or three R 7-1 -CH2C substituted with 6~10 It is aryl.

[0024] In one embodiment, R 7-1 and R 7-2 are independently deuterium, -OH, -NH2, halogen, C 1~3 Alkyl or C substituted with 1, 2 or 3 halogens 1~12 Alkyl (e.g., C 1~8 Alkyl, C 1~6 Alkyl, C 1~5 alkyl), for example, R 7-1 is independently a C substituted with 1, 2 or 3 halogens; 1~12 It is alkyl.

[0025] In one embodiment, [ka] teeth [ka] and; m is 1 or 2; R 1-1 -OH, -NR a R b , -OC 1~12 Alkyl (e.g., -OC 3~9 Alkyl, -OC 3~6 alkyl), -OC 3~12 Cycloalkyl (e.g., -OC 3~7 Cycloalkyl, -OC 3~6 cycloalkyl), a group formed by the loss of an H atom from an amino group on an amino acid, or a group formed by the loss of an H atom from an amino group on a peptide formed by two or more amino acids; R a and R b are independently H, C 1~12 Alkyl, (e.g., C 1~6 Alkyl, C 1~4 Alkyl, C 1~3 alkyl), C 3~12 Cycloalkyl (e.g., C 3~7 Cycloalkyl, C 3~6 Cycloalkyl, C 3~5 cycloalkyl), C 6~10 aryl, or one, two or three R b-1 C replaced with 1~12 is alkyl; R b-1 independently, C 3~12 Cycloalkyl (e.g., C 3~7 Cycloalkyl, C 3~6 Cycloalkyl, C 3~5 cycloalkyl), C 6~10 aryl, 5- to 10-membered heteroaryl, or 1, 2, or 3 R b-1-1 C replaced with 6~10 is aryl; R b-1-1 is independently a C substituted with 1, 2 or 3 halogens; 1~12 Alkyl (e.g., C 1~6 Alkyl, C 1~4 Alkyl, C 1~3alkyl); R 1-2 and R 1-3 are independently H, C 1~12 Alkyl (e.g., C 1~6 Alkyl, C 1~4 Alkyl, C 1~3 alkyl), -COR g a group formed by the loss of an -OH group from a carboxyl group on an amino acid, or a group formed by the loss of an -OH group from a carboxyl group on a peptide formed by two or more amino acids; R g independently, C 1~12 Alkyl (e.g., C 1~8 Alkyl, C 1~6 Alkyl, C 1~4 Alkyl, C 1~3 alkyl), C 3~12 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R g-1 C replaced with 1~12 alkyl, or one, two, or three R g-3 C replaced with 6~10 is aryl; R g-1 and R g-3 are independently halogen, C 6~10 aryl, or one, two or three R g-1-1 C replaced with 6~10 is aryl; R g-1-1 is independently a C substituted with 1, 2 or 3 halogens; 1~12 Alkyl (e.g., C 1~8 Alkyl, C 1~6 Alkyl, C 1~4 Alkyl, C 1~3 alkyl); R 3 -COC 1~12 alkyl, 1, 2 or 3 R 3-1 -COC substituted with 1~12 Alkyl (e.g., -COC 1~8 Alkyl, -COC 1~6 Alkyl, -COC 1~5alkyl), a group formed by the loss of an -OH group from a carboxyl group on an amino acid, or a group formed by the loss of an -OH group from a carboxyl group on a peptide formed by two or more amino acids; R 3-1 are independently -NH2 or -OC 1~12 Alkyl (e.g., -COC 1~5 Alkyl, -COC 1~4 alkyl); R 4 and R 5 independently, C 1~12 is alkyl; The nitrogen-containing heterocycle in formula a-2-2 is a 5-membered ring, and R A2 are independently H, deuterium, —CH, —OH, —NH, or F; R A2 is 1, 2, or 3; x is 1 or 2; R 7 is -CH2C 6~10 Aryl, -CH2C 3~12 Cycloalkyl (e.g., -CHC 3~10 Cycloalkyl, -CH2C 3~8 Cycloalkyl, -CH2C 3~7 Cycloalkyl, -CH2C 3~6 cycloalkyl), or one, two or three R 7-1 -CH2C substituted with 6~10 is aryl; R 7-1 is independently a C substituted with 1, 2 or 3 halogens; 1~12 Alkyl (e.g., C 1~8 Alkyl, C 1~7 Alkyl, C 1~6 Alkyl, C 1~5 alkyl).

[0026] In any embodiment of the present application, in each of the substituents A1 to A7 and B, C 1~12 Alkyl is C 1~12 Alkyl, C 1~11 Alkyl, C 1~10 Alkyl, C 1~9 Alkyl, C 1~8 Alkyl, C1~7 Alkyl, C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl or C 1~2 alkyl; C 3~12 Cycloalkyl is C 3~12 Cycloalkyl, C 3~11 Cycloalkyl, C 3~10 Cycloalkyl, C 3~9 Cycloalkyl, C 3~8 Cycloalkyl, C 3~7 Cycloalkyl, C 3~6 Cycloalkyl, C 3~5 Cycloalkyl, or C 3~4 cycloalkyl; C 6~10 Aryl is C 6~10 Aryl, C 6~9 Aryl, C 6~8 Aryl, or C 6~7 aryl; and the 5-10 membered heteroaryl is independently selected from a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, a 5-8 membered heteroaryl, a 5-7 membered heteroaryl, or a 5-6 membered heteroaryl.

[0027] In one embodiment, R 1-1 In -OC 1~12 C in alkyl 1~12 Alkyl is C 1~6 Alkyl is, for example, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; further for example, tert-butyl.

[0028] In one embodiment, R 1-1 In -OC 3~12 C in cycloalkyl 3~12 Cycloalkyl is C 3~6 Cycloalkyl, for example, cyclopentyl.

[0029] In one embodiment, R 1-1 In -OC 6~10C in aryl 6~10 Aryl is phenyl or naphthyl.

[0030] In one embodiment, R 1-1 In the formula, the group formed when the amino group on the amino acid loses an H atom is [ka] and; R c is -(CH2) o COOH or -(CH2) p CONH2; o and p are independently 0, 1, 2, 3, or 4; for example, o and p are independently 0 or 1; R d are hydrogen, deuterium, and C 1~12 Alkyl (e.g., C 1~6 Alkyl, C 1~4 Alkyl, C 1~3 alkyl), C 3~12 Cycloalkyl (e.g., C 3~7 Cycloalkyl, C 3~6 Cycloalkyl, C 3~5 cycloalkyl), C 6~10 Aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R d-1 C replaced with 1~12 alkyl, 1, 2 or 3 R d-2 C replaced with 3~12 cycloalkyl, 1, 2 or 3 R d-3 C replaced with 6~10 aryl, or one, two or three R d-4 5-10 membered heteroaryl substituted with; for example, R d is C 6~10 aryl, further for example naphthyl; R d-1 , R d-2 , R d-3 and R d-4 independently, C 1~12 Alkyl (e.g., C 1~6 Alkyl, C 1~4 Alkyl, C1~3 alkyl), C 3~12 Cycloalkyl (e.g., C 3~7 Cycloalkyl, C 3~6 Cycloalkyl, C 3~5 cycloalkyl), or C 6~10 It is aryl.

[0031] In one embodiment, R 1-1 In the above, the peptide formed by two or more amino acids is a peptide formed by 2 to 20 amino acids, for example, a peptide formed by 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 amino acids.

[0032] In one embodiment, R a and R b In C 1~12 alkyl, or one, two, or three R b-1 C replaced with 1~12 C in alkyl 1~12 Alkyl is independently C 1~6 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl or n-pentyl; further for example, methyl or n-pentyl.

[0033] In one embodiment, R a and R b In C 3~12 Cycloalkyl is independently C 3~6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or [ka] and further examples include cyclopentyl or [ka] is.

[0034] In one embodiment, R a and R b In C 6~10 Aryl is independently phenyl, biphenyl or naphthyl; for example, phenyl.

[0035] In one embodiment, R a and R b In the formula, the number of heteroatoms in the 5- to 10-membered heteroaryl is 1 or 2; for example, furyl, thienyl, imidazolyl, pyridyl, or quinolinyl.

[0036] In one embodiment, R b-1 In C 3~12 Cycloalkyl is independently C 3~6 Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; further for example, cyclopentyl.

[0037] In one embodiment, R b-1 In C 6~10 aryl, or one, two or three R b-1-1 C replaced with 6~10 C in aryl 6~10 Aryl is independently phenyl or naphthyl; for example, phenyl.

[0038] In one embodiment, R b-1 In the formula, the 5- to 10-membered heteroaryl is independently a 5- or 6-membered heteroaryl.

[0039] In one embodiment, R b-1 In the formula, the number of heteroatoms in the 5- to 10-membered heteroaryl is 1 or 2.

[0040] In one embodiment, R b-1-1 wherein C is substituted with halogen or 1, 2 or 3 halogens 1~12 The halogen in alkyl is independently F, Cl, Br or I, for example F.

[0041] In one embodiment, Rb-1-1 C substituted with 1, 2 or 3 halogens 1~12 C in alkyl 1~12 Alkyl is independently C 1~6 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or n-pentyl; further for example methyl.

[0042] In one embodiment, R 1-2 and R 1-3 In C 1~12 Alkyl is independently C 1~6 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; further for example, methyl, isopropyl, n-pentyl, or n-hexyl.

[0043] In one embodiment, R 1-2 and R 1-3 In C 3~12 cycloalkyl, or one, two, or three R h-1 C replaced with 3~12 C in cycloalkyl 3~12 Cycloalkyl is independently C 3~6 Cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0044] In one embodiment, R 1-2 and R 1-3 In C 6~10 aryl, or one, two or three R h-2 C replaced with 6~10 C in aryl 6~10 Aryl is independently phenyl or naphthyl.

[0045] In one embodiment, R 1-2 and R 1-3 wherein 5 to 10-membered heteroaryl or 1, 2 or 3 R h-3The number of heteroatoms in the 5- to 10-membered heteroaryl substituted with is 1 or 2.

[0046] In one embodiment, R 1-2 and R 1-3 In the above, the peptide formed by two or more amino acids is a peptide formed by 2 to 20 amino acids, for example, a peptide formed by 2 to 10 amino acids.

[0047] In one embodiment, R g In C 1~12 alkyl, or one, two, or three R g-1 C replaced with 1~12 C in alkyl 1~12 Alkyl is independently C 1~6 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; further for example, methyl, ethyl, or n-pentyl.

[0048] In one embodiment, R g In C 3~12 Cycloalkyl is independently C 3~6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or [ka] for example, cyclopentyl or cyclohexyl.

[0049] In one embodiment, R g In C 6~10 aryl, or one, two or three R g-3 C replaced with 6~10 C in aryl 6~10 Aryl is independently phenyl or naphthyl; for example, phenyl.

[0050] In one embodiment, R gwherein a 5- to 10-membered heteroaryl group or one, two, or three R g-4 The 5- to 10-membered heteroaryl in the 5- to 10-membered heteroaryl substituted by is a 5- to 6-membered heteroaryl.

[0051] In one embodiment, R g-1 , R g-3 and R g-4 In the formula, halogen is independently F, Cl, Br or I, for example Cl.

[0052] In one embodiment, R g-1 , R g-3 and R g-4 In C 6~10 aryl, or one, two or three R g-1-1 C replaced with 6~10 C in aryl 6~10 Aryl is independently phenyl or naphthyl; for example, phenyl.

[0053] In one embodiment, R g-1-1 C substituted with 1, 2 or 3 halogens 1~12 C in alkyl 1~12 Alkyl is independently C 1~6 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or n-pentyl; further for example methyl.

[0054] In one embodiment, R g-1-1 C substituted with 1, 2 or 3 halogens 1~12 The halogen in alkyl is independently F, Cl, Br or I, for example F.

[0055] In one embodiment, R 2 In C 1~12 Alkyl is independently C 1~6 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; further for example methyl.

[0056] In one embodiment, R 2 wherein halogen is independently F, Cl, Br or I; for example F.

[0057] In one embodiment, R 3 In -COC 1~12 alkyl, or one, two, or three R 3-1 -COC substituted with 1~12 C in alkyl 1~12 Alkyl is independently C 1~6 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; further for example, methyl, ethyl, or n-pentyl.

[0058] In one embodiment, R 3 In the above, the peptide formed by two or more amino acids is a peptide formed by 2 to 20 amino acids, for example, a peptide formed by 2 to 10 amino acids.

[0059] In one embodiment, R 3-1 In -OC 1~12 C in alkyl 1~12 Alkyl is independently C 1~6 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; further for example methyl.

[0060] In one embodiment, R 4 and R 5 In C 1~12 Alkyl is independently C 1~6 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; further for example methyl.

[0061] In one embodiment, R7 In the formula, -CH2C 3~12 C in cycloalkyl 3~12 Cycloalkyl is independently C 3~6 Cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; for example cyclohexyl.

[0062] In one embodiment, R 7 In the formula, -CH2C 6~10 aryl, or one, two or three R 7-1 C replaced with 6~10 C in aryl 6~10 Aryl is independently phenyl or naphthyl.

[0063] In one embodiment, R 7 In the formula, one, two or three R 7-2 The 5- to 10-membered heteroaryl in -CH2-5- to 10-membered heteroaryl substituted with is a 5- to 6-membered heteroaryl.

[0064] In one embodiment, R 7 In the formula, one, two or three R 7-2 The number of heteroatoms in the 5- to 10-membered heteroaryl in the -CH2-5- to 10-membered heteroaryl substituted with is 1 or 2.

[0065] In one embodiment, R 7-1 , wherein C is substituted with 1, 2 or 3 halogens 1~12 The halogen in alkyl is independently F, Cl, Br or I, for example F.

[0066] In one embodiment, R 7-1 C substituted with 1, 2 or 3 halogens 1~12 C in alkyl 1~12 Alkyl is independently C 1~6 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or n-pentyl; further for example methyl.

[0067] In one embodiment, B is [ka] is.

[0068] In one embodiment, R 1 -CH2COOH, -CH2CH2COOH, [ka] , -CH2CONH2, [ka] , -CH2NH2, -CH2NHCOCH3, -CH2CH2NH2, -CH2NH(CH2)4CH3, -CH2NH(CH2)5CH3, [ka] is.

[0069] In one embodiment, R 3 teeth, [ka] ;for example, [ka] is.

[0070] In one embodiment, B is [ka] ;for example, [ka] is.

[0071] In one embodiment, [ka] teeth [ka] and; [ka] teeth [ka] is.

[0072] In one embodiment, [ka] teeth [ka] , optionally [ka] ,for example, [ka] is.

[0073] In one embodiment, [ka] teeth [ka] , optionally [ka] ;for example, [ka] is.

[0074] In one embodiment, [ka] teeth [ka] , optionally [ka] ;for example, [ka] is.

[0075] In one embodiment, the polypeptide compound is the following compound: [ka] TIFF2026506387000052.tif168149 TIFF2026506387000053.tif173149 TIFF2026506387000054.tif163149 TIFF2026506387000055.tif207149 TIFF2026506387000056.tif166149 TIFF2026506387000057.tif204149 TIFF2026506387000058.tif221149 TIFF2026506387000059.tif214149 The value is selected from either:

[0076] In a second aspect, the present disclosure further provides a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is a compound represented by formula IB; wherein A1, A2, A3, A4, A5, A6, and A7 are linked sequentially via peptide bonds (—CO—NH—); [ka] R 1 is -(CH2) m’ M; m' is 0, 1, 2, 3, 4, 5 or 6; B' is [ka] and; a' is 1, 2 or 3; B1' is CH, B2' and B3' are independently N or C; R 2 ' is independently H, C 1~12 alkyl or halogen, and at least one R 2 ' is a halogen; or B1', B2' and B3' are independently N or CH; R 2 ' is independently C 1~12 alkyl or halogen; The other groups are defined as in the compounds of formula I.

[0077] In one embodiment, in B, C 1~12 Alkyl is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl or C 1~2 alkyl.

[0078] In one embodiment, B' is [ka] is.

[0079] In one embodiment, R 1 is -COOH.

[0080] In one embodiment, the compound of formula IB is the following compound: [ka] The value is selected from either:

[0081] In a third aspect, the present disclosure further provides a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is a compound represented by formula IC; wherein A1, A2, A3, A4, A5, A6, and A7 are linked sequentially via peptide bonds (—CO—NH—); [ka] R 1 is -(CH2) m’ M; m' is 0, 1, 2, 3, 4, 5 or 6; A6' is the formula a-6': [ka] having a structure represented by In the formula, R 7’ is -CH2C 3~12 Cycloalkyl, (e.g., -CHC 3~7 Cycloalkyl, -CH2C 3~6 cycloalkyl), one, two or three R 7-1 C replaced with 6~10 aryl, or one, two or three R7-2 -CH2C substituted with 3~12 is cycloalkyl; R 7-1 and R 7-2 independently, C 1~12 Alkyl (e.g., C 1~6 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, C 1~2 alkyl), or C substituted with 1, 2 or 3 halogens 1~12 is alkyl; The other groups are defined as in the compounds of formula I.

[0082] In one embodiment, R 7’ is -CH2C 3~12 cycloalkyl, or one, two, or three R 7-1 C replaced with 6~10 aryl, for example, -CH2 cyclohexyl, or [ka] is.

[0083] In one embodiment, R 1 is -COOH.

[0084] In one embodiment, the compound of formula IC is the following compound: [ka] is.

[0085] In a fourth aspect, the present disclosure further provides a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound has Formula II: DL; II is expressed as D is a compound of formula I as defined in any one of the preceding embodiments, or a compound of formula I as defined in any one of the preceding embodiments, wherein B, R 1 , or R 3 and a group formed by the loss of an H atom or an OH group at position B', R 1 , or R 3 or a group formed by the loss of an H atom or an OH group at position B, R 1 , or R 3 is a group formed by losing an H atom or an OH group at position L is a non-cleavable linker.

[0086] In one embodiment, L is: -A, -W, -WA, -AW, -WAW, or -AWA; A is a group formed by losing an -OH group from a carboxyl group on an amino acid, a group formed by losing an H atom from an amino group on an amino acid, a group formed by losing an -OH group from a carboxyl group on a peptide formed from more than two amino acids (e.g., 2 to 15, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 amino acids), or a group formed by losing an H atom from an amino group on a peptide formed from two or more amino acids, W is -(Y) g -(CH2) c -NHR t and; Y is independently selected from any one of the following groups, or combinations thereof: -(CH) b -X-, -(CH2) c -C 6~10 Arylene-(CH2) d -, -(CH2) c -5 to 12-membered heterocycloalkyl-(CH2) d -, -(CH2) c -C 3~12 Cycloalkylene-(CH2) d - and -(CH2) c -CO-(CH2) d-; the heteroatoms of the 5- to 12-membered heterocycloalkyl are selected from one or more of N, O, and S; the number of heteroatoms is 1, 2, or 3; X is S, O or NH; R t is H or C 1~12 Alkyl (e.g., C 1~3 Alkyl, C 1~5 Alkyl, C 1~6 alkyl) or R t together with -NH form a 5- to 10-membered nitrogen-containing heterocycloalkyl; g, b, c and d are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0087] In one embodiment, D is selected from any of the following segments: [ka] TIFF2026506387000069.tif187149 TIFF2026506387000070.tif176149 TIFF2026506387000071.tif179149 TIFF2026506387000072.tif110149 .

[0088] In one embodiment, L is selected from any of the following segments: [ka] .

[0089] In one embodiment, the polypeptide compound of formula II is selected from any of the following compounds: [ka] TIFF2026506387000075.tif194149 TIFF2026506387000076.tif203149 TIFF2026506387000077.tif186149 TIFF2026506387000078.tif179149 TIFF2026506387000079.tif50149 .

[0090] In a fifth aspect, the disclosure further provides a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound has the formula III: D-L'-R III is expressed as D is as defined in any one of the preceding embodiments; L' is a radical formed by the loss of an H atom from an amino group on L as defined in any one of the preceding embodiments; R is a group having the function of chelating a metal ion.

[0091] In one embodiment, R is a group formed by the loss of an H or hydroxyl from the chelator shown below, for example: [ka] TIFF2026506387000081.tif216149 Examples include:

[0092] In one embodiment, R is [ka] preferably, [ka] is.

[0093] In one embodiment, the polypeptide compound of formula III is selected from any of the following compounds: [ka] TIFF2026506387000085.tif198149 TIFF2026506387000086.tif164149 TIFF2026506387000087.tif196149 TIFF2026506387000088.tif200149 TIFF2026506387000089.tif165149 .

[0094] In a sixth aspect, the disclosure further provides a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound has the formula V: [D-L'-R]·M V is expressed as D is as defined in any one of the preceding embodiments; L' is as defined in any one of the preceding embodiments; R is as defined in any one of the preceding embodiments; M is a diagnostically active radionuclide or a therapeutically active radionuclide; a diagnostically active radionuclide is 18 F, 99m Tc, 89 Zr, 111 In, 67 Ga, 68 Ga, 43 Sc, 44 Sc, 64 Cu, 86 Y, 152 Tb, 155 Tb, 203 Pb, 123 I,124 I, 125 I, optionally, 64 Cu, 68 Ga, 111 In, 18 F, 99m Tc, 203 Pb, 89 Zr and the therapeutically active radionuclide is selected from 90 Y, 177 Lu, 225 Ac, 212 Pb, 188 Re, 227 Th, 131 I, 211 At, 161 Tb, 149 Tb, 153 Sm, 67 Cu, 47 Sc, optionally 90 Y, 177 Lu, 225 Ac, 212 Pb, and 161 Tb.

[0095] In one embodiment, the diagnostically active radionuclide is 68 Ga, and the therapeutically active radionuclide is 177 This is Lu.

[0096] In one embodiment, the polypeptide compound of formula V is selected from any of the following compounds: [ka] TIFF2026506387000091.tif183149 TIFF2026506387000092.tif155149 .

[0097] In a seventh aspect, the disclosure further provides a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound has the formula VI: [D-L'-R]·Q VI is expressed as D is as defined in any one of the fourth aspects; L' is as defined in any one of the fourth aspects; R is as defined in any one of the fourth aspects; Q is a non-radioactive nuclide; for example, the non-radioactive nuclide is selected from In, Ga, Y and Lu; for example, In.

[0098] In one embodiment, the polypeptide compound is the following compound: [ka] TIFF2026506387000094.tif144149 is.

[0099] In an eighth aspect, the present disclosure further provides a pharmaceutical composition comprising a substance X and a pharmaceutically acceptable adjuvant; wherein substance X is a polypeptide compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0100] In a ninth aspect, the present disclosure further provides a kit comprising a substance X and instructions for use; wherein substance X is a polypeptide compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0101] In a tenth aspect, the present disclosure further provides a use of substance X for the manufacture of a medicament; wherein substance X is a polypeptide compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; and the medicament is used in the diagnosis or treatment of a FAP protein-related disease, preferably a tumor.

[0102] In one embodiment, the tumor is selected from bronchogenic carcinoma, sweat gland carcinoma, breast cancer, ovarian cancer, prostate cancer, melanoma, oral squamous cell carcinoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, renal cancer, skin cancer, glioblastoma, neurilemmoma, meningioma, neuroblastoma, mesothelioma, sarcoma, liposarcoma, chondroioma, osteoma, osteosarcoma, semaginoblastoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureter tumor, bladder tumor, gallbladder cancer, bile duct carcinoma, choriocarcinoma, and pediatric tumors.

[0103] In an eleventh aspect, the present disclosure further provides a use of substance X for the manufacture of a FAP inhibitor; wherein substance X is a polypeptide compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0104] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.

[0105] "Solvate" refers to a substance formed by crystallizing a compound with a solvent (including, but not limited to, water, methanol, ethanol, etc.) Solvates are classified as stoichiometric solvates and non-stoichiometric solvates.

[0106] A "pharmaceutically acceptable salt solvate" refers to a substance formed by combining a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base and a solvent (including, but not limited to, water, methanol, ethanol, etc.), where the pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent is a stoichiometric or non-stoichiometric solvate. Pharmaceutically acceptable salt solvates include, but are not limited to, hydrochloride monohydrate.

[0107] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0108] "Alkyl" refers to a straight- or branched-chain alkyl, consisting solely of carbon and hydrogen atoms and having the specified number of carbon atoms (e.g., C1-C6), including straight- or branched-chain alkyl substituted with cycloalkyl. Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0109] "Cycloalkyl" refers to a saturated cyclic group having a specified number of carbon atoms (e.g., C3-C6) and a ring structure consisting solely of carbon atoms, including bridged cycloalkanes. Cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0110] The term "aryl" refers to any group consisting solely of carbon atoms and having a specified number of carbon atoms (e.g., C6-C 10 Aryl refers to a cyclic group having a ring structure, either monocyclic or fused, in which at least one ring is aromatic (according to Hückel's rule). The aryl is connected to the rest of the molecule by an aromatic or non-aromatic ring. Examples of aryl include, but are not limited to, phenyl or naphthyl groups.

[0111] "Heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3 heteroatoms), and a specified type of heteroatom (one or more of N, O, and S), which may be monocyclic or polycyclic, in which at least one ring is aromatic (according to Hückel's rule). The heteroaryl is attached to the rest of the molecule by an aromatic or non-aromatic ring.

[0112] "Heterocycloalkyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 5-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3 heteroatoms), and a specified type of heteroatom (one or more of N, O, and S).

[0113] The term "amino acid" refers to a compound having at least one amino group and at least one carboxyl group. Amino acids are broadly defined and can be natural or unnatural amino acids.

[0114] The term "pharmaceutically acceptable adjuvants" refers to excipients and additives used in the manufacture of medicines and the compounding of prescriptions, and refers to all substances contained in pharmaceutical preparations in addition to the active ingredient. For more information, please refer to the People's Republic of China Pharmacopoeia (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

[0115] The term "therapeutically effective amount" refers to the amount of compound and radiation administered to a patient that is sufficient to effectively treat the disease. The therapeutically effective amount varies depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc. However, one skilled in the art can adjust the therapeutically effective amount as needed.

[0116] The term "patient" refers to any animal that has received or will receive treatment, preferably a mammal, and most preferably a human, including, but not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0117] "Treatment" refers to any of the following situations: (1) alleviating one or more biological symptoms of a disease; (2) interfering with one or more points in the biological cascade that causes a disease; and (3) slowing the progression of one or more biological symptoms of a disease.

[0118] The above preferred conditions can be arbitrarily combined without departing from the general knowledge in the art to obtain preferred embodiments of the present disclosure.

[0119] The reagents and materials used in this disclosure are commercially available. [Effects of the Invention]

[0120] A favorable and progressive effect of the present disclosure is that the polypeptide compounds of the present disclosure have relatively good inhibitory activity against FAP proteins. [Brief explanation of the drawings]

[0121] [Figure 1] 1 is a bar graph showing the time course of tumor volume after injection administration in tumor-bearing mice. DETAILED DESCRIPTION OF THE INVENTION

[0122] The present disclosure will be further illustrated by the following examples, which are not intended to limit the scope of the present invention to the described examples. In the following examples, experimental methods without specific conditions were performed according to conventional methods and conditions or selected according to the product instructions.

[0123] Example 1 [ka] Step 1: 0.287 g of Fmoc-linker MBHA resin with a substitution degree of 0.35 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained. Deprotection was performed with 10 mL of 20% piperidine (Pip) in DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were charged in an equivalent ratio, and 10 mL of DMF was added. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The resulting mixture was drained and washed sequentially with DMF, dichloromethane (DCM), and methanol (MeOH) to obtain 0.3 g of crude resin. The crude resin was cleaved with 6 mL of solution E (trifluoroacetic acid (TFA):1,2-ethanedithiol (EDT):HO:phenol:triisopropylsilane (TIS) = 90:2.5:2.5:2.5:2.5), suction filtered, centrifuged, washed with methyl tert-butyl ether, and purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in acetonitrile (ACN), linear gradient: 26-56% over 60 min, wavelength: 220 nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe-beta-homoCys-Asp-NH2. Step 2: 26 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 20 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 6.7 mg (1.0 equivalent) of DBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 1 mL of acetic acid was added. The mixture was concentrated and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 33-63% over 60 min, wavelength: 220 nm) to obtain the final product Hex-Cys-Pro-Pro-Thr-Gln-Phe-beta-homoCys-Asp-NH2 (Cys-bridged DBMB) trifluoroacetate. HPLC purity was 98.2%, MS (m / z): 1123.8 [M+H] + .

[0124] Example 2 [ka] Step 1: 0.185 g of Fmoc-beta-homoCys(Trt)-CTC resin with a substitution degree of 0.54 mmol / g was weighed and placed in a reactor. It was immersed in N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 20% piperidine (Pip) in DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added. The resulting mixture was drained and washed with DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was transferred to a cutting tube and cleaved with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) at 25°C, treated with methyl tert-butyl ether, and the crude product was dried and purified by HPLC (preparative chromatography, column: Huapu C18 10μm 100A 20*250mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 37-67% over 60 min, wavelength: 220nm) to obtain the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe-beta-homoCys-OH. Step 2: 10 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 10 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 2.9 mg (1.0 equivalent) of DBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 1 mL of acetic acid was added. The mixture was concentrated and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 37-67% over 60 min, wavelength: 220 nm) to obtain the final product, Hex-Cys-Pro-Pro-Thr-Gln-Phe-beta-homoCys-OH (Cys-bridged DBMB) trifluoroacetate. HPLC purity was 99.3%, MS (m / z): 1009.7 [M+H] + .

[0125] Example 3 [ka] Step 1: 0.13 g of Fmoc-Cys(Trt)-CTC resin with a substitution degree of 0.767 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) / DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added to react. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed successively with DMF, DCM, and MeOH, treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, and the crude product was washed again with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10μm 100A 20*250mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 32-62% over 60 min, wavelength: 220nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Cha-Cys-OH. Step 2: 57 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 60 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 19 mg (1.0 equivalent) of DBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 1 mL of acetic acid was added. The mixture was concentrated and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 40-70% over 60 min, wavelength: 220 nm) to obtain the final product, Hex-Cys-Pro-Pro-Thr-Gln-Cha-Cys-OH (Cys-bridged DBMB) trifluoroacetate. HPLC purity was 99.1%, MS (m / z): 1001.7 [M+H] + .

[0126] Example 4 [ka] Step 1: 0.64 g of Fmoc-Phe-CTC resin with a substitution degree of 0.94 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) in DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed sequentially with DMF, DCM, and MeOH, and then treated with 10 mL of 1% TFA / DCM. The organic phase was washed with water and saturated brine, respectively, and concentrated in vacuo to give the fully protected intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-OH. 239 mg of the above intermediate and 32 mg of HOOBt (1.1 equivalents) were dissolved in 10 mL of DMF and cooled to 0 °C. 38 mg of EDC hydrochloride (1.1 equivalents) and 101 mg of H-Cys(Trt)-CHNHBoc (1.0 equivalents) were added sequentially, and the mixture was reacted at room temperature for 4 hours. The DMF was concentrated, and 10 mL of 5% aqueous phosphoric acid and 20 mL of ethyl acetate were added. The organic phase was washed with water and saturated brine, and then concentrated in vacuo to give the intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys(Trt)-CHNH. The intermediate was treated with mL of solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, and the crude product was dried and purified by HPLC (preparative chromatography, column: Huapu C18 10μm 100A 20*250mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 25-55% over 60 min, wavelength: 220nm) to obtain the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CH2NH2. Step 2: 38 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 40 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 15 mg (1.0 equivalent) of DBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 1 mL of acetic acid was added. The mixture was concentrated and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 32-62% over 60 min, wavelength: 220 nm) to obtain the final product, Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CH2NH2 (Cys-bridged DBMB) trifluoroacetate. HPLC purity was 95.2%, MS (m / z): 980.9 [M+H] + .

[0127] Example 5 [ka] Step 1: 0.64 g of Fmoc-Phe-CTC resin with a substitution degree of 0.94 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) in DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed sequentially with DMF, DCM, and MeOH, and then treated with 10 mL of 1% TFA / DCM. The organic phase was washed with water and saturated brine, respectively, and concentrated in vacuo to give the fully protected intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-OH. 277 mg of the intermediate from the previous step and 37 mg of HOOBt (1.1 equivalents) were dissolved in 10 mL of DMF and cooled to 0 °C. Then, 44 mg of EDC hydrochloride (1.1 equivalents) and H-Cys(Trt)-CHNHAc (1.0 equivalents) were added sequentially, and the mixture was allowed to react at room temperature. After completion of the reaction, the DMF was concentrated, and 10 mL of 5% aqueous phosphoric acid solution and 20 mL of ethyl acetate were added, stirred, and separated. The organic phase was washed sequentially with HO and saturated brine, and concentrated in vacuo to give the intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys(Trt)-CHNHAc. The intermediate was treated successively with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether. The crude product was dried under vacuum and purified by HPLC (preparative chromatography, column: Huapu C18 10μm 100A 20*250mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 30-60% over 60 min, wavelength: 220nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CHNHAc. Step 2: 50 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 50 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 20 mg (1.0 equivalent) of DBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 1 mL of acetic acid was added. The mixture was concentrated and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 35-65% over 60 min, wavelength: 220 nm) to obtain the final product, Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CHNHAc (Cys-bridged DBMB) trifluoroacetate. HPLC purity was 96.9%, MS (m / z): 1022.9 [M+H] + .

[0128] Example 6 [ka] Step 1: 0.31 g of Fmoc-Cys(Trt)-CTC resin with a substitution degree of 0.656 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) / DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed successively with DMF, DCM, and MeOH, treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, and the product was washed again with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10μm 100A 20*250mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 28-58% over 60 min, wavelength: 220nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-OH. Step 2: 56 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 60 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 16 mg (1.0 equivalent) of 2,6-bis(bromomethyl)fluorobenzene in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 1 mL of acetic acid was added. The mixture was concentrated and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 35-65% over 60 min, wavelength: 220 nm) to obtain the final product, Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-OH (Cys-bridged 2,6-bis(bromomethyl)fluorobenzene) trifluoroacetate. HPLC purity was 99.6%, MS (m / z): 1013.9 [M+H] + .

[0129] Example 7 [ka] Step 1: 0.31 g of Fmoc-Cys(Trt)-CTC resin with a substitution degree of 0.656 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) / DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed successively with DMF, DCM, and MeOH, treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, and the product was washed again with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10μm 100A 20*250mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 28-58% over 60 min, wavelength: 220nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-OH. Step 2: 112 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 100 mL of 50 mM aqueous ammonium bicarbonate solution and acetonitrile (volume ratio 1:1). A solution of 68 mg (1.5 equivalents) of 2,4,6-tribromomethyl-1,3,5-triazine in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 97 mg of cysteamine (10 equivalents) was added and stirred for another 2 hours. 1 mL of acetic acid was then added. The mixture was concentrated and lyophilized, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 24-54% over 60 minutes, wavelength: 220 nm) to obtain intermediate 2. Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-OH (Cys-bridged 2,4,6-tribromomethyl-1,3,5-triazine (H-AET)) was obtained. 45 mg of intermediate 2 (1.0 equiv.) and 31 mg of DOTA-NHS (1.5 equiv.) were dissolved in 5 mL of DMF, and then 0.045 mL of DIPEA (6 equiv.) was added. The mixture was reacted at room temperature for 2 hours, concentrated, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 24-54% over 60 min, wavelength: 220 nm) to obtain the final product Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-OH (Cys-bridged 2,4,6-tribromomethyl-1,3,5-triazine (DOTA-AET)) trifluoroacetate. HPLC purity was 98.5%, MS (m / z): 1473.7 [M+H] + .

[0130] Example 8 [ka] Step 1: 0.38 g of Fmoc-beta-homoCys(Trt)-CTC resin with a substitution degree of 0.52 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) / DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added to react. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed successively with DMF, DCM, and MeOH, treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, and the product was washed again with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10μm 100A 20*250mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 37-67% over 60 min, wavelength: 220nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe-beta-homoCys-OH. Step 2: 75 mg (1.0 equiv.) of the intermediate was dissolved in 100 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 44 mg (1.5 equiv.) of TBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, followed by the addition of 64 mg of cysteamine (10 equiv.) and stirring for another 2 hours. 1 mL of acetic acid was added, and the mixture was concentrated and lyophilized. The mixture was then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 27-57% over 60 min, wavelength: 220 nm) to obtain intermediate 2 Hex-Cys-Pro-Pro-Thr-Gln-Phe-beta-homoCys (Cys-bridged TBMB (H-AET)). 57 mg of intermediate 2 (1.0 equivalent) and 39 mg of DOTA-NHS (1.5 equivalents) were dissolved in 5 mL of DMF, and then 0.054 mL of DIPEA (6 equivalents) was added. The mixture was reacted at room temperature for 2 hours, concentrated, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 26-56% over 60 min, wavelength: 220 nm) to obtain the final product Hex-Cys-Pro-Pro-Thr-Gln-Phe-beta-homoCys (Cys-bridged TBMB (DOTA-AET)) trifluoroacetate. HPLC purity was 99.1%, MS (m / z): 743.3 [M+2H] 2+ .

[0131] Example 9 [ka] Step 1: 0.323 g of Fmoc-Cys(Trt)-CTC resin with a substitution degree of 0.619 mmol / g was weighed and placed in a reactor. The resin was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) / DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added to react. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed successively with DMF, DCM, and MeOH, treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, and the product was washed again with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10μm 100A 20*250mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 32-62% in 60 min, wavelength: 220nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Cha-Cys-OH. Step 2: 77 mg (1.0 equiv.) of the final product obtained in Step 1 was dissolved in 100 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 46 mg (1.5 equiv.) of TBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 66 mg of cysteamine (10 equiv.) was added and stirred for another 2 hours. 1 mL of acetic acid was added. The mixture was concentrated and lyophilized. The mixture was then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 30-60% over 60 min, wavelength: 220 nm) to obtain intermediate 2, Hex-Cys-Pro-Pro-Thr-Gln-Cha-Cys (Cys-bridged TBMB (H-AET)). 40 mg of intermediate 2 (1.0 equiv.) and 28 mg of DOTA-NHS (1.5 equiv.) were dissolved in 5 mL of DMF, and then 0.038 mL of DIPEA (6 equiv.) was added. The mixture was reacted at room temperature for 2 hours, concentrated, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 29-59% over 60 min, wavelength: 220 nm) to obtain the final product, Hex-Cys-Pro-Pro-Thr-Gln-Cha-Cys (Cys-bridged TBMB (DOTA-AET)) trifluoroacetate. HPLC purity was 98.4%, MS (m / z): 1477.2 [M+H] + .

[0132] Example 10 [ka] Step 1: 0.64 g of Fmoc-Phe-CTC resin with a substitution degree of 0.94 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) in DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed sequentially with DMF, DCM, and MeOH, and then treated with 10 mL of 1% TFA / DCM. The organic phase was washed with water and saturated brine, respectively, and concentrated in vacuo to give the fully protected intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-OH. 277 mg of the above intermediate and 37 mg of HOOBt (1.1 equivalents) were dissolved in 10 mL of DMF and cooled to 0 °C. Then, 44 mg of EDC hydrochloride (1.1 equivalents) and H-Cys(Trt)-CHNHAc (1.0 equivalents) were added sequentially, and the mixture was allowed to react at room temperature. After completion of the reaction, the DMF was removed by concentration in vacuo, and 10 mL of 5% aqueous phosphoric acid solution and 20 mL of ethyl acetate were added. The organic phase was washed sequentially with HO and saturated brine, respectively, concentrated in vacuo, and drained to give the intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys(Trt)-CHNHAc. 354 mg of the intermediate was treated with mL of solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, respectively. The crude product was washed with 40 mL of methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 30-60% over 60 min, wavelength: 220 nm) to obtain the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CHNHAc. Step 2: 102 mg (1.0 equiv.) of the intermediate was dissolved in 100 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 59 mg (1.5 equiv.) of TBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 86 mg of cysteamine (10 equiv.) was added and stirred for another 2 hours. 1 mL of acetic acid was added. The mixture was concentrated and lyophilized. The mixture was then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 27-57% over 60 min, wavelength: 220 nm) to obtain intermediate 2, Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CHNHAc (Cys-bridged TBMB (H-AET)). 62 mg of intermediate 2 (1.0 equivalent) and 42 mg of DOTA-NHS (1.5 equivalents) were dissolved in 5 mL of DMF, and then 0.058 mL of DIPEA (6 equivalents) was added. The mixture was reacted at room temperature for 2 hours, concentrated, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 26-56% over 60 min, wavelength: 220 nm) to obtain the final product Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CHNHAc (Cys-bridged TBMB (DOTA-AET)) trifluoroacetate. HPLC purity was 99.5%, MS (m / z): 1498.1 [M+H] + .

[0133] Example 11 [ka] Step 1: 0.38 g of Fmoc-beta-homoCys(Trt)-CTC resin with a substitution degree of 0.52 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) / DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added to react. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed successively with DMF, DCM, and MeOH, treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, and the product was washed again with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10μm 100A 20*250mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 33-63% over 60 min, wavelength: 220nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-1Nal-beta-homoCys-OH. Step 2: 72 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 100 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 40 mg (1.5 equivalents) of TBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 58 mg of cysteamine (10 equivalents) was added and stirred for another 2 hours. 1 mL of acetic acid was added, and the mixture was concentrated and lyophilized. The mixture was then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 31-61% over 60 min, wavelength: 220 nm) to obtain intermediate 2, Hex-Cys-Pro-Pro-Thr-Gln-1Nal-beta-homoCys (Cys-bridged TBMB (H-AET)). 39 mg of intermediate 2 (1.0 equivalent) and 26 mg of DOTA-NHS (1.5 equivalents) were dissolved in 5 mL of DMF, and then 0.035 mL of DIPEA (6 equivalents) was added. The mixture was reacted at room temperature for 2 hours, concentrated, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 29-59% over 60 min, wavelength: 220 nm) to obtain the final product Hex-Cys-Pro-Pro-Thr-Gln-1Nal-beta-homoCys (Cys-bridged TBMB (DOTA-AET)) trifluoroacetate. HPLC purity was 99.0%, MS (m / z): 1534.6 [M+H] + .

[0134] Example 12 [ka] Step 1: 0.38 g of Fmoc-beta-homoCys(Trt)-CTC resin with a substitution degree of 0.52 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) / DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added to react. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed successively with DMF, DCM, and MeOH, treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, and the product was washed again with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 32-62% over 60 min, wavelength: 220 nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe(2-CF3)-beta-homoCys-OH. Step 2: 116 mg (1.0 equivalent) of the product obtained in Step 1 was dissolved in 100 mL of 50 mM aqueous ammonium bicarbonate solution and acetonitrile (volume ratio 1:1). A solution of 64 mg (1.5 equivalents) of TBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 92 mg of cysteamine (10 equivalents) was added and stirred for another 2 hours. 1 mL of acetic acid was added. The mixture was concentrated and lyophilized, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 30-70% over 60 minutes, wavelength: 220 nm) to obtain intermediate 2. Hex-Cys-Pro-Pro-Thr-Gln-Phe(2-CF3)-beta-homoCys (Cys-bridged TBMB(H-AET)) was obtained. 63 mg of intermediate 2 (1.0 equivalent) and 41 mg of DOTA-NHS (1.5 equivalents) were dissolved in 5 mL of DMF, and then 0.056 mL of DIPEA (6 equivalents) was added. The mixture was reacted at room temperature for 2 hours, concentrated, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 31-61% over 60 min, wavelength: 220 nm) to obtain the final product Hex-Cys-Pro-Pro-Thr-Gln-Phe(2-CF3)-beta-homoCys(Cys-bridged TBMB(DOTA-AET)) trifluoroacetate. HPLC purity was 99.2%, MS (m / z): 1553.1 [M+H] + .

[0135] Example 13 [ka] Step 1: 0.43 g of Fmoc-2Nal-Wang resin with a substitution degree of 0.464 mmol / g was weighed and placed in a reactor. The resin was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) / DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added to react. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed successively with DMF, DCM, and MeOH, treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, and the product was washed again with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10μm 100A 20*250mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 38-68% over 60 min, wavelength: 220nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe-beta-homoCys-2Nal-OH. Step 2: 83 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 100 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 40 mg (1.5 equivalents) of TBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 58 mg of cysteamine (10 equivalents) was added and stirred for another 2 hours. 1 mL of acetic acid was added, and the mixture was concentrated and lyophilized. The mixture was then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 35-65% over 60 min, wavelength: 220 nm) to obtain intermediate 2, Hex-Cys-Pro-Pro-Thr-Gln-Phe-beta-homoCys-2Nal (Cys-bridged TBMB (H-AET)). 41 mg of intermediate 2 (1.0 equivalent) and 24 mg of DOTA-NHS (1.5 equivalents) were dissolved in 5 mL of DMF, and then 0.0533 mL of DIPEA (6 equivalents) was added. The mixture was reacted at room temperature for 2 hours, concentrated, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 33-63% over 60 min, wavelength: 220 nm) to obtain the final product Hex-Cys-Pro-Pro-Thr-Gln-Phe-beta-homoCys-2Nal (Cys-bridged TBMB (DOTA-AET)) trifluoroacetate. HPLC purity was 97.5%, MS (m / z): 1682 [M+H] + .

[0136] Example 14 [ka] Step 1: 0.64 g of Fmoc-Phe-CTC resin with a substitution degree of 0.94 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) in DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed sequentially with DMF, DCM, and MeOH, and then treated with 10 mL of 1% TFA / DCM. The organic phase was washed with water and saturated brine, respectively, and concentrated in vacuo to give the fully protected intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-OH. 267 mg of the intermediate and 65 mg of HOOBt (2.0 equivalents) were dissolved in 10 mL of DMF and cooled to 0 °C. 77 mg of EDC hydrochloride (2.0 equivalents) and 112 mg of H-Cys(Trt)-CHNH-cyclopentanecarboxylic acid (1.0 equivalents) were added sequentially, and the mixture was allowed to react at room temperature. After completion of the reaction, the DMF was removed by concentration in vacuo, and 10 mL of 5% aqueous phosphoric acid solution and 20 mL of ethyl acetate were added. The organic phase was washed successively with water and saturated brine and concentrated in vacuo to give the intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys(Trt)-CHNH-cyclopentacarboxylic acid.352 mg of the intermediate was treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, and the resulting solid was washed with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 34-64% over 60 min, wavelength: 220 nm) to obtain the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CHNH-cyclopentacarboxylic acid. Step 2: 76 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 100 mL of 50 mM aqueous ammonium bicarbonate solution and acetonitrile (volume ratio 1:1). A solution of 42 mg (1.5 equivalents) of TBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 60 mg of cysteamine (10 equivalents) was added and stirred for another 2 hours. 1 mL of acetic acid was added. The mixture was concentrated and lyophilized, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 32-62% over 60 minutes, wavelength: 220 nm) to give intermediate 2. Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CHNH-cyclopentacarboxylic acid (Cys-bridged TBMB(H-AET)) was obtained. 60 mg of intermediate 2 (1.0 equiv.) and 39 mg of DOTA-NHS (1.5 equiv.) were dissolved in 5 mL of DMF, and then 0.054 mL of DIPEA (6 equiv.) was added. The mixture was reacted at room temperature for 2 hours, concentrated, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 30-60% over 60 min, wavelength: 220 nm) to obtain the final product, Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CHNH-cyclopentacarboxylic acid (Cys-bridged TBMB (DOTA-AET)) trifluoroacetate. HPLC purity was 98.1%, MS (m / z): 1552.1 [M+H] + .

[0137] Example 15 [ka] Step 1: 0.64 g of Fmoc-Phe-CTC resin with a substitution degree of 0.94 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) in DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed sequentially with DMF, DCM, and MeOH, and then treated with 10 mL of 1% TFA / DCM. The organic phase was washed with water and saturated brine, respectively, and concentrated in vacuo to give the fully protected intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-OH. 55 mg of the intermediate and 14 mg of HOOBt (2.0 equivalents) were dissolved in 10 mL of DMF and cooled to 0 °C. Then, 16 mg of EDC hydrochloride (2.0 equivalents) and 46 mg of H-Cys(Trt)-CHNH-(trans-4-aminocyclohexaneacetic acid-beta-Ala-DOTA(OtBu)) (1.0 equivalents) were added sequentially, and the mixture was allowed to react at room temperature. After completion of the reaction, the DMF was removed by concentration in vacuo, and 10 mL of 5% aqueous phosphoric acid solution and 20 mL of ethyl acetate were added. The mixture was stirred and separated. The organic phase was washed successively with water and saturated brine and concentrated in vacuo to give the intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys(Trt)-CHNH-(trans-4-aminocyclohexaneacetic acid-betaAla-DOTA(OtBu)).The intermediate was washed successively with DMF, DCM, and MeOH, treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, and the product was washed again with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10μm 100A 20*250mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 26~56% over 60 min, wavelength: 220nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CHNH-(trans-4-aminocyclohexaneacetic acid-DOTA). Step 2: 16 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 10 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 4.6 mg (1.0 equivalent) of 2,6-bis(bromomethyl)fluorobenzene in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, after which 1 mL of acetic acid was added. The mixture was concentrated and then separated by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A). Purification using a 20*250 mm column (mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 32-62% over 60 min, wavelength: 220 nm) gave the final product Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CHNH-(trans-4-aminocyclohexaneacetic acid-beta Ala-DOTA) (Cys-bridged 2,6-bis(bromomethyl)fluorobenzene) trifluoroacetate. HPLC purity was 96.6%, MS (m / z): 1595.1 [M+H] + .

[0138] Example 16 [ka] Step 1: 0.64 g of Fmoc-Phe-CTC resin with a substitution degree of 0.94 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) in DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed sequentially with DMF, DCM, and MeOH, and then treated with 10 mL of 1% TFA / DCM. The organic phase was washed with water and saturated brine, respectively, and concentrated in vacuo to give the fully protected intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-OH. 77 mg of the intermediate and 19 mg of HOOBt (2.0 equiv.) were dissolved in 10 mL of DMF and cooled to 0 °C. Then, 22 mg of EDC hydrochloride (2.0 equiv.) and 65 mg of H-Cys-CHNH-(D-beta-homoAla-tranexamic acid-DOTA(OtBu)) (1.0 equiv.) were added sequentially, and the mixture was allowed to react at room temperature. After completion of the reaction, the DMF was removed by concentration in vacuo, and 10 mL of 5% aqueous phosphoric acid and 20 mL of ethyl acetate were added. The mixture was stirred and separated. The organic phase was washed successively with water and saturated brine and concentrated in vacuo to give the intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys(Trt)-CHNH-(D-beta-homoAla-tranexamic acid-DOTA(OtBu)).140 mg of the intermediate was washed successively with DMF, DCM, and MeOH, treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, and the product was washed again with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 26-56% over 60 min, wavelength: 220 nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CHNH-(D-beta-homo Ala-tranexamic acid-1-carboxylic acid-DOTA). Step 2: 22 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 10 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 6.2 mg (1.0 equivalent) of 2,6-bis(bromomethyl)fluorobenzene in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, after which 1 mL of acetic acid was added. The mixture was concentrated and then separated by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A). Purification using a 20*250 mm column (mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 30-60% over 60 min, wavelength: 220 nm) gave the final product Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-CHNH-(D-beta-homoAla-tranexamic acid-DOTA) (Cys-bridged 2,6-bis(bromomethyl)fluorobenzene) trifluoroacetate. HPLC purity was 99.4%, MS (m / z): 1608.6 [M+H] + .

[0139] Example 17 [ka] Step 1: 0.35 g of Fmoc-beta-homoCys(Trt)-CTC resin with a substitution degree of 0.59 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained and deprotected with 10 mL of 20% piperidine (Pip) in DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed sequentially with DMF, DCM, and MeOH, and then treated with 10 mL of 1% TFA / DCM. The organic phase was washed with water and saturated brine, respectively, and concentrated in vacuo to give the fully protected intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-1Nal-beta-homoCys(Trt)-OH. 281 mg of the intermediate and 58 mg of HOOBt (2.2 equivalents) were dissolved in 10 mL of DMF and cooled to 0 °C. 68 mg of EDC hydrochloride (2.2 equivalents) and 61 mg of 2-(4-trifluoromethylphenyl)ethylamine (2.0 equivalents) were added sequentially, and the mixture was allowed to react at room temperature. After completion of the reaction, the DMF was removed by concentration in vacuo, and 10 mL of 5% aqueous phosphoric acid solution and 20 mL of ethyl acetate were added. The mixture was stirred and separated. The organic phase was washed successively with water and saturated brine and concentrated in vacuo to give the intermediate Hex-Cys-Pro-Pro-Thr(tBu)-Gln(Trt)-1Nal-beta-homoCys-2-(4-trifluoromethylphenyl)ethylamine.309 mg of the intermediate was washed successively with DMF, DCM, and MeOH, treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, the product was washed again with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 45-75% over 60 min, wavelength: 220 nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-1Nal-beta-homoCys-2-(4-trifluoromethylphenyl)ethylamine. Step 2: 91 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 100 mL of 50 mM aqueous ammonium bicarbonate solution and acetonitrile (volume ratio 1:1). A solution of 43 mg (1.5 equivalents) of TBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 62 mg of cysteamine (10 equivalents) was added and stirred for another 2 hours. 1 mL of acetic acid was added. The mixture was concentrated and lyophilized, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 40-70% over 60 minutes, wavelength: 220 nm) to obtain intermediate 2. Hex-Cys-Pro-Pro-Thr-Gln-1Nal-beta-homoCys-2-(4-trifluoromethylphenyl)ethylamine (Cys-bridged TBMB (H-AET)) was obtained. 60 mg of intermediate 2 (1.0 equivalent) and 34 mg of DOTA-NHS (1.5 equivalents) were dissolved in 5 mL of DMF, and then 0.048 mL of DIPEA (6 equivalents) was added. The mixture was reacted at room temperature for 2 hours, concentrated, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 38-68% over 60 min, wavelength: 220 nm) to obtain the final product Hex-Cys-Pro-Pro-Thr-Gln-1Nal-beta-homoCys-2-(4-trifluoromethylphenyl)ethylamine (Cys-bridged TBMB (DOTA-AET)) trifluoroacetate). HPLC purity was 96.7%, MS (m / z): 853.5 [M+2H] 2+ .

[0140] Example 18 [ka] Step 1: 0.5 g of Fmoc-linker MBHA resin with a substitution degree of 0.405 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained. Deprotection was performed with 10 mL of 20% piperidine (Pip) in DMF. The starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added in an equivalent ratio, and 10 mL of DMF was added to react. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed successively with DMF, DCM, and MeOH, treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, and the product was washed again with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 40-70% over 60 min, wavelength: 220 nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-Phe(2-CF3)-beta-homoCys-2Nal-NH2. Step 2: 103 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 100 mL of 50 mM aqueous ammonium bicarbonate and acetonitrile (volume ratio 1:1). A solution of 47 mg (1.5 equivalents) of TBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 68 mg of cysteamine (10 equivalents) was added and stirred for another 2 hours. 1 mL of acetic acid was added. The mixture was concentrated and lyophilized, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 37-67% over 60 minutes, wavelength: 220 nm) to obtain intermediate 2. Hex-Cys-Pro-Pro-Thr-Gln-Phe(2-CF3)-beta-homoCys-2Nal-NH2 (Cys-bridged TBMB(H-AET)) was obtained. 59 mg of intermediate 2 (1.0 equivalent) and 33 mg of DOTA-NHS (1.5 equivalents) were dissolved in 5 mL of DMF, and then 0.046 mL of DIPEA (6 equivalents) was added. The mixture was reacted at room temperature for 2 hours, concentrated, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 34-64% over 60 min, wavelength: 220 nm) to obtain the final product Hex-Cys-Pro-Pro-Thr-Gln-Phe(2-CF3)-beta-homoCys-2Nal-NH2 trifluoroacetate. HPLC purity was 97.6%, MS (m / z): 875.1 [M+2H] 2+ .

[0141] Example 19 [ka] Step 1: 0.3 g of Fmoc-1Nal-CTC resin with a substitution degree of 0.69 mmol / g was weighed and placed in a reactor. It was immersed in 10 mL of N,N-dimethylformamide (DMF) for 2 hours, then drained. Deprotection was performed with 10 mL of 20% piperidine (Pip) in DMF. Equal amounts of starting materials (amino acid: N,N'-diisopropylcarbodiimide (DIC): 1-hydroxybenzotriazole (HOBt) = 3:3:3) were added, and 10 mL of DMF was added. The resulting mixture was drained and washed with 15 mL of DMF. Each amino acid was added sequentially according to the polypeptide sequence, and all amino acids were linked by solid-phase synthesis. The crude resin was washed sequentially with DMF, DCM, and MeOH, and the resulting crude resin was treated with 10 mL of 1% TFA / DCM. The organic phase was washed with water and saturated brine, respectively, and concentrated in vacuo to give the fully protected intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-1Nal-OH. 233 mg of the intermediate and 55 mg of HOOBt (2.0 equivalents) were dissolved in 10 mL of DMF and cooled to 0 °C. 65 mg of EDC hydrochloride (2.0 equivalents) and 93 mg of H-Cys(Trt)-CHNH-3-(4-trifluoromethylphenyl)propionic acid (1.0 equivalents) were added sequentially, and the mixture was allowed to react at room temperature. After completion of the reaction, the DMF was removed by concentration in vacuo, and 10 mL of 5% aqueous phosphoric acid and 20 mL of ethyl acetate were added. The mixture was stirred and separated. The organic phase was washed successively with water and saturated brine and concentrated in vacuo to give the intermediate Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-1Nal-Cys(Trt)-CHNH-3-(4-trifluoromethylphenyl)propionic acid.323 mg of the intermediate was washed successively with DMF, DCM, and MeOH, treated with solution E (TFA:EDT:HO:phenol:TIS=90:2.5:2.5:2.5:2.5) and methyl tert-butyl ether, centrifuged, and the product was washed again with methyl tert-butyl ether, dried, and purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 34-64% over 60 min, wavelength: 220 nm) to give the intermediate Hex-Cys-Pro-Pro-Thr-Gln-1Nal-Cys-CHNH-3-(4-trifluoromethylphenyl)propanoic acid. Step 2: 56 mg (1.0 equivalent) of the final product obtained in Step 1 was dissolved in 60 mL of 50 mM aqueous ammonium bicarbonate solution and acetonitrile (volume ratio 1:1). A solution of 27 mg (1.5 equivalents) of TBMB in 0.5 mL of acetonitrile was added. The mixture was reacted at room temperature for 1 hour, and then 38 mg of cysteamine (10 equivalents) was added and stirred for another 2 hours. 1 mL of acetic acid was added. The mixture was concentrated and lyophilized, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 41-71% over 60 minutes, wavelength: 220 nm) to give intermediate 2. Hex-Cys-Pro-Pro-Thr-Gln-1Nal-Cys-CH2NH-3-(4-trifluoromethylphenyl)propanoic acid (Cys-bridged TBMB(H-AET)) was obtained. 29 mg of intermediate 2 (1.0 equiv.) and 17 mg of DOTA-NHS (1.5 equiv.) were dissolved in 5 mL of DMF, and then 0.023 mL of DIPEA (6 equiv.) was added. The mixture was reacted at room temperature for 2 hours, concentrated, and then purified by HPLC (preparative chromatography, column: Huapu C18 10 μm 100A 20*250 mm, mobile phase: A: 0.1% TFA in water; B: 0.1% TFA in ACN, linear gradient: 38-68% over 60 min, wavelength: 220 nm) to obtain the final product, Hex-Cys-Pro-Pro-Thr-Gln-1Nal-Cys-CHNH-3-(4-trifluoromethylphenyl)propanoic acid (Cys-bridged TBMB (DOTA-AET)) trifluoroacetate). HPLC purity was 96.1%, MS (m / z): 853.3 [M+2H] 2+ .

[0142] Examples 20 to 25 [ka] To a solution of compound 11 (0.4 mM) in 4.9 mL of sodium acetate (0.4 M, pH 5.0) was added 3 equivalents of indium(III) chloride (1.2 mM). The resulting mixture was vortexed at 50°C for 20 minutes or at room temperature overnight. The resulting crude product was purified by HPLC to give 1.8 mg (61% yield) of a white solid. MS (m / z): 824.5 [M+2H] 2+ .

[0143] [ka] To a solution of compound 14 (0.4 mM) in 4.8 mL of sodium acetate (0.4 M, pH 5.0) was added 3 equivalents of indium(III) chloride (1.2 mM). The resulting mixture was vortexed at 50°C for 20 minutes or at room temperature overnight. The resulting crude product was purified by HPLC to give 2.6 mg (81% yield) of a white solid. MS (m / z): 833.2 [M+2H] 2+ .

[0144] [ka] To a solution of compound 16 (0.4 mM) in 4.6 mL of sodium acetate (0.4 M, pH 5.0) was added 3 equivalents of indium(III) chloride (1.2 mM). The resulting mixture was vortexed at 50°C for 20 minutes or at room temperature overnight. The resulting crude product was purified by HPLC to give 2.5 mg (78% yield) of a white solid. MS (m / z): 861.8 [M+2H] 2+ .

[0145] [ka] To a solution of compound 12 (0.4 mM) in 4.8 mL of sodium acetate (0.4 M, pH 5.0) was added 3 equivalents of indium(III) chloride (1.2 mM). The resulting mixture was vortexed at 50°C for 20 minutes or at room temperature overnight. The resulting crude product was purified by HPLC to give 2.1 mg (66% yield) of a white solid. MS (m / z): 833.5 [M+2H] 2+ .

[0146] [ka] To a solution of compound 13 (0.4 mM) in 4.4 mL of sodium acetate (0.4 M, pH 5.0) was added 3 equivalents of indium(III) chloride (1.2 mM). The resulting mixture was vortexed at 50°C for 20 minutes or at room temperature overnight. The resulting crude product was purified by HPLC to give 1.7 mg (53% yield) of a white solid. MS (m / z): 898.2 [M+2H] 2+ .

[0147] [ka] To a solution of compound 15 (0.4 mM) in 4.7 mL of sodium acetate (0.4 M, pH 5.0) was added 3 equivalents of indium(III) chloride (1.2 mM). The resulting mixture was vortexed at 50°C for 20 minutes or at room temperature overnight. The resulting crude product was purified by HPLC to give 1.8 mg (56% yield) of a white solid. MS (m / z): 854.7 [M+2H] 2+ .

[0148] Examples 26 to 28 [ka] a) Labeled compounds (compounds 11, 14, and 16) were prepared at a concentration of 1 mM in DMSO and diluted to 0.1 mM using 0.1 M sodium acetate buffer at pH 4.5. b) Using a germanium / gallium generator, the eluate was fractionated with 5 mL of 0.1 M HCl, and the most active fraction (1 mL) was collected. 0.25 mL of the eluate was mixed with 0.5 mL of 0.1 M sodium acetate buffer (pH 4.5) and 40 μL of precursor (equivalent to compounds 11, 14, and 16, respectively, 0.1 mM) in a 1.5 mL centrifuge tube as a reaction tube. The mixture was vortexed for 10 seconds to homogenize and then heated at 95 °C and 800 rpm for 15 minutes. c) A C18 column was activated with absolute ethanol, rinsed with pure water until clean, and dried. d) The solution at the end of the reaction was passed through a C18 column, rinsed with pure water, dried, and then rinsed with ethanol. In this case, 3 drops of ethanol were added to one tube, and added to a total of approximately 10 tubes. The tube with the highest radioactivity was used for HPLC quality control. Compound 26 had a purity of 90.88%, compound 27 had a purity of 97.19%, and compound 28 had a purity of 99.79%.

[0149] Examples 29-30 [ka] To 40 μL of each precursor compound (compounds 11 and 16, 0.1 mM), 260 μL of 0.5 M acetic acid / sodium acetate buffer at pH 4.5 and 1.8 μL of 177 Lu (approximately 2 mci) was added to each well, and the mixture was heated at 95°C for 20 minutes. The purity of the labeled compound was determined by radio-HPLC. Chromatography conditions: Mobile phase A: 0.1% TFA-H2O; Mobile phase B: 0.1% TFA-CAN; Chromatography column: Shim-pack VP-ODS150L*4.6, 5μm; Flow rate: 1mL / min; Wavelength: 220nm; Method: Time: 0min 5%B, 15min 95%B; The radio-HPLC result of compound 29 was 96.84%. The radio-HPLC result of compound 30 was 99.54%.

[0150] Example 31 [ka] Compound 31 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 98.9%, MS (m / z): 1058.5 [M+H] + .

[0151] Example 32 [ka] Compound 32 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 99.5%, MS (m / z): 1128.7 [M+H] + .

[0152] Example 33 [ka] Compound 33 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 97%, MS (m / z): 1148.7 [M+H] + .

[0153] Example 34 [ka] Compound 34 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 99.3%, MS (m / z): 1126.7 [M+H] + .

[0154] Example 35 [ka] Compound 35 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 99.2%, MS (m / z): 1140.6 [M+H] + .

[0155] Example 36 [ka] Compound 36 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 99.5%, MS (m / z): 1134.6 [M+H] + .

[0156] Example 37 [ka] Compound 37 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 98.3%, MS (m / z): 1149.7 [M+H] + .

[0157] Example 38 [ka] Compound 38 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 98.1%, MS (m / z): 1124.6 [M+H] + .

[0158] Example 39 [ka] Compound 39 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 98.6%, MS (m / z): 1074.6 [M+H] + .

[0159] Example 40 [ka] Compound 40 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 99%, MS (m / z): 1060.5 [M+H] + .

[0160] Example 41 [ka] Compound 41 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 98.9%, MS (m / z): 1074.5 [M+H] + .

[0161] Example 42 [ka] Compound 42 was synthesized with reference to the synthesis method of compound 4. HPLC purity was 96.4%, MS (m / z): 1060.7 [M+H] + .

[0162] Example 43 [ka] Compound 43 was synthesized with reference to the synthesis method of compound 4. HPLC purity was 98%, MS (m / z): 1118.8 [M+H] + .

[0163] Example 44 [ka] Compound 44 was synthesized with reference to the synthesis method of compound 4. HPLC purity was 96.6%, MS (m / z): 1102.7 [M+H] + .

[0164] Example 45 [ka] Compound 45 was synthesized with reference to the synthesis method of compound 4. HPLC purity was 97.7%, MS (m / z): 1045.6 [M+H] + .

[0165] Example 46 [ka] Compound 46 was synthesized with reference to the synthesis method of compound 4. HPLC purity was 97.1%, MS (m / z): 1048.6 [M+H] + .

[0166] Example 47 [ka] Compound 47 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 99.2%, MS (m / z): 1059.6 [M+H] + .

[0167] Example 48 [ka] Compound 48 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 98.1%, MS (m / z): 1060.7 [M+H] + .

[0168] Example 49 [ka] Compound 49 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 97.7%, MS (m / z): 1077.6 [M+H] + .

[0169] Example 50 [ka] Compound 50 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 97%, MS (m / z): 1065.6 [M+H] + .

[0170] Example 51 [ka] Compound 51 was synthesized with reference to the synthesis method of compound 4. HPLC purity was 97.1%, MS (m / z): 1128.7 [M+H] + .

[0171] Example 52 [ka] Compound 52 was synthesized with reference to the synthesis method of compound 4. HPLC purity was 98.4%, MS (m / z): 1135.7 [M+H] + .

[0172] Example 53 [ka] Compound 53 was synthesized with reference to the synthesis method of compound 4. HPLC purity was 97.3%, MS (m / z): 1140.8 [M+H] + .

[0173] Example 54 [ka] Compound 54 was synthesized with reference to the synthesis method of compound 4. HPLC purity was 97.5%, MS (m / z): 1134.7 [M+H] + .

[0174] Example 55 [ka] Compound 55 was synthesized with reference to the synthesis method of compound 4. HPLC purity was 98.8%, MS (m / z): 1033.6 [M+H] + .

[0175] Example 56 [ka] Compound 56 was synthesized with reference to the synthesis method of compound 4. HPLC purity was 96.4%, MS (m / z): 1045.6 [M+H] + .

[0176] Example 57 [ka] Compound 57 was synthesized with reference to the synthesis method of compound 4. HPLC purity was 97.1%, MS (m / z): 1031.6 [M+H] + .

[0177] Example 58 [ka] Compound 58 was synthesized with reference to the synthesis method of compound 2. HPLC purity was 99.4%, MS (m / z): 1059.7 [M+H] + .

[0178] Example 59 [ka] Compound 59 was synthesized with reference to the synthesis method of compound 10. HPLC purity was 96.5%, MS (m / z): 1030.6 [M+H] + .

[0179] Example 60 [ka] Compound 60 was synthesized with reference to the synthesis method of compound 2.

[0180] Example 61 [ka] Compound 61 was synthesized with reference to the synthesis method of compound 2.

[0181] Example 62 [ka] Compound 62 was synthesized with reference to the synthesis method of compound 1.

[0182] Example 63 [ka] Compound 63 was synthesized with reference to the synthesis method of compound 2.

[0183] Example 64 [ka] Compound 64 was synthesized with reference to the synthesis method of compound 4.

[0184] Example 65 [ka] Compound 65 was synthesized with reference to the synthesis method of compound 4.

[0185] Example 66 [ka] Compound 66 was synthesized with reference to the synthesis method of compound 11.

[0186] Example 67 [ka] Compound 67 was synthesized with reference to the synthesis method of compound 11.

[0187] Example 68 [ka] Compound 68 was synthesized with reference to the synthesis method of compound 11.

[0188] Example 69 [ka] Compound 69 was synthesized with reference to the synthesis method of compound 10.

[0189] Example 70 [ka] Compound 70 was synthesized with reference to the synthesis method of compound 11.

[0190] Example 71 [ka] Compound 71 was synthesized with reference to the synthesis method of compound 10.

[0191] Example 72 [ka] Compound 72 was synthesized with reference to the synthesis method of compound 11.

[0192] Example 73 [ka] Compound 73 was synthesized with reference to the synthesis method of compound 11.

[0193] Example 74 [ka] Compound 74 was synthesized with reference to the synthesis method of compound 10.

[0194] Example 75 [ka] Compound 75 was synthesized with reference to the synthesis method of compound 11.

[0195] Example 76 [ka] Compound 76 was synthesized with reference to the synthesis method of compound 11.

[0196] Example 77 [ka] Compound 77 was synthesized with reference to the synthesis method of compound 11.

[0197] Example 78 [ka] Step 1: 1.28 g of CTC resin (1 mmol) with a substitution degree of 0.78 mmol / g was weighed and placed in a reactor. The raw materials (Fmoc-beta-homoCys(Trt)-OH / N,N-diisopropylethylamine (DIPEA) = 1.5 / 6) were dissolved in 10 mL of dichloromethane (DCM). The solution was added to the reactor and reacted for 3-4 hours. After capping, 1 mL of methanol (MeOH) was added. The resulting mixture was washed sequentially with DCM and N,N-dimethylformamide (DMF). The resulting mixture was then deprotected with 10 mL of 20% piperidine (Pip) / DMF. The raw materials (amino acid / 1-hydroxybenzotriazole (HOBt) / N,N'-diisopropylcarbodiimide (DIC) = 2 / 2 / 2) were dissolved in 10 mL of DMF. The solution was added to the reactor and reacted. Upon completion of the reaction, the solution was drained and the product was washed with 10 mL of DMF. Following the polypeptide sequence, Fmoc-1Nal-OH amino acid, Fmoc-Gln(Trt)-OH amino acid, Fmoc-Thr(tBu)-OH amino acid, Fmoc-Pro-OH amino acid, Fmoc-Pro-OH amino acid, and Fmoc-D-Cys(Trt)-OH amino acid were sequentially added. The product was then deprotected with 10 mL of 20% piperidine (Pip) / DMF. The starting materials (n-hexanoic acid / O-benzotriazazole-tetramethyluronium hexafluorophosphate (HBTU) / DIPEA = 2 / 1.9 / 4) were dissolved in 10 mL of DMF, and the resulting solution was added to the reactor. Upon completion of the reaction, the solution was drained and the peptide resin was washed sequentially with DMF and MeOH. Finally, the peptide resin was treated with cleavage solution (trifluoroacetic acid (TFA) / ethanedithiol (EDT) / HO = 92.5 / 5 / 2.5) and diethyl ether, followed by centrifugation to obtain crude hexanoyl-D-Cys-Pro-Pro-Thr-Gln-1Nal-betahomoCys-OH. Step 2: 500 mg of the crude product (1 equivalent) obtained in Step 1 was dissolved in 100 mL of acetonitrile and water (volume ratio 1 / 1), and a solution of 185 mg (1 equivalent) of 1,3,5-tris(bromomethyl)benzene (TBMB) in 2 mL of acetonitrile was added. The pH of the reaction solution was adjusted to alkaline by adding 1 M aqueous (NH4)2CO3 solution. After 10 min of reaction, a solution of 485 mg (2 equiv.) of 2,2',2"-(10-(2-((2-thioethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTA-AET) in 2 mL of water was added, and then 1 M aqueous (NH4)2CO3 solution was added to adjust the pH of the reaction solution to alkaline. The reaction was continued for 24 h, diluted with 200 mL of water, and purified by RP-HPLC (preparative column size: 1 inch; packing: Luna C18(3); mobile phase: Phase A: 0.1% TFA in H2O, Phase B: 0.1% TFA in 80% acetonitrile in water; elution gradient: 35-65% of Phase B in 60 min; wavelength: 220 nm) and lyophilized to give compound 78. Hexanoyl-(D-Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-1Nal-betahomoCys)-OH trifluoroacetate was obtained. HPLC purity was 95.44%, MS (m / z): 1534.7 [M+H] + .

[0198] Example 79 [ka] Compound 79 (hexanoyl-(Cys(tMeBn(DOTA-AET))-D-Pro-Pro-Thr-Gln-1Nal-beta homo Cys)-OH) was synthesized by referring to the synthesis method of compound 78. During the synthesis, the starting amino acid A1 was converted from S-configuration to R-configuration, while the starting amino acid A2 was converted from S-configuration to R-configuration. HPLC purity was 90.14%, MS (m / z): 1535.74 [M+H] + .

[0199] Example 80 [ka] Compound 80 (hexanoyl-(Cys(tMeBn(DOTA-AET))-Pro-D-Pro-Thr-Gln-1Nal-beta homo Cys)-OH) was synthesized by referring to the synthesis method of compound 78. During the synthesis, the starting amino acid A1 was converted from S-configuration to R-configuration, while the starting amino acid A3 was converted from S-configuration to R-configuration. HPLC purity was 90.13%, MS (m / z): 1534.73 [M+H] + .

[0200] Example 81 [ka] Compound 81 (hexanoyl-(Cys(tMeBn(DOTA-AET))-Pro-Pro-D-Thr-Gln-1Nal-beta homo Cys)-OH) was synthesized by referring to the synthesis method of compound 78. During the synthesis, the starting amino acid A1 was converted from S-configuration to R-configuration, while the starting amino acid A4 was converted from S-configuration to R-configuration. HPLC purity was 92.36%, MS (m / z): 1535.75 [M+H] + .

[0201] Example 82 [ka] Compound 82 (hexanoyl-(Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-D-Gln-1Nal-betahomoCys)-OH) was synthesized by referring to the synthesis method of compound 78. During the synthesis, the starting amino acid A1 was converted from S-configuration to R-configuration, while the starting amino acid A5 was converted from S-configuration to R-configuration. HPLC purity was 94.36%, MS (m / z): 1534.75 [M+H] + .

[0202] Example 83 [ka] Compound 83 (hexanoyl-(Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-D-1Nal-beta homo Cys)-OH) was synthesized by referring to the synthesis method of compound 78. During the synthesis, the starting amino acid A1 was converted from S-configuration to R-configuration, while the starting amino acid A6 was converted from S-configuration to R-configuration. HPLC purity was 94.76%, MS (m / z): 1534.66 [M+H] + .

[0203] Example 84 [ka] Compound 84 (hexanoyl-(Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-1Nal-D-betahomoCys)-OH) was synthesized by referring to the synthesis method of compound 78. During the synthesis, only the starting amino acid A1 was converted from S-configuration to R-configuration, while the starting amino acid A3 was converted from R-configuration to S-configuration. HPLC purity was 90%, MS (m / z): 1534.73 [M+H] + .

[0204] Abbreviation of the compound's structural formula [Table 1]

[0205] Effect Example 1 Method for detecting the inhibitory activity of compounds against FAP protease activity Human recombinant FAP protein (Acrobiosystems, FAP-H82Q6) was diluted to 125 pM FAP working solution in assay buffer (50 mM Tris-HCl, 1 M NaCl, 1 mg / mL BSA, pH 7.5), and FAP substrate (Z-Gly-Pro-AMC (LEONBIO, 68542-93-8)) was diluted to 150 μM substrate working solution in assay buffer. 40 μl of FAP working solution and 20 μl of different concentrations of compounds (4-fold dilution) were aliquoted, followed by 40 μl of substrate working solution. The mixture was mixed uniformly on a shaker for 1 minute at room temperature. The mixture was incubated at room temperature in the dark for 90 minutes. Fluorescence readings were taken at Ex = 380 nm / Em = 460 nm using a microplate reader. The original data was saved, and the IC values ​​of the compounds were calculated. 50 Values ​​were obtained by analyzing the data with Graphpad PRISM using either raw data or calculated % inhibition. Compound IC 50 is ≦100 nM, it indicates that the compound has significant inhibitory activity against FAP protease activity and satisfies the protease activity index of the candidate compound. 3BP-4186 and 3BP-3554 are compounds described in CN114341158A and have the following structures: [ka] .

[0206] [Table 2]

[0207] The results showed that compounds of the present disclosure that were not linked to a chelator had stronger inhibitory activity against FAP protease activity than 3BP-4186.

[0208] [Table 3]

[0209] The results showed that the compounds of the present disclosure linked to a chelator exhibited stronger inhibitory activity against FAP protease activity than 3BP-3554.

[0210] [Table 4]

[0211] The results showed that among compounds 78–84 formed by substituting seven amino acids of compound 11 with their enantiomers, compounds 78, 81, and 84 still exhibited good inhibitory activity against FAP protease activity.

[0212] Effect Example 2 Test of the inhibitory activity of compounds against DPP4 protease activity Human recombinant DPP4 protein (Acrobiosystems, DP4-H5211) was prepared in assay buffer (20 mM Tris-HCl, 100 mM NaCl) to a 125 pM working solution, and DPP4 substrate (H-Gly-Pro-AMC.HBr (LEONBIO, 115035-46-6)) was diluted in assay buffer to a 250 μM DPP4 substrate working solution. 40 μl of the DPP4 working solution and 20 μl of different concentrations of compounds (4-fold dilutions) were aliquoted, followed by the addition of 40 μl of the DPP4 substrate working solution. The mixture was mixed uniformly on a shaker at room temperature for 1 minute. The mixture was incubated at room temperature in the dark for 90 minutes. Readings were taken using a microplate reader at an excitation wavelength of 380 nm and an emission wavelength of 460 nm. The original data was saved, and the IC values ​​of the compounds were calculated. 50 Values ​​were obtained by analyzing the data using Graphpad PRISM.

[0213] [Table 5]

[0214] The results showed that compounds of the present disclosure that were not linked to a chelator had inhibitory activity against DPP4 protease activity comparable to that of 3BP-4186.

[0215] [Table 6]

[0216] The results showed that the compounds of the present disclosure linked to a chelator have inhibitory activity against DPP4 protease activity comparable to that of 3BP-3554.

[0217] Effect Example 3 Inhibitory activity test of compounds against PERP protease activity Human recombinant PREP protein (R&D systems, 4308-SE-010) was prepared in assay buffer (25 mM Tris-HCl, 250 mM NaCl, 2.5 mM DTT, 1 mg / mL BSA) to a 125 pM working solution, and PREP substrate (Z-Gly-Pro-AMC (LEONBIO, 68542-93-8)) was diluted in assay buffer to a 125 μM PREP substrate working solution. 40 μl of PREP working solution and 20 μl of compounds at different concentrations (4-fold dilutions) were aliquoted, followed by 40 μl of PREP substrate working solution. The mixture was mixed uniformly on a shaker at room temperature for 1 minute. The mixture was incubated at room temperature in the dark for 90 minutes. Readings were taken using a microplate reader at an excitation wavelength of 380 nm and an emission wavelength of 460 nm. The original data was saved, and the IC values ​​of the compounds were calculated. 50 Values ​​were obtained by analyzing the data using Graphpad PRISM.

[0218] IC of compounds' inhibitory activity against PREP protease activity 50 IC value of the inhibitory activity of the compound against FAP protease activity 50 The ratios for the values ​​reflect the selectivity of the compounds for PREP protease activity: A>10000, 10000>B>3300, 3300>C>1000, 1000>D>330, 330>E>100, and 100>F.

[0219] [Table 7]

[0220] The results showed that the compounds of the present disclosure that were not linked to a chelator were more selective for PREP than 3BP-4186.

[0221] [Table 8]

[0222] The results showed that the compounds of the present disclosure linked to a chelator were more selective for PREP than 3BP-3554.

[0223] Efficacy Example 4: Plasma stability experiment of the compound in mice Plasma stability experiments were performed using plasma from CD-1 mice. Compounds were diluted to a concentration of 1 mM with methanol. 8.00 μL of 1 mM each test compound was added to 0.792 mL of plasma and mixed uniformly. 50.0 μL of plasma sample was then collected. The remaining sample was placed in a 37°C water bath and incubated for 24 hours. Next, 50.0 μL of plasma sample was collected, and 10 μL of internal standard (100 μM 3BP-3554 as an internal standard for compound 13 and 100 μM compound 13 as an internal standard for other test compounds) was added to each sample and mixed uniformly. After centrifugation, the sample was diluted 1x with 0.2% trifluoroacetic acid and analyzed by LC-MS / MS.

[0224] [Table 9]

[0225] Results showed that compounds of the present disclosure have greater plasma stability in mice than 3BP-3554.

[0226] Effect Example 5 Pharmacokinetics of Compound Male CD-1 mice weighing 30-35 g were selected and the test compound was injected intravenously at 0.2 mg / kg into the tail vein. Plasma samples were collected at 5, 15, 30, and 60 minutes and 2, 4, 8, and 24 hours after administration and processed accordingly. Drug content was analyzed by LC-MS / MS. Among these, compounds 20, 21, and 22 were compounds formed by chelation of compounds 11, 14, and 16 with non-radioactive indium, respectively.

[0227] [Table 10]

[0228] The results showed that the half-life, AUC and clearance rate of the compounds of the present disclosure were better than those of 3BP-3623. 3BP-3623 is a compound described in CN114341158A and has the following structure: [ka] .

[0229] Effect Example 6: Experiment on distribution of compound in tissues Male SCID mice (6-8 weeks old) were inoculated with 5 × 10 HEK293-FAP cells (FAP was highly expressed in HEK293 cells). 6 After 10 days, the tumor size was 200-300 mm 3 Thirty mice were randomly divided into three groups. Each mouse in the three groups received a dose of 100 μCi of the compound 177 Lu-3BP-3554, Compound 29, and Compound 30 were administered, respectively. Blood, kidney, and tumor tissues were collected at 4, 8, 24, 72, and 168 hours, and radioactivity counts were measured for all blood and tissue samples using a gamma counter.

[0230] [Table 11]

[0231] The results showed that the injected dose % / g tissue at different time points for compounds 29 and 30 were: 177 Compounds 29 and 30 were significantly higher than Lu-3BP-3554. 177 Compounds 29 and 30 are also shown to be more highly concentrated in tumor tissues and to persist longer than Lu-3BP-3554. Compounds 29 and 30 also show tissue selectivity for kidney and blood tissues. 177 Lu-3BP-3554; therefore, compounds 29 and 30 177 It had a more favorable safety profile compared with Lu-3BP-3554. 177 Lu-3BP-3554 is a compound described in CN114341158A and has the following structure: [ka] .

[0232] Effect Example 7 Compound efficacy test A stable transfected cell line, HEK-293-FAP, highly expressing FAP was constructed and cultured at 1 × 10 6 HEK-293-FAP cells were subcutaneously injected to establish a NOG tumor-bearing mouse model, which was characterized by tumors reaching approximately 300 mm 3 Tumor-bearing mice were used for the experiment when tumors grew to the maximum. The tumor-bearing mice were divided into a control group, a compound 29 0.4 mCi group (0.4 mCi / mouse), a compound 29 0.8 mCi group (0.8 mCi / mouse), and 177 The mice were randomly divided into four groups, each consisting of six mice, and one group receiving 0.8 mCi of Lu-3BP-3554 (0.8 mCi / mouse). On day 0 of the experiment, mice in each group were injected with 0.1 ml of compound solution according to the dose. Tumor volumes were measured on days 2, 4, 7, 11, 14, 17, and 21 of the experiment. When the tumor volume reached 2000 mm 3 At this time, tumor-bearing mice were euthanized.

[0233] The experimental results showed that compounds 29 and 177 Lu-3BP-3554 was shown to significantly inhibit tumor growth. The tumor inhibitory effect of compound 29 had a dose-response relationship, with the tumor inhibitory effect of the 0.8 mCi group being better than that of the 0.4 mCi group. 177 Compared with Lu-3BP-3554, on day 21 of the experiment, the inhibitory effect on tumors in both the 0.8 mCi and 0.4 mCi groups of Compound 29 was 177 The inhibitory effect was better than that of the Lu-3BP-3554 0.8 mCi group.

Claims

1. A polypeptide compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof (wherein A １ , A ２ , A ３ , A ４ , A ５ , A ６ and A ７ are sequentially linked via peptide bonds (—CO—NH—); 【Chemistry 1】 A ７ has a structure represented by formula a-7, 【Chemistry 2】 "&" indicates that the carbon atom is a chiral carbon, i.e., 【Transformation 3】 teeth 【Chemistry 4】 the "*" end indicates the bond to B; R １ is -(CH ２ ) ｍ M; m is 1, 2, 3, 4, 5 or 6; M is -COR １－１ or -NR １－２ R １－３ and R １－１ is -OH, -NR ａ R ｂ , -OC １～１２ Alkyl, —OC ３～１２ Cycloalkyl, —OC ６～１０ Aryl, —O-5 to 10-membered heteroaryl, a group formed by removing an H atom from an amino group on an amino acid, a group formed by removing an H atom from an amino group on a peptide formed by two or more amino acids, 1, 2 or 3 R ｅ -OC substituted with １～１２ alkyl, 1, 2 or 3 R ｆ -OC substituted with ３～１２ cycloalkyl, 1, 2 or 3 R ｅ－１ -OC substituted with ６～１０ aryl, or one, two or three R ｆ－１ -O-5-10 membered heteroaryl substituted with; R ａ and R ｂ are independently H, C １～１２ Alkyl, C ３～１２ Cycloalkyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R ｂ－１ C substituted with １～１２ alkyl, 1, 2 or 3 R ｂ－２ C substituted with ３～１２ cycloalkyl, 1, 2 or 3 R ｂ－３ C substituted with ６～１０ aryl, or one, two or three R ｂ－４ is a 5-10 membered heteroaryl substituted with R ｂ－１ , R ｂ－２ , R ｂ－３ and R ｂ－４ are independently deuterium, —OH, —NH ２ , -COOH, -CONH ２ , -CN, halogen, C １～１２ Alkyl, C ３～１２ Cycloalkyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R ｂ－１－１ C substituted with ６～１０ aryl, 1, 2 or 3 R ｂ－１－２ 5-10 membered heteroaryl substituted with 1, 2 or 3 R ｂ－１－３ C substituted with ３～１２ cycloalkyl, or one, two, or three R ｂ－１－４ C substituted with １～１２ is alkyl; R ｂ－１－１ , R ｂ－１－２ , R ｂ－１－３ and R ｂ－１－４ are independently １～１２ C substituted with alkyl, halogen, or 1, 2, or 3 halogens １～１２ is alkyl; R ｅ , R ｆ , R ｅ－１ and R ｆ－１ are independently halogen, —OH or —NH ２ and R １－２ and R １－３ are independently H, C １～１２ Alkyl, C ３～１２ Cycloalkyl, C ６～１０ Aryl, 5- to 10-membered heteroaryl, —COR ｇ a group formed when a carboxyl group on an amino acid loses an —OH group; a group formed when a carboxyl group on a peptide formed by two or more amino acids loses an —OH group; one, two or three R ｈ C substituted with １～１２ alkyl, 1, 2 or 3 R ｈ－１ C substituted with ３～１２ cycloalkyl, 1, 2 or 3 R ｈ－２ C substituted with ６～１０ aryl, or one, two or three R ｈ－３ is a 5-10 membered heteroaryl substituted with R ｇ are independently １～１２ Alkyl, C ３～１２ Cycloalkyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R ｇ－１ C substituted with １～１２ alkyl, 1, 2 or 3 R ｇ－２ C substituted with ３～１２ cycloalkyl, 1, 2 or 3 R ｇ－３ C substituted with ６～１０ aryl, or one, two or three R ｇ－４ is a 5-10 membered heteroaryl substituted with R ｇ－１ , R ｇ－２ , R ｇ－３ and R ｇ－４ are independently deuterium, —OH, —NH ２ , -COOH, -CN, halogen, C １～１２ Alkyl, C ３～１２ Cycloalkyl, C ６～１０ aryl, or one, two or three R ｇ－１－１ C substituted with ６～１０ is aryl; R ｇ－１－１ are independently —OH, —NH ２ , -COOH, -CN, halogen, C １～１２ Alkyl or C substituted with 1, 2 or 3 halogens １～１２ is alkyl; R ｈ , R ｈ－１ , R ｈ－２ and R ｈ－３ are independently deuterium, —COOH, —CN, halogen, —OH, or —NH ２ and B is, 【Transformation 5】 and B １ , B ２ and B ３ is independently N or C; a is 1, 2 or 3; R ２ are independently H, C １～１２ alkyl, or halogen; "**" ends with A ７ indicates a bond to the １ indicates a bond to A １ has a structure represented by formula a-1, 【Transformation 6】 "&" indicates that the carbon atom is a chiral carbon, i.e., 【Transformation 7】 teeth 【Transformation 8】 the "#" end indicates the bond to B; In the formula, R ３ Ha, -COC １～１２ Alkyl, -COOC １～１２ alkyl, 1, 2 or 3 R ３－１ -COC substituted with １～１２ alkyl, 1, 2 or 3 R ３－２ -COOC substituted with １～１２ alkyl, a group formed by the loss of an —OH group from a carboxyl group on an amino acid, or a group formed by the loss of an —OH group from a carboxyl group on a peptide formed by two or more amino acids; R ３－１ and R ３－２ are independently deuterium, —NH ２ , —COOH, —CN, halogen, —OH, —NR ３－１－１ R ３－１－２ , or -OC １～１２ is alkyl; R ３－１－１ and R ３－１－２ are independently H or C １～１２ is alkyl; A ２ has a structure represented by formula a-2 or a-2-2, and its nitrogen terminal is A １ The carbonyl end of the ３ is bound to; 【Chemistry 9】 R ４ and R ５ are independently H, C １～１２ alkyl, or one, two or three R ４－１ C substituted with １～１２ is alkyl; R ４－１ are independently deuterium, —OH, halogen, —NH ２ or —COOH; R Ａ２ are independently H, deuterium, -CH ３ , —OH, —NH ２ or F; R Ａ２ is 1, 2, 3 or 4; A ３ has a structure represented by formula a-3, and its nitrogen terminal is A ２ The carbonyl end of the ４ is bound to; 【Chemistry 10】 ； R Ａ３ is H, deuterium, -CH ３ , —OH, —NH ２ or F; R Ａ３ is 1, 2, 3 or 4; A ４ has a structure represented by formula a-4, and its nitrogen terminal is A ３ The carbonyl end of the ５ is bound to; 【Chemistry 11】 ； A ５ has a structure represented by formula a-5, and its nitrogen terminal is A ４ The carbonyl end of the ６ is bound to; 【Chemistry 12】 ； In the formula, R ６ is -(CH ２ ) ｘ COR ６－１ where x is 1, 2 or 3; R ６－１ is -OH or -NH ２ and A ６ has a structure represented by formula a-6, and its nitrogen terminal is A ５ The carbonyl end of the ７ is bound to; 【Chemistry 13】 ； R ７ is -CH ２ C ６～１０ Aryl, —CH ２ -5 to 10-membered heteroaryl, -CH ２ C ３～１２ cycloalkyl, 1, 2 or 3 R ７－１ -CH substituted with ２ C ６～１０ aryl, 1, 2 or 3 R ７－２ -CH substituted with ２ - 5 to 10 membered heteroaryl, or 1, 2 or 3 R ７－３ -CH substituted with ２ C ３～１２ is cycloalkyl; R ７－１ , R ７－２ and R ７－３ are independently deuterium, —OH, —NH ２ , halogen, -CN, C １～１２ Alkyl or C substituted with 1, 2 or 3 halogens １～１２ is alkyl; In said 5- to 10-membered heteroaryl, the heteroatoms in each 5- to 10-membered heteroaryl are independently selected from one or more of N, O and S, and the number of said heteroatoms is independently 1, 2 or 3.

2. 10. The polypeptide compound of claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is: （１） 【Chemistry 14】 teeth 【Chemistry 15】 is; (2) m is 1 or 2; (3) R １－１ is -OH, -NR ａ R ｂ , -OC １～１２ Alkyl, —OC ３～１２ Cycloalkyl, —OC ６～１０ aryl, a group formed by the loss of an H atom from an amino group on an amino acid, or a group formed by the loss of an H atom from an amino group on a peptide formed by two or more amino acids; (4) R ａ and R ｂ are independently H, C １～１２ Alkyl, C ３～１２ Cycloalkyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, or 1, 2, or 3 R ｂ－１ C substituted with １～１２ alkyl, 1, 2 or 3 R ｂ－３ C substituted with ６～１０ is aryl; (5) R ｂ－１ and R ｂ－３ are independently deuterium, —OH, —NH ２ , -COOH, -CONH ２ , -CN, halogen, C ３～１２ Cycloalkyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, or 1, 2, or 3 R ｂ－１－１ C substituted with ６～１０ is aryl; (6) R ｂ－１－１ is independently a C substituted with 1, 2 or 3 halogens １～１２ is alkyl; (7) R １－２ and R １－３ are independently H, C １～１２ Alkyl, -COR ｇ , a group formed by the loss of an —OH group from a carboxyl group on an amino acid, or a group formed by the loss of an —OH group from a carboxyl group on a peptide formed by two or more amino acids; (8) R ｇ are independently １～１２ Alkyl, C ３～１２ Cycloalkyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R ｇ－１ C substituted with １～１２ alkyl, 1, 2 or 3 R ｇ－３ C substituted with ６～１０ aryl, or one, two or three R ｇ－４ is a 5-10 membered heteroaryl substituted with (9) R ｇ－１ , R ｇ－３ and R ｇ－４ are independently —OH, —NH ２ , halogen, C １～１２ Alkyl, C ６～１０ aryl, or one, two or three R ｇ－１－１ C substituted with ６～１０ is aryl; (10) R ｇ－１－１ is independently a C substituted with 1, 2 or 3 halogens １～１２ is alkyl; (11) R ３ Ha, -COC １～１２ alkyl, 1, 2 or 3 R ３－１ -COC substituted with １～１２ alkyl, a group formed by the loss of an —OH group from a carboxyl group on an amino acid, or a group formed by the loss of an —OH group from a carboxyl group on a peptide formed by two or more amino acids; (12) R ３－１ are independently —NH ２ or -OC １～１２ is alkyl; (13) R ４ and R ５ are independently １～１２ alkyl; or the nitrogen-containing heterocycle in the structure represented by formula a-2-2 is a 5-membered ring; (14) x is 2 or 3; (15) R ７ is -CH ２ C ６～１０ Aryl, —CH ２ C ６～１０ Heteroaryl, —CH ２ C ３～１２ cycloalkyl, 1, 2 or 3 R ７－１ -CH substituted with ２ C ６～１０ aryl, or one, two or three R ７－２ -CH substituted with ２ -5 to 10 membered heteroaryl; (16) R ７－１ and R ７－２ are independently deuterium, —OH, —NH ２ , halogen, C １～３ Alkyl or C substituted with 1, 2 or 3 halogens １～１２ is alkyl, A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, which satisfies one or more of the following conditions:

3. 3. The polypeptide compound according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is: (1) R １－１ is -OH, -NR ａ R ｂ , -OC １～１２ Alkyl, —OC ３～１２ cycloalkyl, a group formed by the loss of an H atom from an amino group on an amino acid, or a group formed by the loss of an H atom from an amino group on a peptide formed by two or more amino acids; (2) R ｂ－１ are independently ３～１２ Cycloalkyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, or 1, 2, or 3 R ｂ－１－１ C substituted with ６～１０ is aryl; (3) R ｇ are independently １～１２ Alkyl, C ３～１２ Cycloalkyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R ｇ－１ C substituted with １～１２ alkyl, or one, two or three R ｇ－３ C substituted with ６～１０ is aryl; (4) R ｇ－１ and R ｇ－３ are independently halogen, C ６～１０ aryl, or one, two or three R ｇ－１－１ C substituted with ６～１０ is aryl; (5) R ７ is -CH ２ C ６～１０ Aryl, —CH ２ C ３～１２ cycloalkyl, or one, two, or three R ７－１ -CH substituted with ２ C ６～１０ is aryl; and (6) R ７－１ is independently a C substituted with 1, 2 or 3 halogens １～１２ is alkyl, A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, which satisfies one or more of the following conditions:

4. 3. The polypeptide compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, 【Chemistry 16】 teeth 【Chemistry 17】 and m is 1 or 2; R １－１ is -OH, -NR ａ R ｂ , -OC １～１２ Alkyl, —OC ３～１２ cycloalkyl, a group formed by the loss of an H atom from an amino group on an amino acid, or a group formed by the loss of an H atom from an amino group on a peptide formed by two or more amino acids; R ａ and R ｂ are independently H, C １～１２ Alkyl, C ３～１２ Cycloalkyl, C ６～１０ aryl, or one, two or three R ｂ－１ C substituted with １～１２ is alkyl; R ｂ－１ are independently ３～１２ Cycloalkyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, or 1, 2, or 3 R ｂ－１－１ C substituted with ６～１０ is aryl; R ｂ－１－１ is independently a C substituted with 1, 2 or 3 halogens １～１２ is alkyl; R １－２ and R １－３ are independently H, C １～１２ Alkyl, -COR ｇ a group formed by the loss of an —OH group from a carboxyl group on an amino acid, or a group formed by the loss of an —OH group from a carboxyl group on a peptide formed by two or more amino acids; R ｇ are independently １～１２ Alkyl, C ３～１２ Cycloalkyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R ｇ－１ C substituted with １～１２ alkyl, or one, two or three R ｇ－３ C substituted with ６～１０ is aryl; R ｇ－１ and R ｇ－３ are independently halogen, C ６～１０ aryl, or one, two or three R ｇ－１－１ C substituted with ６～１０ is aryl; R ｇ－１－１ is independently a C substituted with 1, 2 or 3 halogens １～１２ is alkyl; R ３ Ha, -COC １～１２ alkyl, 1, 2 or 3 R ３－１ -COC substituted with １～１２ alkyl, a group formed by the loss of an —OH group from a carboxyl group on an amino acid, or a group formed by the loss of an —OH group from a carboxyl group on a peptide formed by two or more amino acids; R ３－１ are independently —NH ２ or -OC １～１２ is alkyl; R ４ and R ５ are independently １～１２ alkyl; or the nitrogen-containing heterocycle in formula a-2-2 is a 5-membered ring, and R Ａ２ are independently H, deuterium, -CH ３ , —OH, —NH ２ or F; R Ａ２ is 1, 2, or 3; x is 1 or 2; R ７ is -CH ２ C ６～１０ Aryl, —CH ２ C ３～１２ cycloalkyl, 1, 2 or 3 R ７－１ -CH substituted with ２ C ６～１０ is aryl; R ７－１ is independently a C substituted with 1, 2 or 3 halogens １～１２ is alkyl, A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

5. 3. The polypeptide compound according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is: (1) R １－１ In the above, -OC １～１２ The C in alkyl １～１２ Alkyl is C １～６ is alkyl; (2) R １－１ In the above, -OC ３～１２ The C in cycloalkyl ３～１２ Cycloalkyl is C ３～６ is cycloalkyl; (3) R １－１ In the above, -OC ６～１０ The C in the aryl ６～１０ Aryl is phenyl or naphthyl; (4) R １－１ wherein the group formed when the amino group on the amino acid loses an H atom is [Chemistry 18] and R ｃ is -(CH ２ ) ｏ COOH or -(CH ２ ) ｐ CONH ２ and o and p are independently 0, 1, 2, 3, or 4; R ｄ is hydrogen, deuterium, C １～１２ Alkyl, C ３～１２ Cycloalkyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, 1, 2, or 3 R ｄ－１ C substituted with １～１２ alkyl, 1, 2 or 3 R ｄ－２ C substituted with ３～１２ cycloalkyl, 1, 2 or 3 R ｄ－３ C substituted with ６～１０ aryl, or one, two or three R ｄ－４ is a 5-10 membered heteroaryl substituted with R ｄ－１ , R ｄ－２ , R ｄ－３ and R ｄ－４ are independently １～１２ Alkyl, C ３～１２ cycloalkyl, or C ６～１０ is aryl; (5) R １－１ wherein the peptide formed by two or more amino acids is a peptide formed by 2 to 20 amino acids; (6) R ａ and R ｂ In the above, １～１２ alkyl, or one, two or three R ｂ－１ The C substituted with １～１２ The C in alkyl １～１２ Alkyl is independently C １～６ is alkyl; (7) R ａ and R ｂ In the above, ３～１２ Cycloalkyl is independently C ３～６ is cycloalkyl; (8) R ａ and R ｂ In the above, ６～１０ Aryl is independently phenyl, biphenyl, or naphthyl; (9) R ａ and R ｂ wherein the number of heteroatoms in the 5- to 10-membered heteroaryl is 1 or 2; (10) R ｂ－１ In the above, ３～１２ Cycloalkyl is independently C ３～６ is cycloalkyl; (11) R ｂ－１ In the above, ６～１０ aryl, or one, two or three R ｂ－１－１ The C substituted with ６～１０ The C in the aryl ６～１０ Aryl is independently phenyl or naphthyl; (12) R ｂ－１ wherein the 5- to 10-membered heteroaryl is independently a 5- to 6-membered heteroaryl; (13) R ｂ－１ wherein the number of heteroatoms in the 5- to 10-membered heteroaryl is 1 or 2; (14) R ｂ－１－１ wherein the halogen or the C substituted with 1, 2 or 3 halogens １～１２ The halogens in alkyl are independently F, Cl, Br, or I; (15) R ｂ－１－１ wherein the C is substituted with 1, 2 or 3 halogen atoms. １～１２ The C in alkyl １～１２ Alkyl is independently C １～６ is alkyl; (16) R １－２ and R １－３ In the above, １～１２ Alkyl is independently C １～６ is alkyl; (17) R １－２ and R １－３ In the above, ３～１２ cycloalkyl, or one, two, or three R ｈ－１ The C substituted with ３～１２ The C in cycloalkyl ３～１２ Cycloalkyl is independently C ３～６ is cycloalkyl; (18) R １－２ and R １－３ In the above, ６～１０ aryl, or one, two or three R ｈ－２ The C substituted with ６～１０ The C in the aryl ６～１０ Aryl is independently phenyl or naphthyl; (19) R １－２ and R １－３ wherein the 5- to 10-membered heteroaryl or 1, 2, or 3 R ｈ－３ the number of heteroatoms in the 5- to 10-membered heteroaryl substituted with is 1 or 2; (20) R １－２ and R １－３ wherein the peptide formed by two or more amino acids is a peptide formed by 2 to 20 amino acids; (21) R ｇ In the above, １～１２ alkyl, or one, two or three R ｇ－１ The C substituted with １～１２ The C in alkyl １～１２ Alkyl is independently C １～６ is alkyl; (22) R ｇ In the above, ３～１２ Cycloalkyl is independently C ３～６ is cycloalkyl; (23) R ｇ In the above, ６～１０ aryl, or one, two or three R ｇ－３ The C substituted with ６～１０ The C in the aryl ６～１０ Aryl is independently phenyl or naphthyl; (24) R ｇ wherein the 5- to 10-membered heteroaryl group or one, two or three R ｇ－４ The 5- to 10-membered heteroaryl in the 5- to 10-membered heteroaryl substituted by is a 5- to 6-membered heteroaryl; (25) R ｇ wherein the 5- to 10-membered heteroaryl or 1, 2, or 3 R ｇ－４ the number of heteroatoms in the 5- to 10-membered heteroaryl substituted with is 1 or 2; (26) R ｇ－１ , R ｇ－３ and R ｇ－４ wherein the halogens are independently F, Cl, Br or I; (27) R ｇ－１ , R ｇ－３ and R ｇ－４ In the above, ６～１０ aryl, or one, two or three R ｇ－１－１ The C substituted with ６～１０ The C in the aryl ６～１０ Aryl is independently phenyl or naphthyl; (28) R ｇ－１－１ wherein the C is substituted with 1, 2 or 3 halogen atoms. １～１２ The C in alkyl １～１２ Alkyl is independently C １～６ is alkyl; (29) R ｇ－１－１ wherein the C is substituted with 1, 2 or 3 halogen atoms. １～１２ The halogens in alkyl are independently F, Cl, Br, or I; (30) R ２ In the above, １～１２ Alkyl is independently C １～６ is alkyl; (31) R ２ wherein the halogens are independently F, Cl, Br or I; (32) R ３ In the -COC １～１２ alkyl, or one, two or three R ３－１ The -COC substituted with １～１２ The C in alkyl １～１２ Alkyl is independently C １～６ is alkyl; (33) R ３ wherein the peptide formed by two or more amino acids is a peptide formed by 2 to 20 amino acids; (34) R ３－１ In the above, -OC １～１２ The C in alkyl １～１２ Alkyl is independently C １～６ is alkyl; (35) R ４ and R ５ In the above, １～１２ Alkyl is independently C １～６ is alkyl; (36) R ７ In the formula, the —CH ２ C ３～１２ The C in cycloalkyl ３～１２ Cycloalkyl is independently C ３～６ is cycloalkyl; (37) R ７ In the formula, the —CH ２ C ６～１０ aryl, or one, two or three R ７－１ The C substituted with ６～１０ The C in the aryl ６～１０ Aryl is independently phenyl or naphthyl; (38) R ７ In the formula, one, two or three R ７－２ the —CH ２ -The 5- to 10-membered heteroaryl in the 5- to 10-membered heteroaryl is a 5- to 6-membered heteroaryl; (39) R ７ In the formula, one, two or three R ７－２ the —CH ２ - the number of heteroatoms in the 5- to 10-membered heteroaryl is 1 or 2; (40) R ７－１ wherein the C is substituted with 1, 2 or 3 halogen atoms. １～１２ The halogens in alkyl are independently F, Cl, Br, or I; (41) R ７－１ wherein the C is substituted with 1, 2 or 3 halogen atoms. １～１２ The C in alkyl １～１２ Alkyl is independently C １～６ is alkyl; and (42) B is 【Chemistry 19】 That is, A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, which satisfies one or more of the following conditions:

6. 6. The polypeptide compound of claim 5, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is: (1) R １－１ In the above, -OC １～１２ The C in alkyl １～１２ Alkyl is n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; (2) R １－１ In the above, -OC ３～１２ The C in cycloalkyl ３～１２ Cycloalkyl is cyclopentyl; (3) o and p are independently 0 or 1; (4) R ｄ is C ６～１０ is aryl; (5) R １－１ wherein the peptide formed by two or more amino acids is a peptide formed by 2 to 10 amino acids; (6) R ａ and R ｂ In the above, １～１２ alkyl, or one, two or three R ｂ－１ The C substituted with １～１２ The C in alkyl １～１２ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or n-pentyl; (7) R ａ and R ｂ In the above, ３～１２ Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 【Chemistry 20】 is; (8) R ａ and R ｂ In the above, ６～１０ Aryl is independently phenyl; (9) R ａ and R ｂ wherein the 5-10 membered heteroaryl is furyl, thienyl, imidazolyl, pyridyl, or quinolinyl; (10) R ｂ－１ In the above, ３～１２ Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (11) R ｂ－１ In the above, ６～１０ aryl, or one, two or three R ｂ－１－１ The C substituted with ６～１０ The C in the aryl ６～１０ Aryl is independently phenyl; (12) R ｂ－１ wherein the 5- to 10-membered heteroaryl is independently a 5- to 6-membered heteroaryl; (13) R ｂ－１－１ wherein the halogen or the C substituted with 1, 2 or 3 halogens １～１２ The halogen in alkyl is F; (14) R ｂ－１－１ wherein the C is substituted with 1, 2 or 3 halogen atoms. １～１２ The C in alkyl １～１２ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or n-pentyl; (15) R １－２ and R １－３ In the above, １～１２ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; (16) R １－２ and R １－３ In the above, ３～１２ cycloalkyl, or one, two, or three R ｈ－１ The C substituted with ３～１２ The C in cycloalkyl ３～１２ Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (17) R １－２ and R １－３ wherein the peptide formed by two or more amino acids is a peptide formed by 2 to 10 amino acids; (18) R ｇ In the above, １～１２ alkyl, or one, two or three R ｇ－１ The C substituted with １～１２ The C in alkyl １～１２ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; (19) R ｇ In the above, ３～１２ Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 【Chemistry 21】 is; (20) R ｇ In the above, ６～１０ aryl, or one, two or three R ｇ－３ The C substituted with ６～１０ The C in the aryl ６～１０ Aryl is phenyl; (21) R ｇ－１ , R ｇ－３ and R ｇ－４ wherein the halogen is Cl; (22) R ｇ－１ , R ｇ－３ and R ｇ－４ In the above, ６～１０ aryl, or one, two or three R ｇ－１－１ The C substituted with ６～１０ The C in the aryl ６～１０ Aryl is phenyl; (23) R ｇ－１－１ wherein the C is substituted with 1, 2 or 3 halogen atoms. １～１２ The C in alkyl １～１２ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or n-pentyl; (24) R ｇ－１－１ wherein the C is substituted with 1, 2 or 3 halogen atoms. １～１２ The halogen in alkyl is F; (25) R ２ In the above, １～１２ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; (26) R ２ wherein the halogen is F; (27) R ３ In the -COC １～１２ alkyl, or one, two or three R ３－１ The -COC substituted with １～１２ C in alkyl １～１２ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; (28) R ３ wherein the peptide formed by two or more amino acids is a peptide formed by 2 to 10 amino acids; (29) R ３－１ In the above, -OC １～１２ The C in alkyl １～１２ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; (30) R ４ and R ５ In the above, １～１２ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl; (31) R ７ In the formula, the —CH ２ C ３～１２ The C in cycloalkyl ３～１２ Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (32) R ７－１ wherein the C is substituted with 1, 2 or 3 halogen atoms. １～１２ The halogen in alkyl is F; and (33) R ７－１ wherein the C is substituted with 1, 2 or 3 halogen atoms. １～１２ The C in alkyl １～１２ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, or n-pentyl; A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, which satisfies one or more of the following conditions:

7. 6. The polypeptide compound of claim 5, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is: (1) R １－１ In the above, -OC １～１２ The C in alkyl １～１２ Alkyl is tert-butyl; (2) R ｄ is naphthyl; (3) R ａ and R ｂ In the above, １～１２ alkyl, or one, two or three R ｂ－１ The C substituted with １～１２ The C in alkyl １～１２ Alkyl is independently methyl or n-pentyl; (4) R ａ and R ｂ In the above, ３～１２ Cycloalkyl is independently cyclopentyl or 【Chemistry 22】 is; (5) R ｂ－１ In the above, ３～１２ Cycloalkyl is cyclopentyl; (6) R ｂ－１－１ wherein the C is substituted with 1, 2 or 3 halogen atoms. １～１２ The C in alkyl １～１２ Alkyl is methyl; (7) R １－２ and R １－３ In the above, １～１２ Alkyl is independently methyl, isopropyl, n-pentyl, or n-hexyl; (8) R ｇ In the above, １～１２ alkyl, or one, two or three R ｇ－１ The C substituted with １～１２ The C in alkyl １～１２ Alkyl is independently methyl, ethyl, or n-pentyl; (9) R ｇ In the above, ３～１２ Cycloalkyl is independently cyclopentyl, cyclohexyl, or 【Chemistry 23】 is; (10) R ｇ－１－１ wherein the C is substituted with 1, 2 or 3 halogen atoms. １～１２ The C in alkyl １～１２ Alkyl is methyl; (11) R ２ In the above, １～１２ Alkyl is methyl; (12) R ３ In the -COC １～１２ alkyl, or one, two or three R ３－１ The -COC substituted with １～１２ The C in alkyl １～１２ Alkyl is independently methyl, ethyl, or n-pentyl; (13) R ３－１ In the above, -OC １～１２ The C in alkyl １～１２ Alkyl is methyl; (14) R ４ and R ５ In the above, １～１２ Alkyl is methyl; (15) R ７ In the formula, the —CH ２ C ３～１２ The C in cycloalkyl ３～１２ Cycloalkyl is cyclohexyl; and (16) R ７－１ wherein the C is substituted with 1, 2 or 3 halogen atoms. １～１２ The C in alkyl １～１２ Alkyl is methyl, A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, which satisfies one or more of the following conditions:

8. 3. The polypeptide compound according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is: (1) R １ is -CH ２ COOH, -CH ２ CH ２ COOH, 【Chemistry 24】 、-CH ２ CONG ２ 、 【Chemistry 25】 、-CH ２ NH ２ 、-CH ２ NHCOCH ３ 、-CH ２ CH ２ NH ２ 、-CH ２ NH(CH) ２ ) ４ CH ３ 、-CH ２ NH(CH) ２ ) ５ CH ３ 、 【Chemistry 26】 is; (2) R ３ teeth, 【Chemistry 27】 is; (3) B is 【Chemistry 28】 is; （４） 【Chemistry 29】 ； 【Transformation 30】 teeth 【Chemistry 31】 is; （５） 【Chemistry 32】 teeth 【Transformation 33】 , optionally 【Transformation 34】 is; （６） 【Chemistry 35】 teeth 【Transformation 36】 , optionally 【Chemistry 37】 is; and （７） 【Transformation 38】 teeth 【Chemistry 39】 , optionally 【Chemistry 40】 That is, A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, which satisfies one or more of the following conditions:

9. 9. The polypeptide compound of claim 8, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is: (1) R ３ teeth, 【Chemistry 41】 is; (2) B is 【Chemistry 42】 is; （３） 【Chemistry 43】 teeth 【Chemistry 44】 is; （４） 【Chemistry 45】 teeth 【Chemistry 46】 is; （５） 【Chemistry 47】 teeth 【Chemistry 48】 is; and （６） 【Chemistry 49】 teeth [Transformation 50] That is, A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, which satisfies one or more of the following conditions:

10. 2. The polypeptide compound of claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is the following compound: 【Chemistry 51】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, selected from any one of the following:

11. A polypeptide compound represented by formula I-B, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof (wherein A １ , A ２ , A ３ , A ４ , A ５ , A ６ and A ７ are sequentially linked via peptide bonds (—CO—NH—); 【Chemistry 52】 R １ is -(CH ２ ) ｍ’ M; m' is 0, 1, 2, 3, 4, 5 or 6; B' is 【Chemistry 53】 and a' is 1, 2 or 3; B １ ' is CH, and B ２ ' and B ３ ' is independently N or C; R ２ ' is independently H, C １～１２ alkyl or halogen, and at least one R ２ ' is a halogen; or B １ ', B ２ ' and B ３ ' are independently N or CH; R ２ ' is independently C １～１２ alkyl or halogen; The other radicals are as defined in any one of claims 1 to 10.

12. 12. The polypeptide compound of claim 11, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is: (1) B' is 【Chemistry 54】 and (2) R １ is —COOH, A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, which satisfies one or both of the following conditions:

13. 13. The polypeptide compound of claim 12, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: 【Transformation 55】 a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, selected from any one of the following:

14. A polypeptide compound represented by formula IC, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof (wherein A １ , A ２ , A ３ , A ４ , A ５ , A ６ ' and A ７ are sequentially linked via peptide bonds (—CO—NH—); 【Transformation 56】 R １ is -(CH ２ ) ｍ’ M; m' is 0, 1, 2, 3, 4, 5 or 6; A ６ ' has a structure represented by formula a-6', 【Chemistry 57】 ； In the formula, R ７’ is -CH ２ C ３～１２ cycloalkyl, 1, 2 or 3 R ７－１ C substituted with ６～１０ aryl, or one, two or three R ７－２ -CH substituted with ２ C ３～１２ is cycloalkyl; R ７－１ and R ７－２ are independently １～１２ Alkyl or C substituted with 1, 2 or 3 halogens １～１２ is alkyl; The other radicals are as defined in any one of claims 1 to 10.

15. 15. The polypeptide compound of claim 14, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is: (1) R ７’ is -CH ２ C ３～１２ cycloalkyl, or one, two, or three R ７－１ C substituted with ６～１０ is aryl, and (2) R １ is —COOH, A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, which satisfies one or both of the following conditions:

16. 15. The polypeptide compound of claim 14, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein R ７’ But -CH ２ cyclohexyl, or 【Chemistry 58】 A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein

17. 15. The polypeptide compound of claim 14, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is the following compound: 【Chemistry 59】 A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein

18. A polypeptide compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; D-L; II D is a compound of formula I according to any one of the preceding embodiments or a compound of formula I according to any one of claims 1 to 10, １ , or R ３ a group formed by removing an H atom or an OH group at position B', R １ , or R ３ or a group formed by removing an H atom or an OH group at position B, R １ , or R ３ is a group formed by losing an H atom or an OH group at position L is a non-cleavable linker).

19. 19. The polypeptide compound of claim 18, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein L is -A, -W, -W-A, -A-W, -W-A-W, or -A-W-A; A is a group formed by a carboxyl group on an amino acid losing an OH group, a group formed by an amino group on an amino acid losing an H atom, a group formed by a carboxyl group on a peptide formed by two or more amino acids losing an —OH group, or a group formed by an amino group on a peptide formed by two or more amino acids losing an H atom; W is -(Y) ｇ - (CH ２ ) ｃ -NHR ｔ and Y is independently selected from any one of the following groups, or combinations thereof: —(CH ２ ) ｂ -X-, -(CH ２ ) ｃ -C ６～１０ Arylene-(CH ２ ) ｄ -, -(CH ２ ) ｃ -5 to 12-membered heterocycloalkyl-(CH ２ ) ｄ -, -(CH ２ ) ｃ -C ３～１２ Cycloalkylene-(CH ２ ) ｄ - and -(CH ２ ) ｃ -CO-(CH ２ ) ｄ the heteroatoms of said 5- to 12-membered heterocycloalkyl are selected from one or more of N, O and S; the number of said heteroatoms is 1, 2 or 3; X is S, O or NH; R ｔ is H or C １～１２ alkyl or R ｔ together with —NH form a 5- to 10-membered nitrogen-containing heterocycloalkyl; A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein g, b, c, and d are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

20. 19. The polypeptide compound of claim 18, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is: (1) D is selected from any of the following segments: 【Transformation 60】 【change】 【change】 【change】 【change】 and (2) L is selected from any of the following segments: 【Chemistry 61】 A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, which satisfies one or both of the following conditions:

21. 19. The polypeptide compound of claim 18, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is the following compound: 【Transformation 62】 【change】 【change】 【change】 【change】 a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, selected from any one of the following:

22. A polypeptide compound represented by formula III, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: D-L'-R III (D is as defined in any one of claims 18 to 21; L' is a group formed by losing an H atom from the amino group on L defined in any one of claims 18 to 21; R is a group having the function of chelating a metal ion).

23. 23. The polypeptide compound of claim 22, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein R is one of the following: 【Transformation 63】 【change】 【change】 is a group formed by losing an H or hydroxyl group in the chelating agent shown in R is preferably 【Chemistry 64】 A polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein

24. 23. The polypeptide compound of claim 22, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is the following compound: 【Transformation 65】 【change】 【change】 【change】 【change】 【change】 a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, selected from any one of the following:

25. A polypeptide compound represented by formula V, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: [D-L'-R]・M V (D is as defined in any one of claims 18 to 21; L' is as defined in any one of claims 18 to 21; R is as defined in any one of claims 22 to 24; M is a diagnostically active radionuclide or a therapeutically active radionuclide; said diagnostically active radionuclide is １８ F. ９９ｍ Tc, ８９ Zr, １１１ In, ６７ Ga, ６８ Ga, ４３ Sc, ４４ Sc, ６４ Cu, ８６ Y. １５２ Tb, １５５ Tb, ２０３ Pb, １２３ I, １２４ I, １２５ I, optionally, ６４ Cu, ６８ Ga, １１１ In, １８ F. ９９ｍ Tc, ２０３ Pb, ８９ Zr, said therapeutically active radionuclide being selected from ９０ Y. １７７ Lu, ２２５ Ac, ２１２ Pb, １８８ Re, ２２７ Th, １３１ I, ２１１ At, １６１ Tb, １４９ Tb, １５３ Sm, ６７ Cu, ４７ Sc, optionally ９０ Y. １７７ Lu, ２２５ Ac, ２１２ Pb, and １６１ Tb).

26. 26. The polypeptide compound of claim 25, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is the following compound: 【Chemical Formula 66】 【change】 a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, selected from any one of the following:

27. A polypeptide compound represented by formula VI, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: [D-L'-R] Q VI (D is as defined in any one of claims 18 to 21; L' is as defined in any one of claims 18 to 21; R is as defined in any one of claims 22 to 24; Q is a non-radioactive nuclide; said non-radioactive nuclide is selected from In, Ga, Y and Lu, optionally In).

28. 28. The polypeptide compound of claim 27, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the polypeptide compound is the following compound: 【Transformation 67】 【change】 a polypeptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, selected from any one of the following:

29. A pharmaceutical composition comprising a substance X and a pharmaceutically acceptable adjuvant; wherein the substance X is a polypeptide compound according to any one of claims 1 to 28, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

30. A kit comprising a substance X and instructions for use; wherein the substance X is a polypeptide compound according to any one of claims 1 to 28, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

31. 29. Use of a substance X for the manufacture of a medicament for diagnosing or treating a FAP protein-associated disease; wherein the substance X is a polypeptide compound according to any one of claims 1 to 28, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and the FAP protein-associated disease is preferably a tumor.

32. 32. The use of claim 31, wherein the tumor is selected from bronchogenic carcinoma, sweat gland carcinoma, breast cancer, ovarian cancer, prostate cancer, melanoma, oral squamous cell carcinoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, renal cancer, skin cancer, glioblastoma, schwannoma, meningioma, neuroblastoma, mesothelioma, sarcoma, liposarcoma, chondroioma, osteoma, osteosarcoma, semaginoblastoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureter tumor, bladder tumor, gallbladder cancer, bile duct carcinoma, choriocarcinoma, and pediatric tumor.

33. Use of a substance X for the manufacture of an FAP inhibitor, wherein the substance X is a polypeptide compound according to any one of claims 1 to 28, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

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