WO2024198836A1 - Cyclic polypeptide compounds and use thereof - Google Patents

Abstract

Provided are cyclic polypeptide compounds and a use thereof. Specifically, provided are a cyclic polypeptide compound A and a cyclic polypeptide compound B. The cyclic polypeptide compound A is a compound formed by ion chelating of a compound M-L-G and a therapeutic radionuclide, wherein M is a compound X. The cyclic polypeptide compound B is a compound formed by ion chelating of the compound M-L-G and a diagnostic radionuclide, wherein M is the compound X. The compounds can be used for diagnosis and treatment of FAP-related or -mediated tumors, achieve high tumor uptake and long retention time, and has the prospect of being widely applied.

Description

Cyclic polypeptide compounds and their applications

This application claims the priority of Chinese patent application No. 202310307579.5 filed on March 27, 2023. This application cites the entire text of the above Chinese patent application.

This application claims the priority of Chinese patent application No. 202310936916.7 filed on July 27, 2023. This application cites the entire text of the above Chinese patent application.

Technical Field

The invention relates to a cyclic polypeptide compound and application thereof.

Background Art

Chemotherapy remains widely used to treat cancer patients and other diseases. Conventional anticancer chemotherapy drugs act on fundamental mechanisms of cell survival and cannot effectively distinguish between healthy and malignant cells. Furthermore, these drugs do not effectively reach and accumulate at the site of disease after systemic administration. Non-specific mechanisms of action and inefficient localization to tumor sites are responsible for side effects and poor therapeutic efficacy.

In order to treat diseases more effectively, the development of targeted drugs has been one of the hot spots in new drug research and development in recent years. These drugs can selectively locate and exert their effects at the disease site after systemic administration. These drugs are substances that combine representative therapeutic chemicals (such as cytotoxic drugs or radionuclides) with ligands that have targeted cell specificity. Disease-specific monoclonal antibodies, peptides, and small molecule ligands are the preferred ligands for developing targeted drug products. For targeted applications, the use of small molecule ligands has faster and more effective tumor penetration, lower immunogenicity, and lower manufacturing costs than larger molecules (such as peptides and antibodies).

Tumors are complexes composed of tumor cells and their surrounding stromal cells and non-cellular components. The occurrence and development of tumors is a dynamic process in which tumor cells and their microenvironment (TME) promote each other and evolve together. The tumor microenvironment is composed of a variety of heterogeneous cell types, including immune cells, endothelial cells, fibroblasts (cancer associated fibroblasts, CAFs) and their extracellular products. Among them, tumor-associated fibroblasts (cancer associated fibroblasts, CAFs) are the most important stromal cells in the tumor microenvironment, accounting for about 50% of the total number of tumor tissue cells. CAFs play an important role in tumor growth, metastasis, drug resistance and treatment resistance, and are one of the hot topics in tumor diagnosis and treatment research in recent years.

A notable feature of CAFs is the high expression of seprase or fibroblast activation protein (FAP). Both are the same cell surface membrane serine proteases with two activities, dipeptidyl peptidase (DPP) and collagenase, which can degrade dipeptides and type I collagen. FAP and dipeptidyl peptidase IV (PPIV) have similar domains and dipeptidyl peptidase activity and belong to the serine protease family. However, FAP has a unique endopeptidase activity that can cleave gelatin, denatured type I collagen and α2-antifibrillin, while DPPIV does not have this function, so the two can be distinguished. FAP is selectively expressed on the surface of stromal fibroblasts of more than 90% of epithelial malignancies, including breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, skin melanoma, etc. FAP is usually not expressed in benign and precancerous epithelial tumors, such as colorectal adenomas, breast phyllodes tumors, and fibroadenomas. FAP is generally not expressed in normal human tissues, but only exists in the cervix and endometrium, and is expressed briefly during embryonic development. A large number of studies have shown that high expression of FAP in epithelial tumor CAFs is associated with poor prognosis of patients, indicating that its activity is closely related to the development of cancer and the development of cancer cells. Related to cell migration and proliferation.

Nuclear medicine is a medical preparation composed of radioactive isotopes and molecular reagents that target specific organs and tissues. It is a radioactive drug that can be used for imaging diagnosis and clinical treatment. According to its use, it can be divided into diagnostic radionuclide drugs and therapeutic radionuclide drugs.

Diagnostic nuclear medicines include two categories: drugs for organ imaging and drugs for functional measurement. Combined with SPECT or PET, they can study the function and metabolic process of drugs in living bodies at the molecular level, achieve rapid, non-destructive and real-time imaging of physiological and pathological processes, and provide a means for truly early diagnosis and timely treatment.

Therapeutic nuclear medicine refers to radioactive drugs that can be taken orally or injected by patients and can be highly selectively concentrated in diseased tissues. The rays radiated by radioactive isotopes produce local ionizing radiation biological effects, thereby inhibiting or destroying diseased tissues to achieve a therapeutic effect.

In recent years, the use of FAP as a target for tumor diagnosis and treatment has received widespread attention. In terms of diagnosis, compared with FDG imaging, imaging using FAP as a target has a lower background in organs such as the brain and liver, and has a higher detection rate for tumor lesions. However, so far, this type of probe has not shown particularly good results in treatment. The main reason is that the biological activity of this type of compound is often relatively low, the uptake at the lesion site is low, and the retention time in the body is short. In addition, from the perspective of ligand selection, the binding of monomers to receptors presents a one-to-one correspondence, the stability of binding to the receptor is poor, and the low lesion uptake greatly limits the diagnosis and treatment effect. Therefore, using it as a target for nuclear medicine imaging will be a promising strategy for early diagnosis of malignant tumors, assessment of tumor staging, or as a companion diagnosis and efficacy evaluation for tumor treatment.

Summary of the invention

The purpose of the present invention is to solve the current problems in this technical field, such as the low affinity of the compound for FAP, too short retention time at the target or too low uptake in the lesion, etc., and to provide a cyclic polypeptide compound and its application. The cyclic polypeptide compound has the advantages of simple preparation, good stability, high tumor uptake, long retention, etc., and is suitable for clinical promotion and application.

The present invention provides a compound M-L-G or a pharmaceutically acceptable salt thereof

M-L-G;

Wherein, M is compound X;

-L- is a chemical bond or -L ₁ -X ₇ -, wherein L ₁ is T is 0, 1, 2, 3 or 4; K is 0, 1, 2, 3 or 4;

G is

-X ₁ - for

R ¹ is C ₁ ～C ₄ alkylene, C ₃ ～C ₆ cycloalkylene, C ₁ ～C ₄ alkylene- _{C 3} ～C ₆ cycloalkylene, or C ₁ ～C ₄ alkylene substituted by 1 or 2 R ^1-1 ;

Each R ^1-1 is independently a C ₁ ～C ₄ alkyl group, a C ₃ ～C ₆ cycloalkyl group, or a C ₁ ～C ₄ alkyl group substituted by one or two R ^1-1-1 ;

Each R ^1-1-1 is independently a C ₁ ～C ₄ alkyl group or a C ₃ ～C ₆ cycloalkyl group;

R ² is hydrogen or C ₁ ～C ₄ alkyl;

^R3 is _C1 - _C4 alkylene-3-6 membered heterocycloalkylene, 3-6 membered heterocycloalkylene or 6-12 membered heteroarylene; the heteroatoms of the 3-6 membered heterocycloalkylene are selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and at least one N is contained; the heteroatoms of the 6-12 membered heteroarylene are selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and at least one N is contained;

^R4 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

-X ₂ - is -X _2-1 -Y ₁ -; -X _2-1 - is a chemical bond, an unnatural amino acid or a natural amino acid; Y ₁ is

-X ₃ - is -X _3-1 -Y ₂ -; -X _3-1 - is a chemical bond, a non-natural amino acid, a natural amino acid, or a natural amino acid in which N is substituted with a C ₁ ～C ₄ alkyl group; Y ₂ is

R ⁵ is C ₁ ～C ₄ alkyl or C ₁ ～C ₄ alkyl or C ₃ ～C ₆ cycloalkyl substituted by 1 or 2 R ^5-1 ; each R ^5-1 is independently C ₃ ～C ₆ cycloalkyl, C ₆ ～C ₁₀ aryl or C ₆ ～C ₁₀ aryl substituted by 1 or more R ^5-1-1 ; each R ^5-1-1 is independently halogen;

-X ₄ - is a chemical bond, or -Y _2b -Lys-Y ₃ -, L ₂ is C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j -, q is 0, 1, 2, 3 or 4, and j is an integer of 0-10;

-Y _2b - is a chemical bond, L ₃ and L ₄ are each independently C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j'- , q1 and q2 are each independently 0, 1, 2, 3 or 4, and j' is each independently an integer of 0-10;

-Y ₃ - is a chemical bond, L ₅ and L ₆ are each independently C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j" -, q3 and q4 are each independently 0, 1, 2, 3 or 4, and j" is each independently an integer of 0-10;

-X ₅ - for ^R7 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

-X ₇ - is a chemical bond, L ₇ and L ₈ are each independently C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j'' , q5 and q6 are each independently 0, 1, 2, 3 or 4, j''' is an integer of 0-10;

W is -NH-CO- or -NH-CO-NH-;

R ⁸ is a linear C _1-10 alkyl group;

R ⁹ is NOTA, HBED-CC, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA or DEDPA;

R ¹⁰ is a hydroxyl group (-OH) or a chemical bond;

R ¹¹ is a hydroxyl group (-OH) or an amino group (-NH ₂ );

Ring B is

The compound MLG satisfies any of the following conditions:

(1) When R ¹⁰ is a hydroxyl group, L is a chemical bond, and G is connected to -X ₄ -;

(2) When R ¹⁰ is a chemical bond, -LG is -L ₁ -X ₇ -G, and -L ₁ - and the carbonyl group ( connected to the carbonyl group.

In one embodiment, the definitions of certain substituents in the compound M-L-G are as follows, and the definitions of the substituents not mentioned are as described in any of the above embodiments:

In one embodiment, in R ¹ and R ³ , the C ₁ -C ₄ alkylene groups are each independently methylene, ethylene, n-propylene or isopropylene.

In one embodiment, in -L ₂ -, -L ₃ -, -L ₄ -, -L ₅ -, -L ₆ -, -L ₇ - and -L ₈ -, the C ₁ -C ₆ alkylene groups are each independently straight chain C ₁ -C ₆ alkylene groups, such as methylene, ethylene, n-propylene, n-butylene or n-pentylene.

In one embodiment, in R ¹ , the C ₃ -C ₆ cycloalkylene groups are each independently cyclopropylene, cyclobutylene or cyclopentylene.

In one embodiment, in each of R ^1-1 , R ^1-1-1 , R ² , -X ₃ - and R ⁵ , the C ₁ -C ₄ alkyl group is independently methyl, ethyl, n-propyl or isopropyl, for example methyl.

In one embodiment, in each of R ^1-1 , R ^1-1-1 , R ⁵ and R ^5-1 , the C ₃ -C ₆ cycloalkyl group is independently cyclobutane, cyclopentane or cyclohexane.

In one embodiment, in R ³ , the 3-6 membered heterocycloalkylene groups are each independently 4-6 membered heterocycloalkylene groups, and in the 3-6 membered heterocycloalkylene groups, the heteroatom is preferably N, and the number of heteroatoms is preferably 1. For example, the 3-6 membered heterocycloalkylene groups are azetidinylene groups (for example, ) or an azacyclopentylidene group (e.g., ).

In a certain embodiment, in R ³ , the 6-12 membered heteroarylene group is a 6-10 membered heteroarylene group, in which the heteroatom is preferably N, and the number of the heteroatom is preferably 1.

In a certain embodiment, in R ⁴ , the 3-6 membered heterocycloalkylene groups are each independently 4-6 membered heterocycloalkylene groups, and in the 3-6 membered heterocycloalkylene groups, the heteroatom is preferably N, and the number of heteroatoms is preferably 1.

In one embodiment, in -X _2-1 -, the non-natural amino acid residue is or D-alanine (e.g., ).

In one embodiment, in -X _2-1 -, the natural amino acid residue is a glycine group (e.g., ) or L-alanine group (e.g., ).

In one embodiment, in -X _3-1 -, the non-natural amino acid residue is

In one embodiment, in -X _3-1 -, the natural amino acid residue is a glycine group (e.g., ), phenylalanine (e.g. ), for example, the natural amino acid residue is a glycine group (e.g., ).

In one embodiment, in R ^5-1 , the C ₆ ～C ₁₀ aryl groups are each independently phenyl or naphthyl, for example phenyl.

In one embodiment, in R ^5-1-1 , the halogen is fluorine, chlorine or bromine.

In one embodiment, in ^R7 , the 3-6 membered heterocycloalkylene groups are each independently 4-6 membered heterocycloalkylene groups, in which the heteroatom is preferably N, and the number of heteroatoms is preferably 1, for example, the 3-6 membered heterocycloalkylene groups are azacyclopentylene groups (for example, ).

In one embodiment, in R ⁸ , the C _1-10 alkyl group is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl or n-nonyl, for example, n-pentyl or n-butyl.

In one embodiment, _L1 is

In one scheme, _L1 for For example

In one scheme, _L1 for

In one embodiment, -X ₄ - is *-Y _2b -Lys-Y ₃ -, for example Among them, *-end and With NH( NH) connected, Connected to G, L ₃ , L _{4 ,} q1 , q2 , q3 and q4 are each independently as described in any one of the present invention.

In one embodiment, -L- is *-L ₁ -X ₇ -, for example Among them, *-end and Connected to the carbonyl group ( The carbonyl group is connected to is connected to G, and T, K, R ¹¹ , q5, q6 and j″′ are each independently as described in any one of the present invention.

In one embodiment, -X ₁ - is in Connected to _X5 .

In one embodiment, -X ₂ - is -X _2-1 -Y ₁ -, wherein X _2-1 is linked to X ₅ .

In one embodiment, -X ₃ - is -X _3-1 -Y ₂ -, wherein X _3-1 is identical to -NH-( -NH-) connected.

In one embodiment, -X ₄ - is a chemical bond, or *-Y _2b -Lys-Y ₃ -, wherein *- and With -NH-( -NH-) connected.

In one embodiment, -X ₅ - is in Connected to _X2 .

In one embodiment, -X ₇ - is a chemical bond, in Connected to _L1 .

In one embodiment, W is -NH-CO-* or -NH-CO-NH-*, wherein -* is connected to ^R8 .

In one embodiment, T is 3.

In one embodiment, K is 0, 1 or 2, for example, K is 0 or 2, and another example is K is 0 or 1.

In one embodiment, -X ₁ - is

In one embodiment, ^R3 is a 3-6 membered heterocycloalkylene group, wherein the heteroatoms of the 3-6 membered heterocycloalkylene group are selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and at least one N is contained. For example, the 3-6 membered heterocycloalkylene group is an azetidinyl group (for example, ) or an azacyclopentyl group (e.g., ).

In one embodiment, -X _2-1 - is a chemical bond; Y ₁ is

In one embodiment, -X _3-1 - is a chemical bond; Y ₂ is

In one embodiment, -Y ₃ - is

In one embodiment, _L2 is -(O _{- CH2CH2} ) _j- .

In one embodiment, -X ₄ - is a chemical bond or q is 1, L ₂ is -(O-CH ₂ CH ₂ ) _j -, for example, -X ₄ - is a chemical bond.

In one embodiment, -X ₇ - is a chemical bond, For example, chemical bonds or Another example is _L7 and _L8 are each independently -(O- _{CH2CH2 ) j''} , q5 and q6 are each independently 1 or 2, and j''' is an integer of 0-10.

In one embodiment, -Y _2b - is a chemical bond.

In one embodiment, -Y ₃ - is L ₅ and L ₆ are each independently C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j" -, q3 and q4 are each independently 0, 1 or 2 (e.g. 0 or 2), j" is 0, for example, -Y ₃ - is _L5 is _C1 - _C6 alkylene, and q3 is 0, 1 or 2.

In one embodiment, _L3 and _L4 are each independently -(O _{- CH2CH2} ) _j'- .

In one embodiment, L ₅ and L ₆ are each independently C ₁ -C ₆ alkylene.

In one embodiment, _L7 and _{L8 are each independently -(O-CH2CH2 ) j"'} .

In one embodiment, R ⁵ is a C ₁ -C ₄ alkyl group substituted by one or two R ^5-1s ; each R ^5-1 is independently a C ₆ -C ₁₀ aryl group.

In one embodiment, q is 1.

In one embodiment, q1 and q2 are each independently 1, 2 or 4.

In one embodiment, q3 and q4 are each independently 0, 1 or 2, for example 2.

In one embodiment, q5 and q6 are each independently 1 or 2.

In one embodiment, j'", j", j' and j are each independently an integer from 0 to 8, such as 0, 2, 3, 4 or 6 (e.g., 0).

In one embodiment, when -X ₄ - is -Y _2b -Lys-Y ₃ -, R ¹⁰ is a hydroxyl group, L is a chemical bond, and G is connected to -X ₄ -.

In one embodiment, when -X ₄ - is a chemical bond, When R ¹⁰ is a chemical bond.

In one embodiment, -X ₄ - is a chemical bond, -LG is -L ₁ -X ₇ -G, and L ₁ is -X ₇ - is a chemical bond or

In one embodiment, -X ₄ - is a chemical bond, -LG is -L ₁ -X ₇ -G, and L ₁ is -X ₇ - for

In one embodiment, R ⁹ is For example

In one embodiment, R ¹⁰ is hydroxy or a chemical bond, such as hydroxy.

In one embodiment, ring B is

In one embodiment, R ¹¹ is hydroxy.

In one scheme, G is For example

In one embodiment, the compound MLG is compound MLG-1 or compound MLG-2;

-X ₁ -, -X ₂ -, -X ₃ -, -X ₄ -, -X ₅ -, R ⁹ , R ⁸ , Ring B, -L- and G are as defined in any one of the present invention.

In a certain embodiment, in the compound MLG-2,

-L- is -L ₁ -X ₇ -, where L ₁ is T is 3, K is 1;

G is

In compound X, -X ₁ - is

^R3 is a 3-6 membered heterocycloalkylene group, wherein the heteroatoms of the 3-6 membered heterocycloalkylene group are selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

-X ₂ - is -X _2-1 -Y ₁ -; -X _2-1 - is a chemical bond; Y ₁ is

-X ₃ - is -X _3-1 -Y ₂ -; -X _3-1 - is a chemical bond; Y ₂ is

R ⁵ is a C ₁ ～C ₄ alkyl group substituted by 1 or 2 R ^5-1 ; each R ^5-1 is independently a C ₆ ～C ₁₀ aryl group;

-X ₄ - is a chemical bond;

-X ₅ - for ^R7 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

-X ₇ - is a chemical bond or _L7 is -(O- _{CH2CH2 ) j"'} , q5 is 2, j"' is 0;

W is -NH-CO- or -NH-CO-NH-;

R ⁸ is a linear C _1-10 alkyl group;

R ⁹ is

R ¹¹ is a hydroxyl group (-OH);

Ring B is

In one embodiment, in the compound M-L-G-2,

-L- is -L ₁ -X ₇ -, where L ₁ is T is 3, K is 0 or 1;

G is

In compound X, -X ₁ - is

^R3 is a 3-6 membered heterocycloalkylene group, wherein the heteroatoms of the 3-6 membered heterocycloalkylene group are selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

-X ₂ - is -X _2-1 -Y ₁ -; -X _2-1 - is a chemical bond; Y ₁ is

-X ₃ - is -X _3-1 -Y ₂ -; -X _3-1 - is a chemical bond; Y ₂ is

R ⁵ is a C ₁ ～C ₄ alkyl group substituted by 1 or 2 R ^5-1 ; each R ^5-1 is independently a C ₆ ～C ₁₀ aryl group;

-X ₄ - is a chemical bond or L ₂ is -(O-CH ₂ CH ₂ ) _j -, q is 1, and j is an integer from 0 to 10;

-X ₅ - for ^R7 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

-X ₇ - is a chemical bond, _L7 and _L8 are each _{independently -(O-CH2CH2 ) j"'} , q5 and q6 are each independently 1 or 2, and j'' is an integer from 0 to 10;

W is -NH-CO- or -NH-CO-NH-;

R ⁸ is a linear C _1-10 alkyl group;

R ⁹ is

R ¹¹ is a hydroxyl group (-OH);

Ring B is

In one plan,

-L- is a chemical bond or L ₁ -X ₇ -, wherein L ₁ is T is 3; K is 0 or 2;

G is

In compound X, -X ₁ - is

^R3 is a 3-6 membered heterocycloalkylene group, wherein the heteroatoms of the 3-6 membered heterocycloalkylene group are selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

-X ₂ - is -X _2-1 -Y ₁ -; -X _2-1 - is a chemical bond; Y ₁ is

-X ₃ - is -X _3-1 -Y ₂ -; -X _3-1 - is a chemical bond; Y ₂ is

R ⁵ is a C ₁ ～C ₄ alkyl group substituted by 1 or 2 R ^5-1 ; each R ^5-1 is independently a C ₆ ～C ₁₀ aryl group;

-X ₄ - is a chemical bond, or -Y _2b -Lys-Y ₃ -, L ₂ is -(O-CH ₂ CH ₂ ) _j -, q is 1, and j is an integer of 0-10;

-Y _2b - is a chemical bond, L ₃ and L ₄ are each independently C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j'- , q1 and q2 are each independently 1, 2 or 4, and j' is each independently an integer of 0-10;

-Y ₃ - for _L5 and _L6 are each independently _C1 - _{C6 alkylene or -(O-CH2CH2 ) j"} -, q3 and q4 are each independently 2, and j" is 0;

-X ₅ - for ^R7 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

-X ₇ - is a chemical bond, _L7 and _L8 are each independently -(O- _{CH2CH2 ) j''} , q5 and q6 are each independently 1 or 2, j''' is an integer of 0-10;

W is -NH-CO- or -NH-CO-NH-;

R ⁸ is a linear C _1-10 alkyl group;

R ⁹ is

R ¹⁰ is a hydroxyl group (-OH) or a chemical bond;

R ¹¹ is a hydroxyl group (-OH);

Ring B is

In one plan,

-L- is a chemical bond or L ₁ -X ₇ -, wherein L ₁ is T is 3; K is 0, 1 or 2;

G is

In compound X, -X ₁ - is

^R3 is a 3-6 membered heterocycloalkylene group, wherein the heteroatoms of the 3-6 membered heterocycloalkylene group are selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

-X ₂ - is -X _2-1 -Y ₁ -; -X _2-1 - is a chemical bond; Y ₁ is

-X ₃ - is -X _3-1 -Y ₂ -; -X _3-1 - is a chemical bond; Y ₂ is

R ⁵ is a C ₁ ～C ₄ alkyl group substituted by 1 or 2 R ^5-1 ; each R ^5-1 is independently a C ₆ ～C ₁₀ aryl group;

-X ₄ - is a chemical bond, or -Y _2b -Lys-Y ₃ -, L ₂ is -(O-CH ₂ CH ₂ ) _j -, q is 1, and j is an integer of 0-10;

-Y _2b - is a chemical bond, L ₃ and L ₄ are each independently C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j'- , q1 and q2 are each independently 1, 2 or 4, and j' is each independently an integer of 0-10;

-Y ₃ - for L ₅ and L ₆ are each independently C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j" -, q3 and q4 are each independently 0 or 2, and j" is 0;

-X ₅ - for ^R7 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

-X ₇ - is a chemical bond, _L7 and _L8 are each independently -(O- _{CH2CH2 ) j''} , q5 and q6 are each independently 1 or 2, j''' is an integer of 0-10;

W is -NH-CO- or -NH-CO-NH-;

R ⁸ is a linear C _1-10 alkyl group;

R ⁹ is

R ¹⁰ is a hydroxyl group (-OH) or a chemical bond;

R ¹¹ is a hydroxyl group (-OH);

Ring B is

In one plan,

-L- is -L ₁ -X ₇ -, where L ₁ is T is 3; K is 0 or 1;

G is

In compound X, -X ₁ - is

^R3 is a 3-6 membered heterocycloalkylene group, wherein the heteroatoms of the 3-6 membered heterocycloalkylene group are selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

-X ₂ - is -X _2-1 -Y ₁ -; -X _2-1 - is a chemical bond; Y ₁ is

-X ₃ - is -X _3-1 -Y ₂ -; -X _3-1 - is a chemical bond; Y ₂ is

R ⁵ is a C ₁ ～C ₄ alkyl group substituted by 1 or 2 R ^5-1 ; each R ^5-1 is independently a C ₆ ～C ₁₀ aryl group;

-X ₄ - is a chemical bond, or -Y _2b -Lys-Y ₃ -, L ₂ is -(O-CH ₂ CH ₂ ) _j -, q is 1, and j is an integer of 0-10;

-Y _2b - is a chemical bond;

-Y ₃ - for L ₅ is C ₁ -C ₆ alkylene, q3 is 0, 1 or 2;

-X ₅ - for ^R7 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

-X ₇ - for _L7 and _L8 are each independently -(O- _{CH2CH2 ) j''} , q5 and q6 are each independently 1 or 2, j''' is an integer of 0-10;

W is -NH-CO-;

R ⁸ is a linear C _1-10 alkyl group;

R ⁹ is

R ¹⁰ is a hydroxyl group (-OH) or a chemical bond;

R ¹¹ is a hydroxyl group (-OH);

Ring B is

In one embodiment, -X ₁ - is Preferably, -X ₁ - is in Connected to -X ₅ -.

In one embodiment, -X ₂ - is Preferably, -X ₂ - is in Connected to -X ₅ -.

In one embodiment, -X ₃ - is Preferably, -X ₃ - is in With carbonyl ( connected to the carbonyl group.

In one embodiment, -X ₅ - is Preferably, -X ₅ - is in Connected to _X2 .

In one embodiment, ring B is

In one embodiment, R ⁸ is a linear C _1-10 alkyl group.

In one plan, for

In one embodiment, R ¹⁰ is a hydroxyl group or a chemical bond.

In one embodiment, -X ₄ - is or chemical bonds;

Preferably,

-X ₄ - for or chemical bonds, where With NH( -NH-) connected, Connected to G.

In one embodiment, -X ₇ - is or chemical bonds;

Preferably, -X ₇ - is or chemical bonds, where Connected to _L2 .

In one scheme, -LG is

In one embodiment, the compound MLG is any of the following compounds:

The present invention provides a cyclic polypeptide compound A, which is a compound formed by ion chelation of the above-mentioned compound M-L-G and a therapeutic radionuclide.

In some embodiments, the therapeutic radionuclide is ¹⁷⁷ Lu, ⁹⁰ Y, ⁸⁹ Sr, ¹⁸⁸ Re, ²²⁵ Ac, ²¹³ Bi or ²¹² Pb.

In some embodiments, the valence state of the ion containing the therapeutic radionuclide is monovalent, divalent, trivalent, or tetravalent, such as trivalent.

In some embodiments, the therapeutic radionuclide-containing ion is ¹⁷⁷ Lu ³⁺ , ²²⁵ Ac ³⁺ , ⁹⁰ Y ³⁺ , ²¹² Pb ²⁺ or ²¹³ Bi ³⁺ , such as ¹⁷⁷ Lu ³⁺ .

In some embodiments, the cyclic polypeptide compound A is a compound formed by chelating compound MLG with ¹⁷⁷ Lu ³⁺ . The structure of the compound MLG is as described above.

The present invention also provides a cyclic polypeptide compound B, which is a compound formed by ion chelation of compound M-L-G and a diagnostic radionuclide, and the structure of the compound M-L-G is as described above.

In some embodiments, the diagnostic radionuclide is ¹⁸ F, ⁶⁸ Ga, ¹¹¹ In, or ⁶⁴ Cu.

In some embodiments, the valence state of the diagnostic radionuclide-containing ion is monovalent, divalent, trivalent, or tetravalent, such as trivalent.

In some embodiments, the diagnostic radiometal-containing ion is ⁶⁸ Ga ³⁺ or ⁶⁴ Cu ²⁺ .

In some embodiments, the cyclic polypeptide compound B is a compound formed by chelating compound MLG with ⁶⁸ Ga ³⁺ , and the structure of compound MLG is as described above.

The present invention also provides a pharmaceutical composition, which comprises a substance Y and a pharmaceutical excipient, wherein the substance Y is the above-mentioned cyclic polypeptide compound A or the above-mentioned cyclic polypeptide compound B.

The present invention also provides a use of the above-mentioned cyclic polypeptide compound A in the preparation of a drug for treating tumors. The tumor may be a FAP-related tumor, such as breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, prostate cancer, liver cancer or skin melanoma. Preferably, the tumor may be a solid tumor positive for FAP expression, such as breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, prostate cancer, liver cancer or skin melanoma.

The present invention also provides a use of the above-mentioned cyclic polypeptide compound B in the preparation of a drug for diagnosing a tumor. The tumor may be a FAP-related tumor, such as breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, prostate cancer, liver cancer or skin melanoma. Preferably, the tumor may be a solid tumor positive for FAP expression, such as breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, prostate cancer, liver cancer or skin melanoma.

Unless otherwise specified, the terms used in the present invention have the following meanings:

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 the 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. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like. When the 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. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, sulfates, methanesulfonates, acetates, trifluoroacetates, and the like. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002).

the term Both said

The term "alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., _C1 - _C40 , _C1 - _C20 , _C1 - _C4 , or _C1 - _C6 ). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and the like.

The term "alkylene" is a divalent group which is attached to the rest of the molecule by two single bonds and has the same definition as the term "alkyl".

The term "cycloalkyl" refers to a saturated, carbon-containing group having a specified number of carbon atoms (e.g., C ₃ to C ₈ or C ₃ to C ₆ ) Cyclic groups are monocyclic, bridged or spirocyclic. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term "cycloalkylene" is a divalent group which is attached to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term "cycloalkyl".

The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3 to 10 or 3 to 6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom type (one or more of N, O, and S), which is a monocyclic, bridged, or spirocyclic ring, and each ring is saturated. Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, azocyclopentane, azocyclohexane, and the like.

The term "heterocycloalkylene" is a divalent group which is attached to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term "heterocycloalkyl".

The term "aryl" refers to a cyclic group consisting of only carbon atoms, having a specified number of carbon atoms (e.g., C ₆ to C ₁₀ ), which is a single ring or a condensed ring, and at least one ring is aromatic (in accordance with Huckel's rule). The aryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Aryl groups include, but are not limited to, phenyl, naphthyl, etc.

The term "arylene" is a divalent group which is attached to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term "aryl".

The term "heteroaryl" refers to a cyclic group with a specified number of ring atoms (e.g., 6-12 members, 6-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), which is a single ring or a condensed ring, and at least one ring is aromatic (in accordance with Huckel's rule). The heteroaryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring in a condensed ring. Heteroaryl includes, but is not limited to, pyridyl, pyrimidinyl, indolyl, wait.

The term "heteroarylene" is a divalent group which is attached to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term "heteroaryl".

In the structure fragment It means that the structural fragment is connected to other fragments in the molecule through this site. For example, It refers to cyclohexyl.

The term "pharmaceutical excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

The term "therapeutically effective amount" refers to the amount of a compound administered to a patient that is sufficient to effectively treat a disease, a radiation dose. The therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

The term "patient" refers to any animal that has been or is about to be treated, preferably a mammal, most preferably a human. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

The term "treat" refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that leads to a disease; or (3) slowing the progression of one or more biological manifestations of a disease.

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive progressive effect of the present invention is that the present invention provides a class of cyclic polypeptide compounds with high affinity for FAP, which can be used for the diagnosis and treatment of FAP-related or mediated tumors, have high tumor uptake and long retention time, and have broad application prospects.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the competitive binding of compounds to cells

Figure 2 shows the results of the hydrophilicity and lipophilicity test of the compounds.

Figure 3 shows the binding rate of the compound to plasma protein

FIG4 shows the biodistribution of ¹⁷⁷ Lu-labeled compounds in tumor-bearing mice.

Figure 5 shows the PET/CT images of ⁶⁸ Ga-JHDD12 in tumor-bearing mice

Figure 6 shows the PET/CT images of ⁶⁸ Ga-JHDD13 in tumor-bearing mice

Figure 7 shows the PET/CT images of ⁶⁸ Ga-JHDD14 in tumor-bearing mice

FIG8 shows the inhibition of tumor growth by ¹⁷⁷ Lu-labeled compounds in a tumor-bearing mouse model.

FIG. 9 shows the effect of ¹⁷⁷ Lu-labeled compounds on body weight in a tumor-bearing mouse model.

DETAILED DESCRIPTION

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

Structural abbreviations:

Natural amino acid abbreviations:

Unnatural amino acid abbreviation

Intermediate Abbreviation

Chelating Group Abbreviation:

The above chelating group is connected to L via a carbonyl group (CO) through an amidation reaction, for example, via an amide group. The amino acid skeleton sequence of the compound in the embodiment is as follows:

Example 1 Compound Synthesis

General synthesis method:

Taking JHDD01 as an example, it was prepared by a combination of solid phase and liquid phase methods:

1. Use CTC resin (SUNRESIN), HOBt+DIC, and solid phase Fmoc synthesis method to first connect the Fmoc-protected aspartic acid derivative (CAS: 283170-10-5) from the C-terminus, then use Fmoc synthesis method to connect each amino acid (3.0 equivalents) in turn, and use n-hexanoic acid to cap the N-terminus, then remove all protecting groups on aspartic acid carboxylic acid, and couple PEG and OncoFAP (1.5-2.0 equivalents) fragments in turn to complete the condensation reaction, wash with MeOH several times, and drain to obtain 1.5g of resin; then use 15mL of cutting solution (87.5% TFA/7.5% DTT/2.5% TIS/2.5% H2O) for 3 h; after filtration, the cleavage solution was added to 80 mL of ice isopropyl ether to precipitate the solid, centrifuged (3000 r), the supernatant was poured out, and the solid was dried to obtain the crude naked peptide product A (250 mg);

2. Dissolve the crude naked peptide A (250 mg crude product) in 300 mL water/acetonitrile, then add 1,3,5-(tribromomethyl)benzene (54.4 mg 1.3 eq.), stir for 10 minutes, then add saturated NH ₄ HCO ₃ to adjust the pH of the solution to 8, react for 3 hours, then add mercaptoethylamine hydrochloride (CAS: 156-57-0, 117.5 mg 10.0 eq.), react for 30 minutes, LCMS detection, the raw material is completely consumed, MS shows that the cyclized product is generated, and after freeze-drying, it is purified by medium pressure liquid chromatography (Biotage) to obtain product B (50 mg).

3. Reaction: Fmoc-protected ATTDA (CAS: 437655-95-3, 50 mg) and HATU (19.84 mg, 1.5 eq.) were added to 0.2 mL DMF, followed by addition of DIEA (18.45 uL, 4.0 eq.) for activation for 10 min, and addition of compound B (50.0 mg). The reaction was allowed to proceed for 1 hour, and the reaction was complete as detected by LCMS. Compound C was generated, and the product compound C (20 mg) was obtained by flash purification.

4. Reaction: Compound C (20 mg) was dissolved in 20% TEA/DMF and reacted for 3 hours. LCMS detected that the reaction was complete, i.e., the Fmoc protecting group was completely removed. Compound DOTA-NHS ester (6.7 mg, 1.5 eq.) was directly added and reacted for 1 hour. LCMS detected again that the de-Fmoc-protected compound C was completely consumed and JHD00120 was generated. After preparation and purification, the product JHDD01 (8.19 mg) was obtained.

General preparative liquid purification method:

Chromatographic column: Bonnasil-BS C18 (21.2 x 250mm, 5m)

Mobile phase: H ₂ O (0.01% TFA) (A)/acetonitrile (0.01% TFA) (B)

Flow rate: 10mL/min

Detection wavelength: 220nm

Elution program: 15-45% B, 0-60 min.

Analysis Method 1:

Chromatographic column: Shim-pack VP-ODS, (4.6×150mm, 5μm)

Mobile phase: H ₂ O (0.01% TFA) (A)/acetonitrile (0.01% TFA) (B)

Flow rate: 1.0mL/min

Elution program: gradient from 10% to 40% of B at 1.0 mL/min in 20 min, followed by gradient from 40% to 70% of B from 20 to 24 min, gradient from 70% to 10% of B from 24 to 24.1 min, maintain 10% of B from 24.1 to 30 min.

Column temperature: 30°C

Detection: UV (214, 4 nm).

Analysis Method 2:

Chromatographic column: XBridge Peptide BEH C18, (4.6*150mm, 3.5μm)

Mobile phase: A: 0.05% TFA in water, B: 0.05% TFA in ACN

Elution program: 5% B for 1min, 5-65% B within 20min

Flow rate: 1.0mL/min

Column temperature: 40℃

Detection wavelength: 220nM.

Analysis Method 3:

Chromatographic column: Phenomenex Luna 3u C18(2), (4.6*150mm*3um)

Mobile phase: A: 0.1% TFA in 100% water, B: 0.1% TFA in 100% acetonitrile

Flow rate: 0.8mL/min

Detection wavelength: 220nm

Elution program: 15% B, 0.01 min; 15-60% B, 0.01-25.0 min; 60-90% B, 25-30 min.

Analysis Method 4:

Chromatographic column: SHIMADZU Inertsil ODS-SP (4.6*250mm*5um)

Mobile phase A: 0.1% TFA in 100% Water, B: 0.1% TFA in 100% Acetonrtrile

Flow rate: 1mL/min

Detection wavelength: 220nm

Elution program: B: 20%, 0 min; B: 20-80%, 0-25 min; B: 100%, 25.01-30 min.

Analysis Method 5:

Chromatographic column: SepaxGP-C18 (4.6*150mm*5um)

Mobile phase A: 0.1% TFA in 100% Water, B: 0.09% TFA in (80% Acetonrtrile/20% Water)

Flow rate: 1mL/min

Detection wavelength: 220nm

Elution program: B: 39-49% 0-20 minutes.

Analysis Method 6:

Chromatographic column: SHIMADZU Inertsil ODS-SP (4.6*250mm*5um)

Mobile phase A: 0.1% TFA in 100% Water, B: 0.1% TFA in 100% Acetonrtrile

Flow rate: 1mL/min

Detection wavelength: 220nm

Elution program: B: 25% 0 min; B: 25-65% 0-20 min; B: 100%, 20.01-23 min; B: 100%, 23-38 min; B: 100-25%, 38-40 min.

The following compounds were synthesized using the general synthetic method described above.

JHDD01 Hex-[Cys(tMeBn-(DOTA-ATTDA-AET))]-hhy39-Pro-Thr-Gln-Phe-Cys-Asp[DAPEG4-(Onco-FAP)]-OH Synthesis method 2, analysis method 1

JHDD02 Hex-[Cys(tMeBn(AET)Lys(APA-DOTAGA)-OncoFAP)-Pro-Pro-Thr-Gln-Phe-Cys]-OH Synthesis method 2, analysis method 1

JHDD03 Hex-[Cys(tMeBn(AET-AEEAA)Lys(APA-DOTAGA)-OncoFAP)-Pro-Pro-Thr-Gln-Phe-Cys]-OH Synthesis method 2, analysis method 1

JHDD04 Hex-[Cys(tMeBn(AET-ATTDA)lys(APA-DOTAGA)-OncoFAP)-Pro-Pro-Thr-Gln-Phe-Cys]-OH Synthesis method 2, analysis method 1

JHDD05 Hex-[Cys(tMeBn(AET-AHLA)Lys(APA-DOTAGA)-OncoFAP)-Pro-Pro-Thr-Gln-Phe-Cys]-OH Synthesis method 2, analysis method 1

JHDD06 Hex-[Cys(tMeBn(AET-APTA)Lys(APA-DOTAGA)-OncoFAP)-Pro-Pro-Thr-Gln-Phe-Cys]-OH Synthesis method 2, analysis method 1

JHDD07 Hex-[Cys(tMeBn(AET-SA)Lys(EDA-DOTAGA)-OncoFAP)-Pro-Pro-Thr-Gln-Phe-Cys]-OH Synthesis method 2, analysis method 1

JHDD08 Hex-[Cys(tMeBn(DOTA-AET)-Pro-Pro-Thr-Gln-Phe-Cys]-Lys-(AHLA-OncoFAP)-OH Synthesis method 2, analysis method 1

JHDD09 Hex-[Cys(tMeBn(DOTA-AET)-Pro-Pro-Thr-Gln-Phe-Cys]-Lys-(ATTDA-OncoFAP)-OH Synthesis method 2, analysis method 1

JHDD10 Hex-[Cys(tMeBn(DOTA-AET)-Pro-Pro-Thr-Gln-Phe-Cys]-Lys-(AEEAA-OncoFAP)-OH Synthesis method 2, analysis method 1

JHDD11 Hex-[Cys(tMeBn(DOTA-AET)-Pro-Pro-Thr-Gln-Phe-Cys]-Lys-(OncoFAP)-OH Synthesis method 2, analysis method 1

JHDD12 Hex-[Cys(tMeBn(DOTA-AET)-Pro-Pro-Thr-Gln-Phe-Cys]-Lys-(SA-hhy52-Gly-DFCP)-OH Synthesis method 2, analysis method 1

JHDD13 nBu-urea-[Cys(tMeBn(DOTA-AET)-Pro-Pro-Thr-Gln-Phe-Cys]-Lys-(SA-hhy52-Gly-DFCP)-OH Synthesis method 2, analysis method 1

JHDD14 nBu-urea-[Cys(tMeBn(DOTA-AET)-hhy39-Pro-Thr-Gln-Phe-Cys]-Glu-(EDA-SA-hhy52-Gly-DFCP)-OH Synthesis method 2, analysis method 1

The HPLC peak time and mass spectrum of the above compounds are shown in Table 1.

Table 1

Example 2: Cold labeling of compound ¹⁷⁵ Lu: Taking JHDD14 as an example,

Accurately weigh 2.66 mg of the precursor JHDD14 and dissolve it in 1.9 mL of sodium acetate buffer (pH: 5.0), and add 100 uL of lutetium chloride aqueous solution (50 mg/mL). Place the solution in a reactor at 95 degrees to react for 20 minutes. After the reaction solution is cooled, it is purified by prep-HPLC (15-45%, acetonitrile/water) to obtain a white solid product (1.5 mg), HPLC: 11.21 min, 99.83% purity; MS: [M/2+H] ⁺ :895.95.

Example 3: Testing of compound affinity:

The Biacore 8K (Cytiva) instrument was used to detect ligand binding of FAP protein (Sinobiological). FAP protein was captured on SA chip. Before ligand immobilization (flow path 1, 2, flow rate 10 μL/min), FAP protein was immobilized on flow path 2 with flow buffer (10 μg/mL, flow rate 5 μL/min, injection time 600 s), and the sensor surface was conditioned by three consecutive injections of 1 M NaCl in 50 mM NaOH. After each ligand injection, an additional wash with isopropanol in 1 M NaCl and 50 mM NaOH was included (flow path 1, 2, flow rate 10 μL/min, injection time 60 s).

The test compounds were dissolved in 100% dimethyl sulfoxide and diluted to 10 mM, then diluted to the appropriate maximum concentration in assay buffer (PBS, pH 7.4, 1 mM TCEP (tris-(2-hydroxyethyl)phosphine), 0.05% P20, 2% dimethyl sulfoxide). The analytes were run using the following conditions: 15°C assay temperature, assay steps = all set to LMW kinetics; cycle type = single cycle (90 s contact time, 1800 s separation time, 30 uL/min flow rate, channels 1, 2); channel detection = 2-1). Data were evaluated using Biacore Insight evaluation software and fit the 1:1 binding model.

The Biacore results are shown in Table 2 below: pK _D = -LogK _D , where K _D is the binding affinity of the compound to the FAP protein measured by Biacore. It is expressed as K _D (M) = K _d (1/s)/ _Ka (1/Ms). Among them, A: pK _D >8, B: 7<pK _D <8, C: 6<pK _D <7, D: pK _D <6.

In addition, FAPi-46 (CAS: 2374782-04-2) and FAP-2286 (CAS: 2581741-18-4) were used as positive reference compounds.

Example 4: Determination of compound selectivity:

The specificity of the synthesized compounds against recombinant human dipeptidyl peptidase IV (DPPIV), fibroblast activation protein (FAP) or proline oligopeptidase (PREP) is expressed by its half-inhibitory concentration IC ₅₀ for inhibiting protease. The specific steps are:

1) The synthesized compound was dissolved in DMSO to a final concentration of 100 mM.

a) For FAP assay: dilute the test compound to a 1 mM solution using 50 mM Tris, 140 mM NaCl buffer, pH 7.5;

b) For DPPIV test: dilute the test compound to a 1 mM solution using 25 mM Tris, 250 mM NaCl buffer, pH 7.5;

c) For PREP testing: dilute the test compound to a 1 mM solution using 140 mM NaCl buffer, pH 8.0.

2) The 1 mM test compound solution prepared above was serially diluted (1:10) using the corresponding buffer described above and placed on one row of a 96-well plate.

3) Prepare the substrates as DMSO stock solutions (FAP and PREP: 2.5 mM Z-Gly-Pro-AMC (VWR, catalog number I-1145.0050BA) in DMSO; DPPIV: 100 mM Gly-Pro-AMC (VWR, catalog number 100042-646) in DMSO), and then dilute the substrate stock solutions 20-fold using the corresponding buffer dilutions mentioned above.

4) Dilute the enzyme into the appropriate assay buffer. The final enzyme concentrations for DPPIV, FAP, and PREP should be 0.1, 1.2, and 0.6 nM, respectively. Add 180 μl to each of the desired wells in columns 2-10, respectively. Column 1 (A, B, C) should be prepared with 200 μl of the appropriate assay buffer as a control. Column 1 (D, E, F, G, H) should be prepared with 20 μl of the appropriate assay buffer and 180 μl of enzyme as a no inhibitor control.

5) Where appropriate, add 20 microliters of test compound from the dilution plate prepared in step 2 to columns 2-10 of the assay plate. Each sample should be tested in triplicate. Allow to incubate at room temperature for 10 minutes, shaking the plate for the first two minutes.

6) Add 10 μl of the 20x matrix prepared in step 3 to each well and allow to incubate at room temperature for 15 minutes, shaking the plate for the first two minutes.

7) Read the fluorescence at λex:380, λem:460.

The results of the above tests show that the synthesized compound has good selectivity for FAP.

Where, pIC ₅₀ = -Log(IC ₅₀ ), A: pIC ₅₀ >8, B: 7<pIC ₅₀ <8, C: 6<pIC ₅₀ <7, D: pIC ₅₀ <6

Table 2

“-” means not tested.

Example 5: Thermal labeling of compound ¹⁷⁷ Lu

1. Weigh the precursor compound (1 mg) and dissolve it in 0.45 M ascorbic acid buffer, pH 4.5, to a 0.1 mg/mL solution.

2. Labeling according to nuclide: precursor = 1:7-10 (molar ratio): 2mCi ¹⁷⁷ LuCl ₃ and the amount of precursor calculated according to the real-time specific activity were added to the labeling buffer (0.5M pH 4.0 ascorbic acid buffer) system to make the reaction system volume 0.15mL.

3. Incubate the mixture at 95°C for 30 minutes on a thermostatic heater. After the reaction is complete, perform iTLC and Radio-HPLC on the product.

4. iTLC developing agent: 1% EDTA, stationary phase: silica gel 254, developing to 1 cm above the stationary phase, takes about 20 minutes, and the sample volume is 0.5 μL.

5. If the results of iTLC and Radio-HPLC reach 95%, the labeled product is considered qualified.

6. Transfer the reaction solution to a vial, wash the reaction tube with 0.15 mL of saline, and add the washing solution to the vial.

7. Add 6.7 μL DTPA solution (0.25 mM), mix well and set aside. Add 1.0 mg DTPA to 10 mL saline to prepare DTPA stock solution (concentration is 0.25 mM), mix well and set aside.

The final preparation should be a clear solution and should be used immediately upon preparation and only on the same day.

Example 6: Compound Cell Binding Assay

(1) HT1080 8# cells (Suzhou Jinweizhi Biotechnology Co., Ltd.) in the logarithmic growth phase were prepared into a cell suspension, the cell density was adjusted to 1×10 ⁴ /mL, and 1 mL was inoculated into a 24-well cell culture plate and cultured in a 37°C incubator overnight.

(2) Aspirate the cell culture medium, wash the cells once with PBS, and add 975uL of culture medium without additives.

(3) Add 25 μL of a fixed concentration of radioactive ¹⁷⁷ Lu-labeled FAPi-46 (CAS: 2374782-04-2) ligand (final concentration in culture medium: 1.35 μCi/ml) and different concentrations of unlabeled test compounds (final concentration in culture medium: 1000 ng/mL, 100 ng/mL, 10 ng/mL, 1 ng/mL, 0.1 ng/mL, 0.01 ng/mL, 0.001 ng/mL, 0 ng/mL) to each well.

(4) Incubate on ice for 2 hours.

(5) Wash the cells three times with ice-cold PBS.

(6) The cells were lysed with 0.5 mL 1 M sodium hydroxide, washed twice with 0.5 mL PBS, and the sodium hydroxide (0.5 mL) and PBS (0.5 mL × 2) solutions were collected to measure the uptake counts. The results are shown in Table 3 and Figure 1.

Table 3. Compound cell binding assay results

Example 7: Determination of ClogP

Take a certain amount of the following ¹⁷⁷ Lu-labeled compound solutions, add ultrapure water and mix well, and then measure the activity after mixing.

Take 2 EP tubes and add 100 μL saturated n-octanol aqueous solution and 80 μL pure water respectively, add 20 μL of the above ¹⁷⁷ Lu labeled compound solution to each tube, shake and mix for 2 hours, centrifuge at room temperature, 2000 rpm/min, 5 minutes, take 20 μL from the upper layer (lipid layer) and lower layer (water layer) of each tube, and measure the gamma count. The results are shown in Table 4 and Figure 2.

Table 4. Lipophilicity and Hydrophilicity Ratio (ClogP) of Compounds

Example 8: Binding rate of labeled compound to plasma protein

Take 1μCi of the labeled ¹⁷⁷ Lu-labeled compound and add 50μL PBS to obtain a 20μCi/mL reaction solution. Take 50μL of the 20μCi/mL reaction solution and add it to 200μL plasma, mix well and incubate at room temperature for 10min, then add the sample to a 30K ultrafiltration tube (PALL), centrifuge at 13000rpm for 45min, then add 50μL of physiological saline, continue centrifugation for 15min, and count the cannula and filtrate separately.

PPB = [(upper layer count - background count)] / (lower layer count + upper layer count - 2 * background count)] * 100%. The results are shown in Figure 3 and Table 5.

Table 5. Binding rate of compounds to plasma proteins

Example 9: Biodistribution of ¹⁷⁷ Lu-labeled compounds in tumor-bearing mice

Tissue distribution of FAP-positive tumor-bearing mice: 6-9 week old (Balb/c Nude) mice were subcutaneously inoculated with 2x10 ⁶ cells of HT1080 2#FAP (in 50% Matrigel, Corning) on the right shoulder of the animal. When the tumor grew to a size of about 150-350 mm ³ , the ¹⁷⁷ Lu radiolabeled compound was injected into the tail vein of the mouse (about 3.7 MBq/mouse). The animals were euthanized by carbon dioxide inhalation 24 hours after administration, and the blood and organs (liver, kidney, muscle tumors) of the animals were collected after euthanasia.

Blood was collected through the inferior vena cava, and 100 μL was immediately quantified into a designated centrifuge tube (weighed). After the organ was collected, it was washed twice with deionized water and wiped dry, placed in a pre-weighed test tube, weighed again, and the sample weight was calculated. The sample was measured on the day of collection. All blood samples and tissue samples were measured for radioactivity counts using a gamma counter. The results of the tissue distribution test are shown in Table 5, Table 6 and Figure 4.

Table 5. Distribution of compounds in tumor-bearing mice (@24h, %ID/g)

Table 6. Distribution of compounds in tumor-bearing mice (@24h, %ID/g)

Example 10: Imaging results of ⁶⁸ Ga-labeled compounds in tumor-bearing mice

A. JHD compound was dissolved in ascorbic acid buffer to prepare a solution with a concentration of 0.1 mg/mL.

B. Use 5 mL 0.1 M HCl to wash the germanium gallium generator in sections, take the part with the highest activity (0.5 mL), add 0.5 mL of pH = 4.5 metal-free 0.1 M sodium ascorbate buffer, use a 1.5 mL centrifuge tube as a reaction tube, add a certain amount of precursor [1000 (molecular weight) / 14.94 μL (precursor solution) / mCi (nuclide)], vortex mix for 10 seconds, and heat at 95 ° C 800 rpm for 15 minutes;

C. The C18 column is activated with anhydrous ethanol and then rinsed with pure water and dried;

D. Pass the solution after the reaction through a C18 column, rinse with pure water and dry, then rinse with 3 drops of ethanol and connect one tube, for a total of about 10 tubes.

E. The final preparation should be a clear solution and should be used immediately after preparation and only on the same day.

PCT/CT scan

1) Turn on the machine according to the PET/CT operating procedures, open the scanning software, and perform daily calibration;

2) Animal anesthesia preparation: tumor-bearing mice were anesthetized with isoflurane;

3) After the righting reflex of the tumor-bearing mice disappears, the imaging agent is injected into the tail vein;

4) Perform dynamic scanning for 10 minutes at 1 hour and static scanning for 3 hours after drug administration;

5) During the process, record the animal weight, injection dose, injection time, and residual dose according to the record sheet, and record the injection dose measurement time and residual dose measurement time respectively;

6) Use PMOD software to capture animal tumors, muscles and other organs.

The PET-CT results showed that after the ^68Ga -labeled compound was injected into the tail vein of tumor-bearing mice, it could be rapidly distributed to various organs and tumors of the animals and rapidly metabolized out of the body through the kidneys. The uptake of the labeled compound in the tumor changed over time and showed a higher uptake in the tumor. The results are shown in Tables 7-11 and Figures 5, 6 and 7.

Table 7. Distribution changes of ⁶⁸ Ga-labeled compounds in mouse heart over time

Table 8. Distribution changes of 68Ga labeled compounds in mouse liver over time

Table 9. Distribution changes of ⁶⁸ Ga labeled compounds in mouse kidneys over time

Table 10. Distribution changes of ⁶⁸ Ga labeled compounds in mouse muscle over time

Table 11. Distribution changes of ^68Ga labeled compounds in mouse tumors over time

Example 11: Treatment results of ¹⁷⁷ Lu-labeled compounds in tumor-bearing mice

6-8 weeks old (Balb/c Nude) mice were inoculated subcutaneously with 2x10 ⁶ cells of HT1080 2# (50% Matrigel, Corning) on the right shoulder blade of the animal. When the tumor grows to the size required by the experiment, the animals are randomly assigned to 13 experimental groups according to the tumor volume, with 5 animals in each group. The weight and tumor size of the animals are measured. On the day of grouping, the control group (normal saline) and groups 1-12 start to be administered. After the start of the experiment, general health and appearance observations are performed every day, and the weight and tumor size of the animals are measured before each sample sampling time point. Any abnormal observations found during the entire study will need to be recorded in the original data.

The experimental results are shown in Table 12, Table 13 and Figures 8 and 9.

Table 12. Uptake of labeled compounds in tumors over time after injection of 200 μCi/400 μCi ¹⁷⁷ Lu labeled compounds

Table 13. Changes in animal body weight over time after injection of ¹⁷⁷ Lu-labeled compounds

The experimental results showed that the synthesized ¹⁷⁷ Lu-labeled compounds inhibited tumor growth over time after being injected into tumor-bearing mice via the tail vein, and compared with the reference compounds, at the same dose, the synthesized compounds had better effects than the reference compounds.

Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the protection scope of the present invention is limited by the attached claims.

Claims (18)

1. A compound MLG or a pharmaceutically acceptable salt thereof
   MLG;

   Wherein, M is compound X;
   

   -L- is a chemical bond or -L ₁ -X ₇ -, wherein L ₁ is T is 0, 1, 2, 3 or 4; K is 0, 1, 2, 3 or 4;

   G is

   -X ₁ - for

   R ¹ is C ₁ ～C ₄ alkylene, C ₃ ～C ₆ cycloalkylene, C ₁ ～C ₄ alkylene- _{C 3} ～C ₆ cycloalkylene, or C ₁ ～C ₄ alkylene substituted by 1 or 2 R ^1-1 ;

   Each R ^1-1 is independently a C ₁ ～C ₄ alkyl group, a C ₃ ～C ₆ cycloalkyl group, or a C ₁ ～C ₄ alkyl group substituted by one or two R ^1-1-1 ;

   Each R ^1-1-1 is independently a C ₁ ～C ₄ alkyl group or a C ₃ ～C ₆ cycloalkyl group;

   R ² is hydrogen or C ₁ ～C ₄ alkyl;

   ^R3 is _C1 - _C4 alkylene-3-6 membered heterocycloalkylene, 3-6 membered heterocycloalkylene or 6-12 membered heteroarylene; the heteroatoms of the 3-6 membered heterocycloalkylene are selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and at least one N is contained; the heteroatoms of the 6-12 membered heteroarylene are selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and at least one N is contained;

   ^R4 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

   -X ₂ - is -X _2-1 -Y ₁ -; -X _2-1 - is a chemical bond, an unnatural amino acid or a natural amino acid; Y ₁ is

   -X ₃ - is -X _3-1 -Y ₂ -; -X _3-1 - is a chemical bond, a non-natural amino acid, a natural amino acid, or a natural amino acid in which N is substituted with a C ₁ ～C ₄ alkyl group; Y ₂ is

   R ⁵ is C ₁ ～C ₄ alkyl or C ₁ ～C ₄ alkyl or C ₃ ～C ₆ cycloalkyl substituted by 1 or 2 R ^5-1 ; each R ^5-1 is independently C ₃ ～C ₆ cycloalkyl, C ₆ ～C ₁₀ aryl or C ₆ ～C ₁₀ aryl substituted by 1 or more R ^5-1-1 ; each R ^5-1-1 is independently halogen;

   -X ₄ - is a chemical bond, or -Y _2b -Lys-Y ₃ -, L ₂ is C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j -, q is 0, 1, 2, 3 or 4, and j is an integer of 0-10;

   -Y _2b - is a chemical bond, L ₃ and L ₄ are each independently C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j'- , q1 and q2 are each independently 0, 1, 2, 3 or 4, and j' is each independently an integer of 0-10;

   -Y ₃ - is a chemical bond, L ₅ and L ₆ are each independently C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j" -, q3 and q4 are each independently 0, 1, 2, 3 or 4, and j" is each independently an integer of 0-10;

   -X ₅ - for ^R7 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

   -X ₇ - is a chemical bond, L ₇ and L ₈ are each independently C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j'' , q5 and q6 are each independently 0, 1, 2, 3 or 4, j''' is an integer of 0-10; W is -NH-CO- or -NH-CO-NH-;

   R ⁸ is a linear C _1-10 alkyl group;

   R ⁹ is NOTA, HBED-CC, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA or DEDPA;

   R ¹⁰ is a hydroxyl group or a chemical bond;

   R ¹¹ is hydroxyl or amino;

   Ring B is

   The compound M-L-G satisfies any of the following conditions:

   (1) When R ¹⁰ is a hydroxyl group, L is a chemical bond, and G is connected to -X ₄ -;

   (2) When R ¹⁰ is a chemical bond, -LG is -L ₁ -X ₇ -G, and -L ₁ - is connected to the carbonyl group.
2. The compound M-L-G or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound M-L-G satisfies one or more of the following conditions:

   (1) In ^R1 and ^R3 , the _C1 - _C4 alkylene groups are each independently methylene, ethylene, n-propylene or isopropylene;

   (2) In -L ₂ -, -L ₃ -, -L ₄ -, -L ₅ -, -L ₆ -, -L ₇ - and -L ₈ -, the C ₁ -C ₆ alkylene groups are each independently straight-chain C ₁ -C ₆ alkylene groups, such as methylene, ethylene, n-propylene, n-butylene or n-pentylene;

   (3) In R ¹ , the C ₃ -C ₆ cycloalkylene groups are each independently cyclopropylene, cyclobutylene or cyclopentylene;

   (4) In each of R ^1-1 , R ^1-1-1 , each of R ² _, -X ₃ - and R ⁵ , the C ₁ -C ₄ alkyl group is independently methyl, ethyl, n-propyl or isopropyl, for example methyl;

   (5) In each of R ^1-1 , R ^1-1-1 , R ⁵ and R ^5-1 , the C ₃ to C ₆ cycloalkyl group is independently a cyclobutane group, a cyclopentane group or a cyclohexane group;

   (6) In R ³ , the 3-6 membered heterocycloalkylene group is each independently a 4-6 membered heterocycloalkylene group, in which the heteroatom is preferably N, and the number of heteroatoms is preferably 1, for example, the 3-6 membered heterocycloalkylene group is an azetidinylene group or an azetidinylene group, and the azetidinylene group is, for example, The azacyclopentylene group is, for example,

   (7) In R ³ , the 6-12 membered heteroarylene group is a 6-10 membered heteroarylene group, in which the heteroatom is preferably N, and the number of heteroatoms is preferably 1;

   (8) In R ⁴ , the 3-6 membered heterocycloalkylene groups are each independently 4-6 membered heterocycloalkylene groups, and in the 3-6 membered heterocycloalkylene groups, the heteroatom is preferably N, and the number of heteroatoms is preferably 1;

   (9) -X _2-1 -, the non-natural amino acid residue is or a D-alanine group, such as

   (10) In -X _2-1 -, the natural amino acid residue is a glycine group or an L-alanine group. The glycine group is, for example, The L-alanine group is, for example,

   (11) -X _3-1 -, the non-natural amino acid residue is

   (12) -X _3-1 -, the natural amino acid residue is glycine or phenylalanine. For example, the natural amino acid residue is glycine. For example, The phenylalanine group is, for example,

   (13) In R ^5-1 , the C ₆ -C ₁₀ aryl groups are each independently phenyl or naphthyl, for example phenyl;

   (14) In R ^5-1-1 , the halogen is fluorine, chlorine or bromine;

   (15) In ^R7 , the 3-6 membered heterocycloalkylene group is each independently a 4-6 membered heterocycloalkylene group, in which the heteroatom is preferably N, and the number of heteroatoms is preferably 1. For example, the 3-6 membered heterocycloalkylene group is an azacyclopentylene group, and the azacyclopentylene group is, for example,

   (16) In R ⁸ , the C _1-10 alkyl group is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl or n-nonyl, such as n-pentyl or n-butyl;

   (17)L ₁ for example If

   (18)L ₁ for
3. The compound M-L-G or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound M-L-G satisfies one or more of the following conditions:

   (1) -X ₄ - is *-Y _2b -Lys-Y ₃ -, for example Among them, *-end and Connected to NH, connected to G, L ₃ , L ₄ , q1, q2, q3 and q4 are each independently as described in claim 1;

   (2) -L- is *-L ₁ -X ₇ -, for example Among them, *-end and connected to the carbonyl group, T, K, R ¹¹ , q5, q6 and j'' are each independently as described in claim 1;

   (3) -X ₁ - is in Connected to X ₅ ;

   (4) -X ₂ - is -X _2-1 -Y ₁ -, wherein X _2-1 is linked to X ₅ ;

   (5) -X ₃ - is -X _3-1 -Y ₂ -, wherein X _3-1 is linked to -NH-;

   (6) -X ₄ - is a chemical bond, or *-Y _2b -Lys-Y ₃ -, wherein *- and Connected to -NH-;

   (7) -X ₅ - is in Connected to X ₂ ;

   (8) -X ₇ - are each independently a chemical bond, in Connected to L ₁ ;

   (9) W is -NH-CO-* or -NH-CO-NH-*, wherein -* is connected to R ⁸ .
4. The compound M-L-G or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound M-L-G satisfies one or more of the following conditions:

   (1) T is 3;

   (2) K is 0 or 2;

   (3) -X ₁ - is

   (4) R ³ is a 3-6 membered heterocycloalkylene group, wherein the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and at least one N is contained; for example, the 3-6 membered heterocycloalkylene group is an azetidinyl group or an aziridine group; the azetidinyl group is, for example, The azacyclopentyl group is, for example,

   (5) -X _2-1 - is a chemical bond; Y ₁ is

   (6) -X _3-1 - is a chemical bond; Y ₂ is

   (7) R ⁵ is a C ₁ -C ₄ alkyl group substituted by 1 or 2 R ^5-1 ;

   (8) _L2 is -(O- _{CH2CH2 ) j-} ;

   (9) L ₃ and L ₄ are each independently -(O-CH ₂ CH ₂ ) _j' -;

   (10) L ₅ and L ₆ are each independently C ₁ -C ₆ alkylene;

   (11) L ₇ and L ₈ are each independently -(O-CH ₂ CH ₂ ) _j"' ;

   (12) Each R ^5-1 is independently a C ₆ -C ₁₀ aryl group;

   (13)q is 1;

   (14) q1 and q2 are each independently 1, 2 or 4;

   (15) q3 and q4 are each independently 2;

   (16) q5 and q6 are each independently 1 or 2;

   (17) j'", j", j' and j are each independently an integer from 0 to 8, such as 0, 2, 3, 4 or 6;

   (18)-Y ₃ - is

   (19) R ⁹ is

   (20) R ¹⁰ is a hydroxyl group or a chemical bond;

   (21) Ring B is

   (22) R ¹¹ is hydroxyl;

   (23) G is

   (24) When -X ₄ - is -Y _2b -Lys-Y ₃ -, R ¹⁰ is a hydroxyl group, L is a chemical bond, and G is connected to -X ₄ -;

   (25) When -X ₄ - is a chemical bond, When R ¹⁰ is a chemical bond.
5. The compound M-L-G or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound M-L-G satisfies one or more of the following conditions:

   (1) L ₁ is

   (2) K is 0, 1 or 2, for example, K is 0 or 1;

   (3) -X ₄ - is a chemical bond or q is 1, L ₂ is -(O-CH ₂ CH ₂ ) _j -, for example, -X ₄ - is a chemical bond;

   Preferably, -X ₄ - is a chemical bond, -LG is -L ₁ -X ₇ -G, and L ₁ is -X ₇ - is a chemical bond or

   Alternatively, -X ₄ - is a chemical bond, -LG is -L ₁ -X ₇ -G, and L ₁ is -X ₇ - for

   (4) -X ₇ - is a chemical bond, For example, chemical bonds or Another example is _L7 and _L8 are each independently -(O- _{CH2CH2 ) j''} , q5 and q6 are each independently 1 or 2, j''' is an integer of 0-10;

   (5) -Y _2b - is a chemical bond;

   (6) -Y ₃ - is L ₅ and L ₆ are each independently C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j" -, q3 and q4 are each independently 0, 1 or 2, j" is 0, for example, -Y ₃ - is L ₅ is C ₁ -C ₆ alkylene, q3 is 0, 1 or 2;

   (7) q3 and q4 are each independently 0, 1 or 2;

   (8) R ⁹ is

   (9) R ¹⁰ is hydroxyl;

   (10) G is
6. The compound MLG or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound MLG is compound MLG-1 or compound MLG-2;
   

   -X ₁ -, -X ₂ -, -X ₃ -, -X ₄ -, -X ₅ -, R ⁹ , R ⁸ , Ring B, -L- and G are as defined in any one of claims 1 to 5.
7. The compound M-L-G or a pharmaceutically acceptable salt thereof according to claim 1 or 6, characterized in that it is any of the following schemes:

   Solution 1:

   In the compound MLG, -L- is a chemical bond or -L- is L ₁ -X ₇ -, wherein L ₁ is T is 3; K is 0 or 2;

   G is

   In compound X, -X ₁ - is

   ^R3 is a 3-6 membered heterocycloalkylene group, wherein the heteroatoms of the 3-6 membered heterocycloalkylene group are selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

   -X ₂ - is -X _2-1 -Y ₁ -; -X _2-1 - is a chemical bond; Y ₁ is

   -X ₃ - is -X _3-1 -Y ₂ -; -X _3-1 - is a chemical bond; Y ₂ is

   R ⁵ is a C ₁ ～C ₄ alkyl group substituted by 1 or 2 R ^5-1 ; each R ^5-1 is independently a C ₆ ～C ₁₀ aryl group;

   -X ₄ - is a chemical bond, or -Y _2b -Lys-Y ₃ -, L ₂ is -(O-CH ₂ CH ₂ ) _j -, q is 1, and j is an integer of 0-10;

   -Y _2b - is a chemical bond, L ₃ and L ₄ are each independently C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j'- , q1 and q2 are each independently 1, 2 or 4, and j' is each independently an integer of 0-10;

   -Y ₃ - for _L5 and _L6 are each independently _C1 - _{C6 alkylene or -(O-CH2CH2 ) j"} -, q3 and q4 are each independently 2, and j" is 0;

   -X ₅ - for ^R7 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

   -X ₇ - is a chemical bond, _L7 and _L8 are each independently -(O- _{CH2CH2 ) j''} , q5 and q6 are each independently 1 or 2, j''' is an integer of 0-10;

   W is -NH-CO- or -NH-CO-NH-;

   R ⁸ is a linear C _1-10 alkyl group;

   R ⁹ is

   R ¹⁰ is a hydroxyl group or a chemical bond;

   R ¹¹ is a hydroxyl group;

   Ring B is

   Scheme 2: The compound M-L-G is in the middle,

   -L- is a chemical bond or L ₁ -X ₇ -, wherein L ₁ is T is 3; K is 0, 1 or 2;

   G is

   In compound X, -X ₁ - is

   ^R3 is a 3-6 membered heterocycloalkylene group, wherein the heteroatoms of the 3-6 membered heterocycloalkylene group are selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

   -X ₂ - is -X _2-1 -Y ₁ -; -X _2-1 - is a chemical bond; Y ₁ is

   -X ₃ - is -X _3-1 -Y ₂ -; -X _3-1 - is a chemical bond; Y ₂ is

   R ⁵ is a C ₁ ～C ₄ alkyl group substituted by 1 or 2 R ^5-1 ; each R ^5-1 is independently a C ₆ ～C ₁₀ aryl group;

   -X ₄ - is a chemical bond, or -Y _2b -Lys-Y ₃ -, L ₂ is -(O-CH ₂ CH ₂ ) _j -, q is 1, and j is an integer of 0-10;

   -Y _2b - is a chemical bond, L ₃ and L ₄ are each independently C ₁ -C ₆ alkylene or -(O-CH ₂ CH ₂ ) _j'- , q1 and q2 are each independently 1, 2 or 4, and j' is each independently an integer of 0-10;

   -Y ₃ - for _L5 and _L6 are each independently _C1 - _C6 alkylene or -(O- CH ₂ CH ₂ ) _j" -, q3 and q4 are each independently 0 or 2, j" is 0;

   -X ₅ - for ^R7 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

   -X ₇ - is a chemical bond, _L7 and _L8 are each independently -(O- _{CH2CH2 ) j''} , q5 and q6 are each independently 1 or 2, j''' is an integer of 0-10;

   W is -NH-CO- or -NH-CO-NH-;

   R ⁸ is a linear C _1-10 alkyl group;

   R ⁹ is

   R ¹⁰ is a hydroxyl group or a chemical bond;

   R ¹¹ is a hydroxyl group;

   Ring B is

   Scheme 3: The compound M-L-G is in the middle,

   -L- is -L ₁ -X ₇ -, where L ₁ is T is 3; K is 0 or 1;

   G is

   In compound X, -X ₁ - is

   ^R3 is a 3-6 membered heterocycloalkylene group, wherein the heteroatoms of the 3-6 membered heterocycloalkylene group are selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

   -X ₂ - is -X _2-1 -Y ₁ -; -X _2-1 - is a chemical bond; Y ₁ is

   -X ₃ - is -X _3-1 -Y ₂ -; -X _3-1 - is a chemical bond; Y ₂ is

   R ⁵ is a C ₁ ～C ₄ alkyl group substituted by 1 or 2 R ^5-1 ; each R ^5-1 is independently a C ₆ ～C ₁₀ aryl group;

   -X ₄ - is a chemical bond, or -Y _2b -Lys-Y ₃ -, L ₂ is -(O-CH ₂ CH ₂ ) _j -, q is 1, and j is an integer of 0-10;

   -Y _2b - is a chemical bond;

   -Y ₃ - for L ₅ is C ₁ -C ₆ alkylene, q3 is 0, 1 or 2;

   -X ₅ - for ^R7 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

   -X ₇ - for _L7 and _L8 are each independently -(O- _{CH2CH2 ) j'"} , q5 and q6 are each independently 1 or 2, j'' is an integer of 0-10;

   W is -NH-CO-;

   R ⁸ is a linear C _1-10 alkyl group;

   R ⁹ is

   R ¹⁰ is a hydroxyl group or a chemical bond;

   R ¹¹ is a hydroxyl group;

   Ring B is

   Option 4:

   In the compound M-L-G-2,

   -L- is -L ₁ -X ₇ -, where L ₁ is T is 3, K is 1;

   G is

   In compound X, -X ₁ - is

   ^R3 is a 3-6 membered heterocycloalkylene group, wherein the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

   -X ₂ - is -X _2-1 -Y ₁ -; -X _2-1 - is a chemical bond; Y ₁ is

   -X ₃ - is -X _3-1 -Y ₂ -; -X _3-1 - is a chemical bond; Y ₂ is

   R ⁵ is a C ₁ ～C ₄ alkyl group substituted by 1 or 2 R ^5-1 ; each R ^5-1 is independently a C ₆ ～C ₁₀ aryl group;

   -X ₄ - is a chemical bond;

   -X ₅ - for ^R7 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

   -X ₇ - is a chemical bond or _L7 is -(O- _{CH2CH2 ) j"'} , q5 is 2, j"' is 0;

   W is -NH-CO- or -NH-CO-NH-;

   R ⁸ is a linear C _1-10 alkyl group;

   R ⁹ is

   R ¹¹ is a hydroxyl group;

   Ring B is

   Scheme 5: In the compound M-L-G-2,

   -L- is -L ₁ -X ₇ -, where L ₁ is T is 3, K is 0 or 1;

   G is

   In compound X, -X ₁ - is

   ^R3 is a 3-6 membered heterocycloalkylene group, wherein the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

   -X ₂ - is -X _2-1 -Y ₁ -; -X _2-1 - is a chemical bond; Y ₁ is

   -X ₃ - is -X _3-1 -Y ₂ -; -X _3-1 - is a chemical bond; Y ₂ is

   R ⁵ is a C ₁ ～C ₄ alkyl group substituted by 1 or 2 R ^5-1 ; each R ^5-1 is independently a C ₆ ～C ₁₀ aryl group;

   -X ₄ - is a chemical bond or L ₂ is -(O-CH ₂ CH ₂ ) _j -, q is 1, and j is an integer from 0 to 10;

   -X ₅ - for ^R7 is a 3-6 membered heterocycloalkylene group; the heteroatom of the 3-6 membered heterocycloalkylene group is selected from one or more of N, O and S, the number of heteroatoms is 1, 2 or 3, and contains at least one N;

   -X ₇ - is a chemical bond, _L7 and _L8 are each independently -(O- _{CH2CH2 ) j'"} , q5 and q6 are each independently 1 or 2, j'' is an integer of 0-10;

   W is -NH-CO- or -NH-CO-NH-;

   R ⁸ is a linear C _1-10 alkyl group;

   R ⁹ is

   R ¹¹ is a hydroxyl group;

   Ring B is
8. The compound M-L-G or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound M-L-G satisfies one or more of the following conditions:

   (1) -X ₁ - is Preferably, -X ₁ - is in Connected to -X ₅ -;

   (2) -X ₂ - is Preferably, -X ₂ - is in Connected to -X ₅ -;

   (3) -X ₃ - is Preferably, -X ₃ - is in Connected to the carbonyl group;

   (4) -X ₅ - is Preferably, -X ₅ - is in Connected to X ₂ ;

   (5) Ring B is

   (6) R ⁸ is a linear C _1-10 alkyl group;

   (7) for

   (8) R ¹⁰ is a hydroxyl group or a chemical bond;

   (9) -X ₄ - is or chemical bonds;

   Preferably, -X ₄ - is or chemical bonds, where Connected to NH, Connected to G;

   (10) -X ₇ - or chemical bonds;

   Preferably, -X ₇ - is or chemical bonds, where Connected to _L2 ;

   (11)-LG is
   
   
9. The compound MLG or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structure of the compound MLG is any one of the following:
   
   
   
   
   
10. A cyclic polypeptide compound A, wherein the cyclic polypeptide compound A is a compound formed by chelating the compound M-L-G according to any one of claims 1 to 9 and an ion of a therapeutic radionuclide.
11. The cyclic polypeptide compound A according to claim 10, characterized in that the cyclic polypeptide compound A satisfies one or more of the following conditions:

    (1) The therapeutic radionuclide is ¹⁷⁷ Lu, ⁹⁰ Y, ⁸⁹ Sr, ¹⁸⁸ Re, ²²⁵ Ac, ²¹³ Bi or ²¹² Pb;

    (2) The valence state of the therapeutic radionuclide ion is monovalent, divalent, trivalent or tetravalent;

    (3) The therapeutic radionuclide ion is ¹⁷⁷ Lu ³⁺ , ²²⁵ Ac ³⁺ , ⁹⁰ Y ³⁺ , ²¹² Pb ²⁺ or ²¹³ Bi ³⁺ .
12. The cyclic polypeptide compound A according to claim 10, characterized in that the cyclic polypeptide compound A is The compound MLG is chelated with ¹⁷⁷ Lu ³⁺ to form a compound.
13. A cyclic polypeptide compound B, wherein the cyclic polypeptide compound B is a compound formed by chelating the ions of a compound M-L-G and a diagnostic radionuclide, and the structure of the compound M-L-G is as described in any one of claims 1 to 9.
14. The cyclic polypeptide compound B according to claim 13, characterized in that the cyclic polypeptide compound B satisfies one or more of the following conditions:

    (1) The diagnostic radionuclide is ¹⁸ F, ⁶⁸ Ga, ¹¹¹ In or ⁶⁴ Cu;

    (2) The valence state of the diagnostic radionuclide ion is monovalent, divalent, trivalent or tetravalent;

    (3) The diagnostic radioactive metal ion is ⁶⁸ Ga ³⁺ or ⁶⁴ Cu ²⁺ .
15. The cyclic polypeptide compound B according to claim 13, characterized in that the cyclic polypeptide compound B is a compound formed by chelating compound MLG with ⁶⁸ Ga ³⁺ , and the structure of the compound X is as described in any one of claims 1-9.
16. A pharmaceutical composition comprising a substance Y and a pharmaceutical excipient, wherein the substance Y is the cyclic polypeptide compound A as described in any one of claims 10 to 12 or the cyclic polypeptide compound B as described in any one of claims 13 to 15.
17. A use of a cyclic polypeptide compound A as described in any one of claims 10 to 12 in the preparation of a drug for treating a tumor, wherein the tumor may be a solid tumor positive for FAP expression, such as breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, prostate cancer, liver cancer or skin melanoma.
18. A use of a cyclic polypeptide compound B as described in any one of claims 13 to 15 in the preparation of a drug for diagnosing a tumor, wherein the tumor may be a solid tumor that is positive for FAP expression, such as breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, prostate cancer, liver cancer or skin melanoma.