Irreversible FAP inhibitor and use thereof

Abstract

The present invention relates to the field of medicine, relates to an irreversible FAP inhibitor and a use thereof, and a use of the compound in a drug for diagnosing and / or treating tumors, rheumatoid arthritis, non-alcoholic fatty liver disease, atherosclerosis, myocardial infarction, liver fibrosis, pulmonary fibrosis, and renal fibrosis, and in particular to a compound represented by formula I, or an isomer thereof, or a pharmaceutically acceptable salt or metal complex thereof, and a use thereof. Substituents in formula I have the same definitions as those in the description.

Description

An irreversible FAP inhibitor and its uses

[0001] This invention claims priority to an earlier application filed on November 14, 2024, with China National Intellectual Property Administration, patent application number 202411632725.2, entitled "An Irreversible FAP Inhibitor and Its Use". The entire contents of the aforementioned earlier application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the pharmaceutical field, specifically relating to an irreversible FAP inhibitor and its uses, as well as the use of such compounds for the diagnosis and / or treatment of tumors, immune diseases or inflammatory diseases. Background Technology

[0003] Fibroblast activation protein (FAP) is an important biomarker on the surface of tumor-associated fibroblasts. It is highly expressed in over 90% of stromal fibroblasts in epithelial cancers and is widely distributed in many cancer types, such as sarcoma, prostate cancer, breast cancer, lung cancer, pancreatic cancer, head and neck cancer, and colorectal cancer. Studies have shown that FAP promotes tumor development and progression through multiple mechanisms, including promoting tumor angiogenesis, tumor growth, immune evasion, and assisting tumor metastasis. Furthermore, and importantly, due to its low expression levels in healthy tissues, FAP is considered a promising target for tumor diagnosis and treatment.

[0004] Furthermore, FAP is highly expressed in arthritis, atherosclerotic plaques, and fibrotic tissue. FAP hydrolyzes and breaks down substrates such as type I and type III collagen, α2-antifibrinolytic enzyme, and fibroblast growth factor, creating a pro-fibrotic environment that promotes immune cell infiltration, synovial fibroblast proliferation, and angiogenesis. This is associated with the worsening of rheumatoid arthritis, non-alcoholic fatty liver disease, and atherosclerosis. Therefore, FAP inhibitors can be used for the diagnosis and treatment of tumors, rheumatoid arthritis, non-alcoholic fatty liver disease, and atherosclerosis.

[0005] This invention provides an irreversible FAP inhibitor and corresponding metal complexes and pharmaceutical compositions for the diagnosis and / or treatment of FAP-mediated diseases. Summary of the Invention

[0006] Purpose of the invention: The purpose of this invention is to overcome the shortcomings of the existing technology and provide an irreversible FAP inhibitor and its uses.

[0007] To achieve the above objectives, the technical solution provided by the present invention is as follows:

[0008] On one hand, the present invention provides a compound of Formula I, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or an optical isomer thereof, or a stereoisomer thereof:

[0009] W is selected from CR1 or N;

[0010] R1, R2, and R3 are each independently selected from hydrogen, halogens, -CN, -NR8R9、C 1-8 Alkyl, C 2-8 Unsaturated alkyl or -OR 13 Among them, R1, R2, and R3 are selected from R6 and R7 are each independently selected from hydrogen, halogens, and C. 2-4 Unsaturated alkyl or C 1-4 Alkyl, wherein C 1-4 Alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, dimethyl sulfone, C 2-4 Unsaturated alkyl or C 1-4 Alkyl group; or R6, R7 forming a 3- to 6-membered carbon ring or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered carbon ring or the 3- to 6-membered heterocycle is optionally substituted by one or more of the following substituents: O or halogen, wherein the 3- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, N;

[0011] L is selected from -NHCO-, -NHSO2-, and -NR. 10 CONH-, -CONHCO-, -NR 14 CSNH- or R 10 R 14 Selected from hydrogen, C 1-8 Alkyl or C 2-8 Unsaturated alkyl groups;

[0012] M is selected from C 1-8 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 2-4 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, O, C. 3-5 Cycloalkyl, hydroxyl, -NH2 or -N3, wherein C 3-5 The cycloalkyl group is optionally substituted with one or more halogens, O or hydroxyl groups, wherein the 4- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, or N;

[0013] R4 and R5 are each independently selected from hydrogen, halogens, -CN, -NO2, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, -OR 15 or -NR 11 R 12 C 1-8 Alkyl or C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, R... 11 R 12 Replaced;

[0014] R8, R9, R 11 R 12 R 13 R 15 Each independently selected L2 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K1 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 16 OR key; L3 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) a Or a key, a = 1 to 10, where C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K2 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 17 , AA or bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 , AA or key; L4 and L5 are independently selected from C. 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) b Or bond, b = 1~10, where C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K4 is selected from NR. 28 Carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl

[0015] Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6-membered heterocycloalkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6-membered heterocycle contains 1-2 atoms optionally selected from O, S, or N;

[0016] X, Y, and Z are each independently selected from CH, N, and CSO2NR. 19 R 26 CSO2R 27 CNHCOR 21 COR 20 , where R 19 R 20 R 21 R 27 Each independently selected L6 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, NR 22 R 23 O, hydroxyl, C 1-6 Alkyl or C 2-6 Unsaturated alkyl substitution, wherein C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K5 is selected from carbonyl, thiocarbonyl, sulfonyl, ... O, S, NR 29 OR key; L7 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) d OR bond, d = 1 to 10, where C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, C. 1-6 Alkyl substitution, wherein C 1-6 The alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K6 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 30 , AA or bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 , AA or key; L8, L9, L 10 Each is selected independently from C 1-6 Alkyl, C 2-6Unsaturated alkyl groups, (OCH2CH2) e e = 1 to 10 or bond, where C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, or NR. 24 R 25 C 1-6 Alkyl substitution, wherein C 1-6 Alkyl groups may optionally be substituted with one or more halogens, O, or hydroxyl groups; K8 and K9 are each independently selected from NR. 32 Carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6 membered heterocyclic alkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, or N; wherein R 16 R 17 R 18 R 28 R 29 R 30 R 31 R 32 Each is independently selected from H and C 1-3 Alkyl or C 2-3 Unsaturated alkyl group, R 22 R 23 R 24 R 25 Independently selected from H and C 1-3 Alkyl, C 2-3 Unsaturated alkyl groups R 26 Selected from H, C 1-6 Alkyl, C 2-6 Unsaturated alkyl, C 3-6 Cycloalkyl, wherein AA is selected from amino acid residues, wherein the amino acid is selected from glycine, phenylalanine, arginine, N... ω N ω- Dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine, or isoleucine; ring A1 and ring A2 are independently selected from naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic rings, wherein the naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic ring may be halogenated, CN, nitro, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl substituted.

[0017] In some embodiments, the compound, or its metal complex, or its pharmaceutically acceptable salt, or its ester, or its optical isomer, or its stereoisomer, is represented by Formula I-1:

[0018] R2 and R3 are each independently selected from hydrogen, halogen, -CN, -NR8R9, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl or -OR 13 R6 and R7 are each independently selected from hydrogen, halogens, and C. 2-4 Unsaturated alkyl or C 1-4 Alkyl, wherein C 1-4 Alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, dimethyl sulfone, C 2-4 Unsaturated alkyl or C 1-4 Alkyl group; or R6, R7 forming a 3- to 6-membered carbon ring or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered carbon ring or the 3- to 6-membered heterocycle is optionally substituted by one or more of the following substituents: O or halogen, wherein the 3- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, N;

[0019] L is selected from -NHCO-, -NHSO2-, and -NR. 10 CONH-, -CONHCO-, -NR 14 CSNH- or R 10 R 14 Selected from hydrogen, C 1-8 Alkyl or C 2-8 Unsaturated alkyl groups;

[0020] M is selected from C 1-8 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 2-4 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl or C2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, O, C. 3-5 Cycloalkyl, hydroxyl, -NH2 or -N3, wherein C 3-5 The cycloalkyl group is optionally substituted with one or more halogens, O or hydroxyl groups, wherein the 4- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, or N;

[0021] R4 and R5 are each independently selected from hydrogen, halogens, -CN, -NO2, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, -OR 15 or -NR 11 R 12 C 1-8 Alkyl or C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, R... 11 R 12 Replaced;

[0022] R8, R9, R 11 R 12 R 13 R 15 Each independently selected L2 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K1 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 16 OR key; L3 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) a Or a key, a = 1 to 10, where C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K2 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 17 , AA or bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 , AA or key; L4 and L5 are independently selected from C. 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) b OR key, b = 1 to 10, where C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K4 is selected from NR. 28Carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl

[0023] Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6-membered heterocycloalkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6-membered heterocycle contains 1-2 atoms optionally selected from O, S, or N;

[0024] X, Y, and Z are each independently selected from CH, N, and CSO2NR. 19 R 26 CSO2R 27 CNHCOR 21 COR 20 , where R 19 R 20 R 21 R 27 Each independently selected L6 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, NR 22 R 23 O, hydroxyl, C 1-6 Alkyl or C 2-6 Unsaturated alkyl substitution, wherein C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K5 is selected from carbonyl, thiocarbonyl, sulfonyl, ... O, S, NR 29 OR key; L7 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) d OR bond, d = 1 to 10, where C 1-8 Alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, C. 1-6 Alkyl substitution, wherein C 1-6 The alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K6 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 30 , AA or bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 , AA or key; L8, L9, L 10 Each is selected independently from C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) e e = 1 to 10 or a bond, where C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, or NR. 24 R 25 C 1-6 Alkyl substitution, wherein C 1-6 Alkyl groups may optionally be substituted with one or more halogens, O, or hydroxyl groups; K8 and K9 are each independently selected from NR. 32 Carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6 membered heterocyclic alkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, or N; wherein R 16 R 17 R 18 R 28 R 29 R 30 R 31 R 32 Each is independently selected from H and C 1-3 Alkyl or C 2-3 Unsaturated alkyl group, R 22 R 23 R 24 R 25 Independently selected from H and C 1-3 Alkyl, C 2-3 Unsaturated alkyl groups R 26 Selected from H, C 1-6 Alkyl, C 2-6 Unsaturated alkyl, C 3-6Cycloalkyl, wherein AA is selected from amino acid residues, wherein the amino acid is selected from glycine, phenylalanine, arginine, N... ω N ω - Dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine, or isoleucine; ring A1 and ring A2 are independently selected from naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic rings, wherein the naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic ring may be halogenated, CN, nitro, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl substituted.

[0025] In some embodiments, the compound, or its metal complex, or its pharmaceutically acceptable salt, or its ester, or its optical isomer, or its stereoisomer, is represented by formula I-1-1, I-1-2, or I-1-3:

[0026] R2 and R3 are each independently selected from hydrogen, halogen, -CN, -NR8R9, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl or -OR 13 R6 and R7 are each independently selected from hydrogen, halogens, and C. 2-4 Unsaturated alkyl or C 1-4 Alkyl, wherein C 1-4 Alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, dimethyl sulfone, C 2-4 Unsaturated alkyl or C 1-4 Alkyl group; or R6, R7 forming a 3- to 6-membered carbon ring or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered carbon ring or the 3- to 6-membered heterocycle is optionally substituted by one or more of the following substituents: O or halogen, wherein the 3- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, N;

[0027] L is selected from -NHCO-, -NHSO2-, and -NR. 10 CONH-, -CONHCO-, -NR 14 CSNH- or R 10 R 14 Selected from hydrogen, C 1-8 Alkyl or C 2-8 Unsaturated alkyl groups;

[0028] M is selected from C 1-8 Alkyl, C 3-6Cycloalkyl, 4-6 membered heterocyclic alkyl, C 2-4 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, O, C. 3-5 Cycloalkyl, hydroxyl, -NH2 or -N3, wherein C 3-5 The cycloalkyl group is optionally substituted with one or more halogens, O or hydroxyl groups, wherein the 4- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, or N;

[0029] R4 and R5 are each independently selected from hydrogen, halogens, -CN, -NO2, and C. 1-8 Alkyl or C 2-8 Unsaturated alkyl groups, -OR 15 or -NR 11 R 12 C 1-8 Alkyl or C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; V is selected from O, NR. 33 SO2NR 26 SO2, NHCO, CO or bonds;

[0030] L2 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K1 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 16 OR key; L3 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) a Or a key, a = 1 to 10, where C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K2 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 17 , AA or bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 , AA or key; L4 and L5 are independently selected from C. 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) b OR key, b = 1 to 10, where C 1-6 Alkyl, C 2-6The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K4 is selected from NR. 28 Carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl

[0031] Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6-membered heterocyclic alkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6-membered heterocycle contains 1-2 atoms optionally selected from O, S, or N; L6 is selected from C. 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, NR 22 R 23 O, hydroxyl, C 1-6 Alkyl or C 2-6 Unsaturated alkyl substitution, wherein C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K5 is selected from carbonyl, thiocarbonyl, sulfonyl, ... O, S, NR 29 OR key; L7 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) d OR bond, d = 1 to 10, where C 1-8 Alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, C. 1-6 Alkyl substitution, wherein C 1-6 The alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K6 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 30 , AA or bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 , AA or key; L8, L9, L 10 Each is selected independently from C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) e e = 1 to 10 or a bond, where C1-6 Alkyl, C 2-6 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, or NR. 24 R 25 C 1-6 Alkyl substitution, wherein C 1-6 Alkyl groups may optionally be substituted with one or more halogens, O, or hydroxyl groups; K8 and K9 are each independently selected from NR. 32 Carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6 membered heterocyclic alkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, or N; wherein R 16 R 17 R 18 R 28 R 29 R 30 R 31 R 32 Each is independently selected from H and C 1-3 Alkyl or C 2-3 Unsaturated alkyl group, R 22 R 23 R 24 R 25 Independently selected from H and C 1-3 Alkyl, C 2-3 Unsaturated alkyl groups R 26 Selected from H, C 1-6 Alkyl, C 2-6 Unsaturated alkyl, C 3-6 Cycloalkyl, wherein AA is selected from amino acid residues, wherein the amino acid is selected from glycine, phenylalanine, arginine, N... ω N ω - Dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine, or isoleucine; ring A1 and ring A2 are independently selected from naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic rings, wherein the naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic ring may be halogenated, CN, nitro, C1-4 Alkyl, C 2-4 Unsaturated alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl substituted;

[0032] R8, R9, R 11 R 12 R 13 R 15 R 33 Each independently selected

[0033] X, Y, and Z are each independently selected from CH, N, and CSO2NR. 34 R 35 CSO2R 36 CNHCOR 37 COR 38 , where R 34 R 36 R 37 R 38 Each independently selected L 11 L 13 Independently selected from C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups or bonds, wherein C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups are optionally surrounded by one or more halogens, NR 39 R 40 O, hydroxyl, C 1-4 Alkyl or C 2-4 Unsaturated alkyl substitution, wherein C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups may optionally be substituted with one or more halogens, O, or hydroxyl groups; K 10 K 12 Independently selected from carbonyl, sulfonyl, O, S, NR 41 OR key; L 12 L 14 Independently selected from C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups, (OCH2CH2) f Or key, f = 1 to 3, where C 1-4 Alkyl or C 2-4 Unsaturated alkyl groups may optionally be substituted with one or more halogens, O, or hydroxyl groups; K 11 K 13 Independently selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 42 , AA, COO, CONH, SO3, SO2NH or bond; J, T are independently selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups, wherein C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 Cycloalkyl groups and 4-6-membered heterocyclic alkyl groups are optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6-membered heterocycle contains 1-2 atoms optionally selected from O, S, or N; R 35 Selected from H, C 1-6 Alkyl, C 2-6 Unsaturated alkyl, C 3-6 cycloalkyl; R 39 R 40 Each is independently selected from H and C 1-3 Alkyl or C 2-3 Unsaturated alkyl groups R 41 R 42 Independently selected from H and C 1-3 Alkyl or C 2-3 Unsaturated alkyl group; wherein AA is selected from amino acid residues, and the amino acid is selected from glycine, phenylalanine, arginine, N... ω N ω - Dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine, or isoleucine; ring A3 is independently selected from a naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic ring, wherein the naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic ring may be halogenated, CN, nitro, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl substituted.

[0034] In some embodiments, the compound, or its metal complex, or its pharmaceutically acceptable salt, or its ester, or its optical isomer, or its stereoisomer, is represented by Formula I-2:

[0035] W is selected from CR1 or N;

[0036] R1 and R2 are each independently selected from hydrogen, halogens, -CN, -NR8R9, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl or -OR 13R6 and R7 are each independently selected from hydrogen, halogens, and C. 2-4 Unsaturated alkyl or C 1-4 Alkyl, wherein C 1-4 Alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, dimethyl sulfone, C 2-4 Unsaturated alkyl or C 1-4 Alkyl group; or R6, R7 forming a 3- to 6-membered carbon ring or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered carbon ring or the 3- to 6-membered heterocycle is optionally substituted by one or more of the following substituents: O or halogen, wherein the 3- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, N;

[0037] L is selected from -NHCO-, -NHSO2-, and -NR. 10 CONH-, -CONHCO-, -NR 14 CSNH- or R 10 R 14 Selected from hydrogen, C 1-8 Alkyl or C 2-8 Unsaturated alkyl groups;

[0038] M is selected from C 1-8 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 2-4 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, O, C. 3-5 Cycloalkyl, hydroxyl, -NH2 or -N3, wherein C 3-5 The cycloalkyl group is optionally substituted with one or more halogens, O or hydroxyl groups, wherein the 4- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, or N;

[0039] R4 and R5 are each independently selected from hydrogen, halogens, -CN, -NO2, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, -OR 15 or -NR 11 R 12 C 1-8 Alkyl or C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, R... 11 R 12 Replaced;

[0040] R8, R9, R 11 R 12 R 13R 15 Each independently selected L2 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K1 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 16 OR key; L3 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) a Or a key, a = 1 to 10, where C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K2 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 17 , AA or bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 , AA or key; L4 and L5 are independently selected from C. 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) b OR key, b = 1 to 10, where C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K4 is selected from NR. 28 Carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl

[0041] Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6-membered heterocycloalkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6-membered heterocycle contains 1-2 atoms optionally selected from O, S, or N;

[0042] X, Y, and Z are each independently selected from CH, N, and CSO2NR. 19 R 26 CSO2R 27 CNHCOR 21 COR 20, where R 19 R 20 R 21 R 27 Each independently selected L6 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, NR 22 R 23 O, hydroxyl, C 1-6 Alkyl or C 2-6 Unsaturated alkyl substitution, wherein C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K5 is selected from carbonyl, thiocarbonyl, sulfonyl, ... O, S, NR 29 OR key; L7 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) d OR bond, d = 1 to 10, where C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, C. 1-6 Alkyl substitution, wherein C 1-6 The alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K6 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 30 ... AA or bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 , AA or key; L8, L9, L 10 Each is selected independently from C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) e e = 1 to 10 or a bond, where C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, or NR. 24 R 25 C 1-6 Alkyl substitution, wherein C 1-6 Alkyl groups may optionally be substituted with one or more halogens, O, or hydroxyl groups; K8 and K9 are each independently selected from NR. 32 Carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6 membered heterocyclic alkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, or N; wherein R 16 R 17 R 18 R 28 R 29 R 30 R 31 R 32 Each is independently selected from H and C 1-3 Alkyl or C 2-3 Unsaturated alkyl group, R 22 R 23 R 24 R 25 Independently selected from H and C 1-3 Alkyl, C 2-3 Unsaturated alkyl groups R 26 Selected from H, C 1-6 Alkyl, C 2-6 Unsaturated alkyl, C 3-6 Cycloalkyl, wherein AA is selected from amino acid residues, wherein the amino acid is selected from glycine, phenylalanine, arginine, N... ω N ω - Dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine, or isoleucine; ring A1 and ring A2 are independently selected from naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic rings, wherein the naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic ring may be halogenated, CN, nitro, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl substituted.

[0043] In some embodiments, the compound, or its metal complex, or its pharmaceutically acceptable salt, or its ester, or its optical isomer, or its stereoisomer, is represented by formula I-2-1, I-2-2, or I-2-3:

[0044] W is selected from CR1 or N;

[0045] R1 and R2 are each independently selected from hydrogen, halogens, -CN, -NR8R9, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl or -OR 13 R6 and R7 are each independently selected from hydrogen, halogens, and C. 2-4 Unsaturated alkyl or C 1-4 Alkyl, wherein C 1-4 Alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, dimethyl sulfone, C 2-4 Unsaturated alkyl or C 1-4 Alkyl group; or R6, R7 forming a 3- to 6-membered carbon ring or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered carbon ring or the 3- to 6-membered heterocycle is optionally substituted by one or more of the following substituents: O or halogen, wherein the 3- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, N;

[0046] L is selected from -NHCO-, -NHSO2-, and -NR. 10 CONH-, -CONHCO-, -NR 14 CSNH- or R 10 R 14 Selected from hydrogen, C 1-8 Alkyl or C 2-8 Unsaturated alkyl groups;

[0047] M is selected from C 1-8 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 2-4 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, O, C. 3-5 Cycloalkyl, hydroxyl, -NH2 or -N3, wherein C 3-5 The cycloalkyl group is optionally substituted with one or more halogens, O or hydroxyl groups, wherein the 4- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, or N;

[0048] R4 and R5 are each independently selected from hydrogen, halogens, -CN, -NO2, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, -OR 15 or -NR 11 R 12 C 1-8 Alkyl or C 2-8The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; V is selected from O, NR. 33 SO2NR 26 SO2, NHCO, CO;

[0049] L2 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K1 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 16 OR key; L3 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) a Or a key, a = 1 to 10, where C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K2 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 17 , AA or bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 , AA or key; L4 and L5 are independently selected from C. 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) b OR key, b = 1 to 10, where C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K4 is selected from NR. 28 Carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl

[0050] Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6-membered heterocyclic alkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6-membered heterocycle contains 1-2 atoms optionally selected from O, S, or N; L6 is selected from C. 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8Alkyl, C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, NR 22 R 23 O, hydroxyl, C 1-6 Alkyl or C 2-6 Unsaturated alkyl substitution, wherein C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K5 is selected from carbonyl, thiocarbonyl, sulfonyl, ... O, S, NR 29 OR key; L7 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) d OR bond, d = 1 to 10, where C 1-8 Alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, C. 1-6 Alkyl substitution, wherein C 1-6 The alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K6 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 30 , AA or bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 , AA or key; L8, L9, L 10 Each is selected independently from C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) e e = 1 to 10 or a bond, where C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, or NR. 24 R 25 C 1-6 Alkyl substitution, wherein C 1-6 Alkyl groups may optionally be substituted with one or more halogens, O, or hydroxyl groups; K8 and K9 are each independently selected from NR. 32 Carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6The cycloalkyl group or 4-6 membered heterocyclic alkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, or N; wherein R 16 R 17 R 18 R 28 R 29 R 30 R 31 R 32 Each is independently selected from H and C 1-3 Alkyl or C 2-3 Unsaturated alkyl group, R 22 R 23 R 24 R 25 Independently selected from H and C 1-3 Alkyl, C 2-3 Unsaturated alkyl groups R 26 Selected from H, C 1-6 Alkyl, C 2-6 Unsaturated alkyl, C 3-6 Cycloalkyl, wherein AA is selected from amino acid residues, wherein the amino acid is selected from glycine, phenylalanine, arginine, N... ω N ω - Dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine, or isoleucine; ring A1 and ring A2 are independently selected from naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic rings, wherein the naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic ring may be halogenated, CN, nitro, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl substituted;

[0051] R8, R9, R 11 R 12 R 13 R 15 R 33 Each independently selected

[0052] X, Y, and Z are each independently selected from CH, N, and CSO2NR. 34 R 35 CSO2R 36 CNHCOR 37 COR 38 , where R 34 R 36 R 37 R38 Each independently selected L 11 L 13 Independently selected from C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups or bonds, wherein C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups are optionally surrounded by one or more halogens, NR 39 R 40 O, hydroxyl, C 1-4 Alkyl or C 2-4 Unsaturated alkyl substitution, wherein C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups may optionally be substituted with one or more halogens, O, or hydroxyl groups; K 10 K 12 Independently selected from carbonyl, sulfonyl, O, S, NR 41 OR key; L 12 L 14 Independently selected from C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups, (OCH2CH2) f Or key, f = 1 to 3, where C 1-4 Alkyl or C 2-4 Unsaturated alkyl groups may optionally be substituted with one or more halogens, O, or hydroxyl groups; K 11 K 13 Independently selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 42 , AA, COO, CONH, SO3, SO2NH or bond; J, T are independently selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups, wherein C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 Cycloalkyl groups and 4-6-membered heterocyclic alkyl groups are optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6-membered heterocycle contains 1-2 atoms optionally selected from O, S, or N; R 35 Selected from H, C 1-6 Alkyl, C 2-6 Unsaturated alkyl, C 3-6 cycloalkyl; R 39 R 40 Each is independently selected from H and C 1-3 Alkyl or C 2-3 Unsaturated alkyl groups R 41 R 42 Independently selected from H and C 1-3 Alkyl or C 2-3 Unsaturated alkyl group; wherein AA is selected from amino acid residues, and the amino acid is selected from glycine, phenylalanine, arginine, N... ω N ω - Dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine, or isoleucine; ring A3 is independently selected from a naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic ring, wherein the naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic ring may be halogenated, CN, nitro, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl substituted.

[0053] In some embodiments, the compound, or its metal complex, or its pharmaceutically acceptable salt, or its ester, or its optical isomer, or its stereoisomer, is represented by Formula I-3:

[0054] W is selected from CR1 or N;

[0055] R1 and R3 are each independently selected from hydrogen, halogens, -CN, -NR8R9, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl or -OR 13 R6 and R7 are each independently selected from hydrogen, halogens, and C. 2-4 Unsaturated alkyl or C 1-4 Alkyl, wherein C 1-4 Alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, dimethyl sulfone, C 2-4 Unsaturated alkyl or C 1-4 Alkyl group; or R6, R7 forming a 3- to 6-membered carbon ring or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered carbon ring or the 3- to 6-membered heterocycle is optionally substituted by one or more of the following substituents: O or halogen, wherein the 3- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, N;

[0056] L is selected from -NHCO-, -NHSO2-, and -NR. 10 CONH-, -CONHCO-, -NR 14 CSNH- or R 10 R 14 Selected from hydrogen, C 1-8Alkyl or C 2-8 Unsaturated alkyl groups;

[0057] M is selected from C 1-8 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 2-4 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, O, C. 3-5 Cycloalkyl, hydroxyl, -NH2 or -N3, wherein C 3-5 The cycloalkyl group is optionally substituted with one or more halogens, O or hydroxyl groups, wherein the 4- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, or N;

[0058] R4 and R5 are each independently selected from hydrogen, halogens, -CN, -NO2, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, -OR 15 or -NR 11 R 12 C 1-8 Alkyl or C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, R... 11 R 12 Replaced;

[0059] R8, R9, R 11 R 12 R 13 R 15 Each independently selected L2 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K1 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 16 OR key; L3 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) a Or a key, a = 1 to 10, where C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K2 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 17 , AA or bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 , AA or key; L4 and L5 are independently selected from C. 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) b OR key, b = 1 to 10, where C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K4 is selected from NR. 28 Carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl

[0060] Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6-membered heterocycloalkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6-membered heterocycle contains 1-2 atoms optionally selected from O, S, or N;

[0061] X, Y, and Z are each independently selected from CH, N, and CSO2NR. 19 R 26 CSO2R 27 CNHCOR 21 COR 20 , where R 19 R 20 R 21 R 27 Each independently selected L6 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, NR 22 R 23 O, hydroxyl, C 1-6 Alkyl or C 2-6 Unsaturated alkyl substitution, wherein C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K5 is selected from carbonyl, thiocarbonyl, sulfonyl, ... O, S, NR 29 OR key; L7 is selected from C 1-8 Alkyl, C 2-8Unsaturated alkyl groups, (OCH2CH2) d OR bond, d = 1 to 10, where C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, C. 1-6 Alkyl substitution, wherein C 1-6 The alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K6 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 30 ... AA or bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 , AA or key; L8, L9, L 10 Each is selected independently from C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) e e = 1 to 10 or a bond, where C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, or NR. 24 R 25 C 1-6 Alkyl substitution, wherein C 1-6 Alkyl groups may optionally be substituted with one or more halogens, O, or hydroxyl groups; K8 and K9 are each independently selected from NR. 32 Carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6 membered heterocyclic alkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, or N; wherein R 16 R 17 R 18 R 28 R 29 R 30 R 31 R 32 Each is independently selected from H and C 1-3 Alkyl or C 2-3 Unsaturated alkyl group, R 22 R23 R 24 R 25 Independently selected from H and C 1-3 Alkyl, C 2-3 Unsaturated alkyl groups R 26 Selected from H, C 1-6 Alkyl, C 2-6 Unsaturated alkyl, C 3-6 Cycloalkyl, wherein AA is selected from amino acid residues, wherein the amino acid is selected from glycine, phenylalanine, arginine, N... ω N ω - Dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine, or isoleucine; ring A1 and ring A2 are independently selected from naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic rings, wherein the naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic ring may be halogenated, CN, nitro, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl substituted.

[0062] In some embodiments, the compound, or its metal complex, or its pharmaceutically acceptable salt, or its ester, or its optical isomer, or its stereoisomer, is represented by formula I-3-1, I-3-2, or I-3-3:

[0063] W is selected from CR1 or N;

[0064] R1 and R3 are each independently selected from hydrogen, halogens, -CN, -NR8R9, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl or -OR 13 R6 and R7 are each independently selected from hydrogen, halogens, and C. 2-4 Unsaturated alkyl or C 1-4 Alkyl, wherein C 1-4 Alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, dimethyl sulfone, C 2-4 Unsaturated alkyl or C 1-4 Alkyl group; or R6, R7 forming a 3- to 6-membered carbon ring or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered carbon ring or the 3- to 6-membered heterocycle is optionally substituted by one or more of the following substituents: O or halogen, wherein the 3- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, N;

[0065] L is selected from -NHCO-, -NHSO2-, and -NR.10 CONH-, -CONHCO-, -NR 14 CSNH- or R 10 R 14 Selected from hydrogen, C 1-8 Alkyl or C 2-8 Unsaturated alkyl groups;

[0066] M is selected from C 1-8 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 2-4 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, O, C. 3-5 Cycloalkyl, hydroxyl, -NH2 or -N3, wherein C 3-5 The cycloalkyl group is optionally substituted with one or more halogens, O or hydroxyl groups, wherein the 4- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, or N;

[0067] R4 and R5 are each independently selected from hydrogen, halogens, -CN, -NO2, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, -OR 15 or -NR 11 R 12 C 1-8 Alkyl or C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; V is selected from O, NR. 33 SO2NR 26 SO2, NHCO, CO;

[0068] L2 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K1 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 16 OR key; L3 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) a Or a key, a = 1 to 10, where C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K2 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 17 , AA or bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 , AA or key; L4 and L5 are independently selected from C. 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) b OR key, b = 1 to 10, where C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K4 is selected from NR. 28 Carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl

[0069] Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6-membered heterocycloalkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6-membered heterocycle contains 1-2 atoms optionally selected from O, S, or N;

[0070] L6 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups are optionally surrounded by one or more halogens, NR 22 R 23 O, hydroxyl, C 1-6 Alkyl or C 2-6 Unsaturated alkyl substitution, wherein C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K5 is selected from carbonyl, thiocarbonyl, sulfonyl, ... O, S, NR 29 OR key; L7 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) d OR bond, d = 1 to 10, where C 1-8 Alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, C. 1-6 Alkyl substitution, wherein C 1-6The alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K6 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 30 ... AA or bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 , AA or key; L8, L9, L 10 Each is selected independently from C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) e e = 1 to 10 or a bond, where C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups are optionally surrounded by one or more halogens, O, hydroxyl groups, or NR. 24 R 25 C 1-6 Alkyl substitution, wherein C 1-6 Alkyl groups may optionally be substituted with one or more halogens, O, or hydroxyl groups; K8 and K9 are each independently selected from NR. 32 Carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6 membered heterocyclic alkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, or N; wherein R 16 R 17 R 18 R 28 R 29 R 30 R 31 R 32 Each is independently selected from H and C 1-3 Alkyl or C 2-3 Unsaturated alkyl group, R 22 R 23 R 24 R 25 Independently selected from H and C 1-3 Alkyl, C 2-3 Unsaturated alkyl groups R 26 Selected from H, C 1-6Alkyl, C 2-6 Unsaturated alkyl, C 3-6 Cycloalkyl, wherein AA is selected from amino acid residues, wherein the amino acid is selected from glycine, phenylalanine, arginine, N... ω N ω - Dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine, or isoleucine; ring A1 and ring A2 are independently selected from naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic rings, wherein the naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic ring may be halogenated, CN, nitro, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl substituted.

[0071] R8, R9, R 11 R 12 R 13 R 15 R 33 Each independently selected

[0072] X, Y, and Z are each independently selected from CH, N, and CSO2NR. 34 R 35 CSO2R 36 CNHCOR 37 COR 38 , where R 34 R 36 R 37 R 38 Each independently selected L 11 L 13 Independently selected from C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups or bonds, wherein C 1-6 Alkyl, C 2-6 Unsaturated alkyl groups are optionally surrounded by one or more halogens, NR 39 R 40 O, hydroxyl, C 1-4 Alkyl or C 2-4 Unsaturated alkyl substitution, wherein C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups may optionally be substituted with one or more halogens, O, or hydroxyl groups; K 10 K 12 Independently selected from carbonyl, sulfonyl, O, S, NR 41 OR key; L 12 L14 Independently selected from C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups, (OCH2CH2) f Or key, f = 1 to 3, where C 1-4 Alkyl or C 2-4 Unsaturated alkyl groups may optionally be substituted with one or more halogens, O, or hydroxyl groups; K 11 K 13 Independently selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 42 , AA or bond; J and T are independently selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl groups, wherein C 1-4 The alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 Cycloalkyl groups and 4-6-membered heterocyclic alkyl groups are optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6-membered heterocycle contains 1-2 atoms optionally selected from O, S, or N; R 35 Selected from H, C 1-6 Alkyl, C 2-6 Unsaturated alkyl, C 3-6 cycloalkyl; R 39 R 40 Each is independently selected from H and C 1-3 Alkyl or C 2-3 Unsaturated alkyl groups R 41 R 42 Independently selected from H and C 1-3 Alkyl or C 2-3 Unsaturated alkyl group; wherein AA is selected from amino acid residues, and the amino acid is selected from glycine, phenylalanine, arginine, N... ω N ω - Dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine, or isoleucine; ring A3 is independently selected from a naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic ring, wherein the naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, or benzo5- to 9-membered heteroaromatic ring may be halogenated, CN, nitro, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkyl substituted.

[0073] In some embodiments, the compound, or its metal complex, or its pharmaceutically acceptable salt, or its ester, or its optical isomer, or its stereoisomer, R6 and R7 are each independently selected from H, fluorine, chlorine, methyl, ethyl, trifluoromethyl, and trifluoroethyl, wherein R6 and R7 form a 3- to 6-membered carbon ring. Selected from:

[0074] When R6 and R7 form a 3- to 6-membered heterocyclic ring... Selected from:

[0075] In some embodiments, the compound, or its metal complex, or its pharmaceutically acceptable salt, or its ester, or its optical isomer, or its stereoisomer, R4 and R5 are each independently selected from hydrogen, halogen, -CN, -NO2, -OR. 15 -NR 11 R 12 -CH2R 11 -COR 11 -CH=CHR 11 -C≡CR 11 -CH2R 12 -COR 12 -CH=CHR 12 or -C≡CR 12 ;R 11 R 12 R 15 Each independently selected L2 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups or bonds, wherein C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K1 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 16 OR key; L3 is selected from C 1-8 Alkyl, C 2-8 Unsaturated alkyl groups, (OCH2CH2) a Or a key, a = 1 to 10, where C 1-8 Alkyl, C 2-8 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K2 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, and NR. 17 , AA or bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 , AA or key; L4 and L5 are independently selected from C.1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) b OR key, b = 1 to 10, where C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K4 is selected from NR. 28 Carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl Where C 1-4 Alkyl, C 2-4 The unsaturated alkyl group is optionally substituted with one or more halogens, O, hydroxyl, S, phenyl, or naphthyl groups, wherein C 3-6 The cycloalkyl group or 4-6-membered heterocycloalkyl group is optionally substituted with one or more halogens, O, S, or hydroxyl groups, wherein the 4-6-membered heterocycle contains 1-2 atoms optionally selected from O, S, or N.

[0076] In some embodiments, the compound, or its metal complex, or its pharmaceutically acceptable salt, or its ester, or its optical isomer, or its stereoisomer, wherein ring A1 is selected from:

[0077] Ring A2 is selected from:

[0078] In some embodiments, the compound, or its metal complex, or its pharmaceutically acceptable salt, or its ester, or its optical isomer, or its stereoisomer, is selected from any of the following compounds:

[0079] On the other hand, the present invention provides a pharmaceutical composition comprising the said compound or salt or metal complex, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0080] Furthermore, the use of the aforementioned compound or salt or metal complex, its solvate, metabolite, cocrystal or prodrug, or the aforementioned composition in a medicament for diagnosing and / or treating FAP-mediated diseases.

[0081] Furthermore, in the stated use, the disease is selected from rheumatoid arthritis, non-alcoholic fatty liver disease, atherosclerosis, myocardial infarction, liver fibrosis, pulmonary fibrosis, renal fibrosis, sarcoma, glioblastoma, ovarian cancer, breast cancer, cervical cancer, lung cancer, pancreatic cancer, mesothelioma, skin cancer, colorectal cancer, bladder cancer, gastric cancer, endometrial cancer, or thyroid cancer.

[0082] Detailed description of the invention

[0083] Unless otherwise stated, the terms used in the specification and claims shall have the following meanings.

[0084] "Alkyl" refers to a saturated aliphatic hydrocarbon group. It includes straight-chain or branched groups with 1 to 20 carbon atoms. Preferably, it is a medium-sized alkyl group containing 1 to 8 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, etc. The alkyl group can be substituted or unsubstituted.

[0085] "Cx-y" is intended to include groups containing x to y carbons in the chain. For example, the term "C 1-4 "Alkyl" refers to a saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl containing 1 to 4 carbons.

[0086] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0087] The term "optionally" means that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation may or may not occur, and the description includes both the possibility that the event or situation may occur and the possibility that it does not occur.

[0088] In some implementations, "replaced by one or more groups" means that one, two, three, or four hydrogen atoms of a specified atom or group are replaced by the same or different groups selected from a specified range of groups.

[0089] The definitions and conventions of stereochemistry used in this invention are generally referenced in the following literature: SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Elielj E. and Wilenj S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0090] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers, etc.

[0091] "Pharmaceutically acceptable salts" refers to those salts that retain the bioavailability and properties of the parent compound.

[0092] "Pharmaceutical composition" refers to a mixture of one or more of the compounds of this invention or their pharmaceutically acceptable salts, solvates, hydrates or prodrugs with other chemical components, such as pharmaceutically acceptable carriers.

[0093] "Solvate" refers to an association formed by one or more solvent molecules with the compounds of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0094] "Pharmaceutical carriers" refer to those that do not cause significant irritation to the organism and do not interfere with the biological activity and properties of the administered compound.

[0095] Inactive ingredients in a pharmaceutical composition.

[0096] The beneficial effects of this invention are:

[0097] This invention discloses a compound having the structure of formula (I) or its stereoisomer, and its pharmaceutically acceptable salt or metal complex.

[0098] This invention evaluated the affinity and selectivity of compounds for FAP by testing their inhibitory effects on the activities of FAP and its family proteins DPP2 and DPP4 hydrolases. The results showed that the compounds exhibited good affinity and selectivity for FAP. Kinetic analysis of the inhibition of FAP substrate enzyme activity by some compounds and identification using FAP peptide fingerprinting revealed that compounds of general formula (I) are irreversible inhibitors of FAP proteins. Furthermore, cellular fluorescence staining and competition assays further demonstrated the high specificity of compounds of general formula (I) in binding to FAP, thus elucidating the application of such compounds in the preparation of drugs for the diagnosis and / or treatment of FAP-mediated diseases.

[0099] The abbreviations for the reaction reagents mentioned in the instructions are as follows: DMF: N,N-dimethylformamide; DMA: N,N-dimethylacetamide; DIEA: N,N-diisopropylethylamine; DCM: dichloromethane; DMAP: 4-dimethylaminopyridine; DPPA: diphenyl azidophosphate; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; EtOH: ethanol; EtOAc(EA): ethyl acetate; THF: tetrahydrofuran; TEA: triethylamine; HCl: hydrogen chloride; LiOH·H2O: lithium hydroxide monohydrate; MeOH: methanol; ACN: acetonitrile; AcOH: acetic acid; MeI: iodomethane; Pd(dppf)Cl2·CH2Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium(II)dichloromethane complex; BOP: benzotriazine-1-oxytris(dimethylamino)phosphine hexafluorophosphate; t-BuOH: tert-butanol; BnSH: benzyl thiol; Pd2(dba)3: tridibenzylacetone dipalladium; NaBH3CN: sodium cyanoborohydride; NaOMe: sodium methoxide; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate. Attached Figure Description

[0100] Figure 1 shows the fingerprint identification of the peptide binding to FAP protein Ser624 by compound 20;

[0101] Figure 2 shows the fluorescent gel results of FAP, DPP4, and HSA labeled with fluorescent molecule 82 in the example;

[0102] Figure 3 shows the staining results of fluorescent molecule 82 cells in the example;

[0103] Figure 4 shows the results of inhibiting the fluorescent molecule 82-labeled FAP protein in non-fluorescent live cells in the example. Detailed Implementation

[0104] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are implemented under the premise of the technical solution of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0105] Example:

[0106] Synthesis of intermediates:

[0107] Intermediate 1:

[0108] In a reaction flask, indigo (3.25 g, 22.1 mmol) and sodium hydroxide (12.0 g, 0.3 mol) were added and dissolved in 100 mL of water. The mixture was stirred at 80 °C for 1 h. The mixture was then cooled to 25 °C, and propionaldehyde (1.28 g, 22.1 mmol, 1.61 mL) was added. The mixture was then stirred at 100 °C for 11 h. LC-MS showed the presence of the target molecular weight. The reaction mixture was adjusted to pH 5-6 with 1 M HCl, the suspension was filtered, and the filtrate was concentrated under reduced pressure to give crude yellow solid intermediate 1 (3 g).

[0109] Intermediate 2:

[0110] Following the synthesis method of intermediate 1, using 5-methoxyindigo (5g) as the raw material, crude yellow solid intermediate 2 (1.81g) was obtained.

[0111] Intermediate 3:

[0112] 2,2-Diethylmalonyl dichloro (1.14 g, 5.78 mmol) was dissolved in DCM (10 mL), and DIEA (1.36 g, 10.5 mmol) and N-Boc-2-hydroxypropanediamine (1 g, 5.26 mmol) were added sequentially. The mixture was stirred at 25 °C for 12 hours. Thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) showed that N-Boc-2-hydroxypropanediamine was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give a yellow oily intermediate 3-1 (600 mg).

[0113] HCl / EtOAc (4M, 2mL) was added to intermediate 3-1 (100mg, 318μmol), and the mixture was stirred at 25°C for 1 hour. LC-MS showed that intermediate 3-1 was completely consumed. The reaction mixture was filtered, the filter cake was collected and dried under vacuum to give a white solid intermediate 3 hydrochloride (55mg). MS (ESI) + ):m / z 215.1[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.97 (br s, 3H), 5.78 (d, J = 6.0Hz, 1H), 4.00-3.91 (m, 1H), 3.35-3.31 (m, 2H), 2.92 (br d, J=12.4Hz, 1H), 2.74-2.63 (m, 1H), 1.70 (q, J=7.6Hz, 4H), 0.92 (t, J=7.6Hz, 6H).

[0114] Intermediate 4:

[0115] To a methanol (10 mL) solution of p-nitrobenzenenitrile (1 g, 6.75 mmol), NaOMe (729.46 mg, 13.50 mmol) was added, and the mixture was stirred at 25 °C for 12 hours. LC-MS showed that the p-nitrobenzenenitrile was completely consumed. The reaction mixture was filtered, and the residue was washed with methanol (5 mL x 3). The filtrates were combined and concentrated under reduced pressure to give crude yellow solid intermediate 4-1 (1.1 g).

[0116] Intermediate 4-1 crude product (1.1 g, 6.11 mmol), ethyl 2-diazo-3-oxobutyrate (1.05 g, 6.72 mmol), silver hexafluoroantimonate (167.84 mg, 488.45 μmol), and di-1,2,3,4,5-pentamethylcyclopentene rhodium dichloride (71.78 mg, 122.11 μmol) were suspended in methanol (15 mL). The mixture was degassed by N2 and repeated three times. The mixture was then heated to 50 °C and stirred for 12 hours under N2 atmosphere. LC-MS showed that intermediate 4-1 was completely consumed. The reaction mixture was filtered, and the filter cake was washed with methanol (5 mL * 3). The filtrates were combined and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give intermediate 4-2 (170 mg, yield 9.59%), a pale yellow solid.

[0117] LiOH·H₂O (122.88 mg, 2.93 mmol) was added to a mixed solution of intermediate 4-2 (170 mg, 585.66 μmol) in THF (2 mL) and water (2 mL). The mixture was heated to 80 °C and stirred for 12 hours. LC-MS showed that intermediate 4-2 was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters Xbridge BEH C18 100*30 mm, 10 μm; [H₂O(10 mMNH₄HCO₃)-ACN]; 1%–35%) to give a yellow solid intermediate 4-3 (50 mg, 32.56% yield). MS (ESI) + ):m / z263.2[M+H] + .

[0118] Intermediate 5:

[0119] 5-Bromo-3-chloroisoquinoline (700 mg, 2.89 mmol) was dissolved in DMA (5 mL), and DIEA (746 mg, 5.77 mmol, 1.01 mL) and N,N,N'-trimethyl-1,3-propanediamine (1.34 g, 11.6 mmol, 1.69 mL) were added sequentially. The mixture was heated to 140 °C and stirred for 12 hours. The reaction mixture was diluted with water (30 mL), extracted with EtOAc (10 mL * 3), and the combined organic layers were washed with saturated brine (10 mL) and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane / methanol = 1 / 0 * 0 / 1) to give a yellow solid intermediate 5-1 (800 mg, 77.4%).

[0120] Intermediate 5-1 (750 mg, 2.33 mmol) was dissolved in DMA (9 mL), and TEA (471 mg, 4.65 mmol, 647 μL) and Pd(dppf)Cl2·CH2Cl2 (190 mg, 232 μmol) were added sequentially under nitrogen protection. The mixture was degassed and replaced with CO three times. The mixture was stirred at 110 °C for 12 hours under a CO (15 psi) atmosphere. It was diluted with water (15 mL), extracted with EtOAc (10 mL * 3), and the combined organic layers were washed with saturated brine (10 mL * 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH = 1 / 1 to 0 / 1) to obtain crude yellow oily intermediate 5-2 (700 mg).

[0121] THF (9 mL) and water (3 mL) were added to crude intermediate 5-2 (300 mg), and after stirring to dissolve, sodium hydroxide (398 mg, 9.95 mmol) was added. The mixture was heated to 80 °C and stirred for 12 hours. LC-MS showed that intermediate 5-2 was completely consumed. The reaction mixture was concentrated under reduced pressure, and the resulting green solid was purified by preparative HPLC (Xbridge BEH C18 100*30 mm, 10 μm; H2O (10 mM NH4HCO3)-ACN, 1–30%) to obtain crude yellow intermediate 5 (47 mg).

[0122] Intermediate 6:

[0123] TEA (8.55 mL, 61.5 mmol), TosCl (5.85 g, 30.7 mmol), and DMAP (250 mg, 2.05 mmol) were added sequentially to a DCM (50 mL) solution of 4-tert-butyloxycarbonyl-1-(3-hydroxypropyl)piperazine (5.00 g, 20.5 mmol). The mixture was stirred at 25 °C for 2 hours. LC-MS showed that 4-tert-butyloxycarbonyl-1-(3-hydroxypropyl)piperazine was completely consumed. The reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with brine (30 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude yellow oily intermediate 6-1 (8.00 g).

[0124] The crude intermediate 2 (5.00 g, 23.0 mmol) was added to hydrobromic acid (10 mL, 43.0%), heated to 130 °C under N2 protection and stirred for 2 hours. The mixture was then concentrated under reduced pressure to obtain a brown solid crude intermediate 6-2 (5.00 g).

[0125] Potassium carbonate (10.2 g, 73.8 mmol) and crude intermediate 6-1 (7.85 g, 19.7 mmol) were added sequentially to a DMF (50 mL) solution of crude intermediate 6-2 (5.00 g, 24.6 mmol). The mixture was heated to 60 °C and stirred for 12 hours. LC-MS showed that intermediate 6-2 was completely consumed. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with brine (50 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (SiO2, ethyl acetate / methanol = 10 / 1 to 0 / 1) to give a yellow oily intermediate 6-3 (1.20 g).

[0126] Water (5 mL) and sodium hydroxide (365 mg, 9.15 mmol) were added to a MeOH (5 mL) solution of intermediate 6-3 (1.20 g, 1.83 mmol). The mixture was heated to 70 °C and stirred for 1 hour. LC-MS showed that intermediate 6-3 was completely consumed. 1 N hydrochloric acid was added to adjust the pH of the reaction mixture to 5, and a solid precipitated. The solid was filtered, the filter cake was collected, and dried under reduced pressure. The obtained solid was purified by preparative HPLC (Phenomenex Gemini C1875*40 mm*5 μm; [H2O(10 mMNH4HCO3)-ACN], 5%–40%) to give a yellow solid intermediate 6 (180 mg). 1H NMR (400MHz, CD3OD) δ8.56(s,1H),7.87(d,J=9.2Hz,1H),7.35(dd,J=2.8,9.2Hz,1H),7.29(d,J=2.8Hz,1H),4.29-4.21(m,2H), 3.75-3.64(m,4H),3.34-3.32(m,1H),3.30-3.28(m,1H),3.27-3.20(m,4H),2.55-2.49(m,3H),2.38-2.21(m,2H),1.49(s,9H).

[0127] Intermediate 7 and Intermediate 8:

[0128] 10.0 g (44.2 mmol) of 5-bromoindoline-2,3-dione was added to an aqueous solution of sodium hydroxide (3 M, 100 mL), heated to 80 °C, and stirred for 1 hour. The reaction mixture was cooled to 25 °C, and 3.22 mL (44.2 mmol) of propionaldehyde was added. The mixture was heated to 100 °C and stirred for 11 hours. The pH of the reaction mixture was adjusted to 5-6 with 1 N hydrochloric acid. The mixture was filtered, and the filtrate was concentrated under reduced pressure and then slurried with acetic acid (300 mL) at 25 °C for 30 min. The mixture was filtered, and the filter cake was collected and dried under reduced pressure to obtain a yellow solid intermediate 7 crude product (5.00 g).

[0129] DMF (723 μL, 9.40 mmol) and (COCl)₂ (3.29 mL, 37.6 mmol) were added to 30 mL of DCM containing crude intermediate 7 (5.00 g, 18.0 mmol). The mixture was cooled to 0 °C and stirred for 1 hour. Methanol (5 mL) was added, and the mixture was stirred at 0 °C for 10 min. LC-MS showed that intermediate 7 was completely consumed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenexluna C18 100*40 mm, 5 μm; [H₂O (0.2% FA)-ACN], 20%–60%) to give a yellow solid intermediate 8-1 (1.00 g, yield 19.0%).

[0130] Under N2 protection, Cs2CO3 (1.40 g, 4.28 mmol) and BrettPhos-Pd-G4 (198 mg, 214 μmol) were added sequentially to a solution of intermediate 8-1 (600 mg, 2.14 mmol) and 3-(methylamino)-1-propanol (382 mg, 4.28 mmol) in 1,4-dioxane (10 mL). The mixture was heated to 90 °C and stirred for 12 hours. BrettPhos-Pd-G4 (198 mg, 214 μmol) was then added, and the reaction was continued at 90 °C for another 12 hours. LC-MS showed complete consumption of intermediate 8-1. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to rapid silica gel column chromatography (LC-MS). Purification was performed using 20.0 g of ethyl acetate / petroleum ether (0–100%; 120 mL / min) to give a yellow oily intermediate 8-2 (400 mg, yield 64.8%).

[0131] At 0°C, TEA (435 μL, 3.12 mmol) and MsCl (243 μL, 3.14 mmol) were added sequentially to a DCM (5 mL) solution of intermediate 8-2 (300 mg, 1.04 mmol). The mixture was stirred and kept at this temperature for 0.5 h. LC-MS showed that intermediate 8-2 was completely consumed. The reaction was quenched with water (5 mL), extracted with DCM (5 mL * 2), and the organic layers were combined. The mixture was washed with brine (5 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude yellow oily intermediate 8-3 (360 mg).

[0132] Potassium carbonate (407 mg, 2.95 mmol) and tert-butylpiperazine-1-carboxylic acid ester (274 mg, 1.47 mmol) were added sequentially to a 10 mL solution of crude intermediate 8-3 (360 mg, 982 μmol) in ACN. The mixture was heated to 80 °C and stirred for 12 hours. LC-MS showed that intermediate 8-3 was completely consumed. The solution was diluted with water (10 mL), extracted with EtOAc (10 mL * 3), and the organic phases were combined. The mixture was washed with brine (10 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude yellow oily intermediate 8-4 (450 mg).

[0133] LiOH·H₂O (165 mg, 3.94 mmol) was added to a mixed solution of crude intermediate 8-4 (360 mg, 789 μmol) in THF (3 mL), water (2 mL), and methanol (3 mL). The mixture was heated to 80 °C and stirred for 24 hours. LC-MS showed that intermediate 8-4 was completely consumed. The pH of the reaction mixture was adjusted to 6 with 1 N hydrochloric acid (2 mL), and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Gemini C1875*40 mm, 5 μm; [H₂O(10 mMNH₄HCO₃)-ACN], 5%–40%) to give a yellow solid intermediate 8 (110 mg, yield 31.5%). MS (ESI) was then used. + ):m / z443.3[M+H] + .

[0134] Intermediate 9:

[0135] DIEA (477.46 mg, 3.69 mmol) and 5-(chlorosulfonyl)-1-naphthic acid (0.5 g, 1.85 mmol) were added to a DCM (5 mL) solution of propargylamine (122.08 mg, 2.22 mmol). The mixture was stirred at 25 °C for 12 hours. LC-MS showed that the (chlorosulfonyl)-1-naphthic acid was completely consumed. The pH of the reaction mixture was adjusted to 1 with 1 N hydrochloric acid, and a solid precipitated. The solid was filtered, washed with water (5 mL), and dried to give a pale yellow solid intermediate 9 (150 mg). Intermediate 10:

[0136] DIEA (477.46 mg, 3.69 mmol) and 5-(chlorosulfonyl)-1-naphthic acid (0.5 g, 1.85 mmol) were added to a DCM (5 mL) solution of cyclopropylamine (126.76 mg, 2.22 mmol). The mixture was stirred at 25 °C for 12 hours. LC-MS showed that the (chlorosulfonyl)-1-naphthic acid was completely consumed. The pH of the reaction mixture was adjusted to 1 with 1 N hydrochloric acid, and a solid precipitated. The solid was filtered, washed with water (5 mL), and dried to give a pale yellow solid, intermediate 10 (138 mg). Intermediate 11:

[0137] DIEA (63.6 mg, 491 μmol) and cyclopropylamine (14.1 mg, 245 μmol) were added to a DCM (2 mL) solution of methyl 4-(chlorosulfonyl)-1-naphthyl acid (70 mg, 245 μmol). The mixture was stirred at 25 °C for 12 h. LC-MS showed that methyl 4-(chlorosulfonyl)-1-naphthyl acid was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to give a colorless oily intermediate 11-1 (75 mg).

[0138] To a THF (1 mL) solution of intermediate 11-1 (75 mg, 245 μmol), water (1 mL) and LiOH·H₂O (51.5 mg, 1.23 mmol) were added sequentially. The mixture was heated to 70 °C and stirred for 2 hours. LC-MS showed that intermediate 5-1 was completely consumed. The reaction mixture was diluted with water (2 mL), and the pH was adjusted to 5 with 1 N hydrochloric acid. The mixture was then extracted with EtOAc (2 mL * 3). The combined organic phases were washed with brine (2 mL * 2), dried over sodium sulfate, filtered, and the filtrate was concentrated to obtain a white solid crude intermediate 11 (70 mg).

[0139] Intermediate 12:

[0140] Fe (9.62 g, 172 mmol) and ammonium chloride (9.21 g, 172 mmol) were added to a mixed solution of intermediate 4-2 (5.00 g, 17.2 mmol) in ethanol (50 mL) and water (5 mL). The mixture was heated to 80 °C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 0 / 1) to give a yellow oily intermediate 12-1 (4.20 g).

[0141] To a THF (40 mL) solution of intermediate 12-1 (3.00 g, 11.5 mmol), 3-[tert-butyl(dimethyl)silyl]oxypropionaldehyde (2.60 g, 13.8 mmol), AcOH (659 μL, 11.5 mmol), and NaBH3CN (1.45 g, 23.0 mmol) were added sequentially, and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (40 mL), extracted with EtOAc (30 mL x 3), the organic phases were combined, washed with brine (20 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 51 to 0 / 1) to give a yellow oily intermediate 12-2 (2.00 g).

[0142] Potassium carbonate (1.92 g, 13.9 mmol) and MeI (432 μL, 6.90 mmol) were added sequentially to a 20 mL solution of intermediate 12-2 (2.00 g, 4.62 mmol) in ACN. The mixture was heated to 60 °C and stirred for 12 hours. The reaction mixture was diluted with water (5 mL), extracted with EtOAc (3 mL x 3), the organic phases were combined, washed with brine (3 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to give a colorless oily intermediate 12-3 (1.67 g).

[0143] To a THF (25 mL) solution of intermediate 12-3 (1.67 g, 3.74 mmol), TBAF (1 M, 7.48 mL) was added, and the mixture was stirred at 25 °C for 1 hour. LC-MS showed that intermediate 12-3 was completely consumed. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL * 3), the organic phases were combined, washed with brine (20 mL * 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 0 / 1) to give a yellow oily intermediate 12-4 (1.16 g). 1 HNMR(400MHz, CDCl3)δ8.03(d,J=9.2Hz,1H),7.05-7.00(m,1H),6.98-6.94(m,1H),4.51-4.43(m,2H),4.10-4.06(m,3H ),3.77-3.69(m,2H),3.64-3.56(m,2H),3.09-3.04(m,3H),2.60-2.54(m,3H),1.92-1.83(m,2H),1.45(t,J=7.2Hz,3H).

[0144] At 0°C, TEA (377 μL, 2.71 mmol) and MsCl (243 μL, 3.14 mmol) were added sequentially to a DCM (5 mL) solution of intermediate 12-4 (300 mg, 903 μmol). The mixture was stirred and kept at this temperature for 0.5 h. LC-MS showed that intermediate 12-4 was completely consumed. The reaction mixture was diluted with water (8 mL), extracted with DCM (5 mL * 3), the organic phases were combined, washed with brine (5 mL * 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude yellow oily intermediate 12-5 (370 mg).

[0145] Potassium carbonate (373 mg, 2.70 mmol) and N-tert-butyloxycarbonylpiperazine (184 mg, 991 μmol) were added sequentially to a 5 mL solution of crude intermediate 12-5 in ACN. The mixture was heated to 80 °C and stirred for 12 hours. LC-MS showed that intermediate 12-5 was completely consumed. The reaction mixture was diluted with water (8 mL), extracted with EtOAc (5 mL x 3), the organic phases were combined, washed with brine (5 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give a yellow oily intermediate 12-6 (240 mg). 1 H NMR (400MHz, DMSO-d6) δ7.94 (d, J = 9.2Hz, 1H), 7.23-7.10 (m, 1H), 6.73-6.63 (m, 1H), 4.06-4.01 (m, 2H), 4.01-3.98 (m, 3H), 3.48 (br t,J=7.2Hz,2H),3.32-3.27(m,4H),2.99(s,3H),2.43(s,3H),2.33-2.21(m,6H),1.75-1.64(m,2H),1.42-1.37(m,9H),1.37-1.33(m,3H).

[0146] Potassium hydroxide (134 mg, 2.40 mmol) was added to a mixed solution of intermediate 12-6 (240 mg, 479 μmol) in MeOH (2 mL) and water (2 mL). The mixture was heated to 80 °C and stirred for 14 hours. The pH of the reaction mixture was adjusted to 5 with 1 N hydrochloric acid, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Gemini C1875*40 mm, 5 μm; [H2O(10 mM NH4HCO3)-ACN], 10%–50%) to give a white solid intermediate 12 (12.0 mg, yield 5.30%). 1 H NMR (400MHz, DMSO-d6) δ7.94(d,J=9.2Hz,1H),7.17(dd,J=2.4,9.2Hz,1H),6.81(d,J=2.0Hz,1H),3.99(s,3H),3.51-3. 45(m,4H),3.01-2.97(m,3H),2.53-2.51(m,2H),2.48-2.42(m,3H),2.34-2.25(m,6H),1.77-1.65(m,2H),1.39(s,9H).

[0147] Intermediate 13:

[0148] To a toluene (10 mL) solution of intermediate 10 (500 mg, 1.72 mmol), DPPA (708.49 mg, 2.57 mmol) and TEA (521.02 mg, 5.15 mmol) were added sequentially. After stirring at 25 °C for 2 hours, ethanol (711.61 mg, 15.45 mmol) was added, and the mixture was heated to 70 °C under N2 protection and stirred for 2 hours. Then, EtOH (3 mL) and potassium hydroxide (866.65 mg, 15.45 mmol) were added, and the mixture was stirred at 70 °C for 4 hours. LC-MS showed that intermediate 10 was completely consumed. The reaction mixture was diluted with water (10 mL), extracted with EA (5 mL x 3), the organic phases were combined and washed with brine (5 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by rapid silica gel column chromatography to give a brown oily intermediate 13 (150 mg, yield 33.32%).

[0149] Intermediate 14:

[0150] Under N2 protection, TEA (3.71 mL, 26.7 mmol) and Pd(dppf)Cl2·CH2Cl2 (1.09 g, 1.33 mmol) were added to a mixed solution of 8-bromoquinazoline-4-ol (3 g, 13.3 mmol) in methanol (10 mL) and DMA (30 mL). The reaction mixture was degassed and replaced with CO (50 psi) three times. Subsequently, the mixture was heated to 80 °C and stirred for 12 hours under a CO (50 psi) atmosphere. LC-MS showed that 8-bromoquinazoline-4-ol was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was slurried with DCM (10 mL) and EtOAc (10 mL) at 25 °C for 10 min. The residue was filtered and the cake was collected to give crude yellow solid intermediate 14-1 (1 g).

[0151] Under N2 protection, BOP (1.41 g, 3.18 mmol), DBU (745 mg, 4.9 mmol), and N2 were added sequentially to a DMF (5 mL) solution of crude intermediate 14-1 (500 mg, 2.45 mmol). 1 N 1 N 3 Trimethyl-1,3-propanediamine (569 mg, 4.9 mmol) was reacted with stirring at 25 °C for 2 h. LC-MS showed that intermediate 14-1 was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (SiO2, DCM / MeOH = 5 / 1) to give a yellow oily intermediate 14-2 (340 mg, yield 45.92%). 1HNMR(400MHz,DMSO-d6)δ8.50-8.46(m,1H),8.29-8.23(m,1H),7.93-7.86(m,1H),7.53-7.46(m,1H), 3.88-3.83(m,3H),3.78-3.72(m,2H),3.36(s,3H),2.39-2.32(m,2H),2.20(s,6H),1.93-1.85(m,2H).

[0152] Intermediate 14-2 (340 mg, 1.12 mmol) was dissolved in THF (2 mL), followed by the addition of water (2 mL) and LiOH·H2O (235 mg, 5.62 mmol). The mixture was heated to 80 °C and stirred for 12 hours. LC-MS showed that intermediate 14-2 was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Phenomenex Gemini C1875*40 mm, 5 μm; [H2O(10 mMNH4HCO3)-ACN], 2%–15%) to obtain crude yellow oily intermediate 14 (40 mg).

[0153] Intermediate 15:

[0154] Intermediate 4 (910 mg, 3.47 mmol) and TEA (1.40 g, 13.9 mmol) were dissolved in toluene (9 mL) and t-BuOH (9 mL). The mixture was heated to 80 °C under N2 protection, and DPPA (899 μL, 4.16 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred for 6 hours. LC-MS showed that intermediate 4 was completely consumed. The reaction mixture was cooled to 25 °C and quenched with water (10 mL). The reaction mixture was filtered, the filter cake was washed with water (5 mL), the filtrates were combined, extracted with ethyl acetate (15 mL * 2), the organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to rapid silica gel column chromatography (…). 40.0 g; ethyl acetate / petroleum ether, 0-5%; 80 mL / min) was purified by chromatography to give a red solid intermediate 15-1 (360 mg, yield 31.1%).

[0155] TFA (575 μL, 7.74 mmol) was added to a THF (4.3 mL) solution of intermediate 15-1 (430 mg, 1.29 mmol), and the reaction was stirred at 25 °C for 14 hours. LC-MS showed that intermediate 15-1 was completely consumed. DIEA was added to adjust the pH of the reaction mixture to 8, then water (5 mL) was added for dilution, followed by extraction with DCM (3 mL * 2). The organic phases were combined, washed with brine (5 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to rapid silica gel column chromatography (…). 12.0 g; ethyl acetate / petroleum ether, 0–10%; 40 mL / min) was purified by chromatography to give a red solid intermediate 15 (280 mg, yield 93.1%). MS (ESI) + ):m / z234.1[M+H] + .

[0156] Intermediate 16:

[0157] To a DCM (40 mL) solution of 6-hydroxynaphthyl acid (1.00 g, 5.31 mmol), DMF (40.9 μL, 531 μmol) and oxalyl chloride (558 μL, 6.38 mmol) were added sequentially. The mixture was stirred at 25 °C for 1 h, followed by the addition of methanol (10 mL) and stirring at 25 °C for another 30 min. The mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography to give a yellow solid intermediate 16-1 (350 mg, yield 32.6%).

[0158] Under N2 protection, a solution of intermediate 16-1 (350 mg, 1.73 mmol) in DCM (3 mL) was cooled to -78 °C, and DIEA (905 μL, 5.19 mmol) and trifluoromethanesulfonic anhydride (343 μL, 2.08 mmol) were added. The mixture was stirred and kept at this temperature for 1 hour. The reaction was quenched with ammonium chloride (5 mL), extracted with DCM (5 mL x 2), and the organic phases were combined, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography to give a white solid intermediate 16-2 (408 mg, 70.5% yield). 1 H NMR (400MHz, DMSO-d6) δ8.93 (d, J = 9.6 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.30-8.23 (m, 2H), 7.79-7.72 (m, 2H), 3.95 (s, 3H).

[0159] Intermediate 16-2 (350 mg, 1.05 mmol), DIEA (406 mg, 3.14 mmol), BnSH (293 μL, 2.50 mmol), Pd2(dba)3 (95.9 mg, 105 μmol), and Xantphos (60.6 mg, 105 μmol) were added to 1,4-dioxane (4 mL), degassed, and purged with N2 three times. The mixture was then heated to 100 °C under N2 atmosphere and stirred for 12 hours. LC-MS showed that intermediate 16-2 was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography to give a yellow oily intermediate 16-3 (320 mg, 99.1% yield). 1 H NMR (400MHz, DMSO-d6) δ8.65 (br d, J=9.0Hz, 1H), 8.14-8.03 (m, 2H), 7.96 (br s,1H),7.64-7.53(m,2H),7.48-7.39(m,3H),7.33-7.28(m,2H),4.39(br s,2H),3.92(d,J=2.8Hz,3H).

[0160] Intermediate 16-3 (320 mg, 1.04 mmol) was dissolved in AcOH (2 mL), THF (0.4 mL), and water (0.4 mL). The mixture was cooled to 0 °C, and NCS (554 mg, 4.15 mmol) was added. After the addition was complete, the mixture was heated to 25 °C and stirred for 1 hour. LC-MS showed that intermediate 16-3 was completely consumed. The mixture was diluted with water (5 mL), extracted with EtOAc (2 mL x 3), and the organic phases were combined. The extract was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was used for preparative thin-layer chromatography (SiO2). 2, Purification with petroleum ether / ethyl acetate (5 / 1) yielded a colorless oily intermediate 16-4 (120 mg, yield 40.6%). 1 H NMR (400MHz, DMSO-d6) δ8.70(d,J=8.8Hz,1H),8.29-8.21(m,2H),8.17-8.11(m,1H),7.84(dd,J=1.6,8.8Hz,1H),7.62(t,J=7.6Hz,1H),3.94(s,3H).

[0161] To a DCM (1 mL) solution of intermediate 16-4 (120 mg, 421 μmol), DIEA (109 mg, 843 μmol) and cyclopropylamine (35.0 μL, 506 μmol) were added, and the mixture was stirred at 25 °C for 8 hours. LC-MS showed that intermediate 16-4 was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to give a colorless colloidal intermediate 16-5 (100 mg, yield 77.7%).

[0162] LiOH·H₂O (68.7 mg, 1.64 mmol) was added to a mixed solution of intermediate 16-5 (100 mg, 327 μmol) in THF (1 mL) and water (1 mL). The mixture was heated to 70 °C and stirred for 2 hours. LC-MS showed that intermediate 16-5 was completely consumed. The pH of the reaction mixture was adjusted to 1 with 1 N hydrochloric acid, filtered, and the filter cake was collected. The solid was washed with water (5 mL) and dried to obtain a white solid crude intermediate 16 (90.0 mg).

[0163] Intermediate 17:

[0164] To a solution of 5-bromo-3-chloroisoquinoline (6.00 g, 24.7 mmol) in THF (50 mL), DIEA (9.59 g, 74.2 mmol) and 4-methylaminobutanol (5.10 g, 49.5 mmol) were added sequentially. The mixture was pumped into a flow chemistry reactor and reacted at 240 °C for 0.5 h. LC-MS showed complete consumption of 5-bromo-3-chloroisoquinoline. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography. The sample was purified by chromatography (80.0 g; ethyl acetate / petroleum ether, 0-84%; 100 mL / min) to give a green oily intermediate 17-1 (1.00 g, yield 13.1%).

[0165] DMP (3.23 g, 7.61 mmol) was added to a mixed solution of intermediate 17-1 (1.47 g, 4.75 mmol) in DCM (10 mL) and THF (10 mL). The mixture was stirred at 25 °C for 1 hour. LC-MS showed that intermediate 17-1 was completely consumed. The solution was diluted with saturated sodium sulfite aqueous solution (20 mL), extracted with DCM (10 mL x 3), and the organic layers were combined. The mixture was washed with brine (10 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to rapid silica gel column chromatography (…). 20.0 g; ethyl acetate / petroleum ether, 0-13%; 80 mL / min) was purified by chromatography to give a yellow oily intermediate 17-2 (1.40 g, yield 95.9%).

[0166] N-Cbz-piperazine (1.20 g, 5.47 mmol) and intermediate 17-2 (1.40 g, 4.56 mmol) were dissolved in THF (15 mL), and AcOH (27.4 mg, 456 μmol) and NaBH3CN (573 mg, 9.12 mmol) were added sequentially. The mixture was stirred at 25 °C for 12 hours. LC-MS showed that intermediate 17-2 was completely consumed. The mixture was diluted with water (10 mL), extracted with EtOAc (10 mL * 3), and the organic phases were combined. The extract was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to rapid silica gel column chromatography (…). 20.0 g; ethyl acetate / petroleum ether, 0-100%; 80 mL / min) was purified by chromatography to give a yellow oily intermediate 17-3 (1.10 g, yield 47.2%).

[0167] Intermediate 17-3 (1.10 g, 2.15 mmol) was degassed three times with a mixture of DMA (10 mL) and methanol (10 mL) under N2 protection. Then, under N2 protection, diphenylcyclohexylphosphide palladium dichloromethane (176 mg, 215 μmol) and TEA (599 μL, 4.30 mmol) were added sequentially, followed by degassed three times with CO. The reaction was stirred for 12 hours under a CO (50 psi) atmosphere. LC-MS showed complete consumption of intermediate 17-3. The solution was diluted with water (10 mL), extracted with EtOAc (10 mL x 3), and the organic phases were combined. The solution was washed with brine (10 mL x 3), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to rapid silica gel column chromatography (…). 20.0 g; ethyl acetate / petroleum ether, 0-44%; 80 mL / min) was purified by chromatography to give a yellow oily intermediate 17-4 (950 mg, yield 90.0%).

[0168] Water (2 mL) and lithium hydroxide (232 mg, 9.68 mmol) were added sequentially to a THF (10 mL) solution of intermediate 17-4 (950 mg, 1.94 mmol), and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Phenomenex Gemini C1875*40 mm, 5 μm; [H2O(10 mMNH4HCO3)-ACN], 20%–50%) to give a yellow solid intermediate 17 (300 mg, yield 32.5%).

[0169] Intermediate 18:

[0170] Potassium carbonate (1.43 g, 10.38 mmol) and crude intermediate 6-1 (2.48 g, 6.23 mmol) were added sequentially to a DMF (5 mL) solution of intermediate 16-1 (1.05 g, 5.19 mmol). The mixture was heated to 60 °C and stirred for 12 hours. LC-MS showed that intermediate 16-1 was completely consumed. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with brine (50 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (SiO2, ethyl acetate / methanol = 10 / 1 to 0 / 1) to give a yellow oily intermediate 18-1 (1.56 g).

[0171] LiOH·H2O (98.0 mg, 2.33 mmol) was added to a mixed solution of intermediate 18-1 (200 mg, 467 μmol) in THF (2 mL) and water (1 mL). The mixture was heated to 70 °C and stirred for 2 hours. LC-MS showed that intermediate 18-1 was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Phenomenex Gemini C1875*40 mm, 5 μm; [H2O(10 mM NH4HCO3)-ACN], 10%-50%) to give a white solid intermediate 18 (150 mg, yield 77.5%). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.77 (d, J = 9.2Hz, 1H), 8.03 (d, J = 8.0Hz, 1H), 7.96 (d, J = 7.2Hz, 1H), 7.51 (t, J = 7.6Hz, 1H), 7.40 (d, J = 2.0Hz, 1H), 7.27 (dd, J = 2.4, 9.2Hz, 1H), 4.14 (br t, J = 6.4Hz, 2H), 3.31 (br s, 6H), 2.38–2.30 (m, 4H), 1.97–1.86 (m, 2H), 1.39 (s, 9H). Intermediate 19:

[0172] Under nitrogen protection and at 0°C, 1.00 g (3.98 mmol) of 8-bromo-1-naphthic acid was slowly added to 3 mL of HSO3Cl. The mixture was heated to 60°C and stirred for 12 hours. The reaction mixture was then slowly poured into 10 mL of ice water to quench the reaction, precipitating a solid. The solid was filtered, and the filter cake was collected and washed with 3 mL of water. The mixture was then dried under reduced pressure to obtain 1.00 g of crude yellow solid intermediate 19-1. 1 H NMR (400MHz, DMSO-d6) δ9.06 (dd, J = 1.6, 8.4Hz, 1H), 7.89 (s, 2H), 7.71-7.57 (m, 2H).

[0173] DIEA (996 μL, 5.72 mmol) and 3-methoxypropyl-1-amine (305 mg, 3.43 mmol) were added to a dichloromethane solution (1.00 g) of crude intermediate 19-1 in 15 mL, and the mixture was stirred at 25 °C for 0.5 h. The mixture was diluted with water (5 mL), extracted with dichloromethane (5 mL x 3), and the aqueous phase was collected and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex luna C18 100 x 40 mm, 5 μm; [H₂O (0.2% formic acid)-ACN], 15%–50%) to give a white solid intermediate 19 (130 mg, yield 11.3%). 1 H NMR (400MHz, DMSO-d6) δ13.59-13.42(m,1H),8.84-8.80(m,1H),8.20-8.15(m,1H),8.14-8.11(m,1H),8.04(d,J =8.0Hz,1H),7.86-7.78(m,2H),3.16-3.11(m,2H),3.03-2.96(m,3H),2.84(q,J=6.4Hz,2H),1.59-1.44(m,2H).

[0174] Intermediate 20:

[0175] Under nitrogen protection, triethylamine (688 μL, 4.94 mmol) and DPPA (5.49 μL, 2.43 mmol) were added sequentially to a mixed solution of intermediate 19 (650 mg, 1.62 mmol), toluene (6.5 mL), and tert-butanol (6.5 mL). The mixture was heated to 80 °C and stirred for 12 hours. The reaction was quenched with water (10 mL), extracted with ethyl acetate (5 mL x 3), and the organic phases were combined and washed with saturated brine (10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to rapid silica gel column chromatography (…). Purification was performed using 12.0 g of ethyl acetate / hexane (0–18%) at a flow rate of 80 mL / min to obtain crude purple oil intermediate 20-1 (350 mg).

[0176] Trifluoroacetic acid (1 mL) was added to a solution of crude intermediate 20-1 (350 mg) in dichloromethane (3.5 mL), and the mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Phenomenex Luna C1875*30 mm, 3 μm; [H2O(0.1% TFA)-ACN], 20%–50%) to give trifluoroacetate of intermediate 20 as a yellow solid (140 mg, yield 38.9%). 1H NMR (400MHz, DMSO-d6) δ7.95-7.87(m,2H),7.83-7.79(m,1H),7.78-7.73(m,1H),7.43(t,J=8.0Hz,1H), 6.99 (d, J = 7.6Hz, 1H), 3.14 (t, J = 6.0Hz, 2H), 3.03 (s, 3H), 2.78 (q, J = 6.4Hz, 2H), 1.50 (q, J = 6.4Hz, 2H).

[0177] Intermediate 21:

[0178] Under nitrogen protection and at 0°C, 10.0 g (53.1 mmol) of 2-hydroxy-1-naphthic acid was added in portions to 50 mL of HSO3Cl. The ice bath was removed, and the reaction mixture was heated to 20°C and stirred for 12 hours. The mixture was quenched with ice water (200 mL) at 0°C, precipitating a solid. The solid was collected by filtration, washed with water (10 mL x 3), and dried under reduced pressure to obtain 15.0 g of crude, grayish-white solid intermediate 21-1. 1 H NMR (400MHz, DMSO-d6) δ8.35 (d, J = 9.2 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.74 (dd, J = 1.6, 9.2 Hz, 1H), 7.21 (d, J = 9.2 Hz, 1H).

[0179] DIEA (27.3 mL, 157 mmol) was added to a DCM (150 mL) solution of crude intermediate 21-1 (15.0 g, 52.3 mmol) and cyclopropylamine (3.58 g, 62.8 mmol, 4.35 mL), and the mixture was stirred at 20 °C for 2 hours. The mixture was then concentrated under reduced pressure, and the resulting residue was subjected to rapid silica gel column chromatography (…). 120 g; ethyl acetate / hexane, 0-100% → methanol / ethyl acetate, 0-30%; 100 mL / min) was purified to give a yellow oily intermediate 21-2 (16.0 g, yield 97.9%). 1 H NMR (400MHz, DMSO-d6) δ9.72(d,J=9.2Hz,1H),8.99-8.85(m,2H),8.11(d,J=2.0Hz,1H),7.85(d,J=9.2Hz,1H),7.72(d,J =2.4Hz, 1H), 7.63 (dd, J = 2.0, 9.2Hz, 1H), 7.01 (d, J = 8.8Hz, 1H), 2.11-2.03 (m, 1H), 0.46-0.39 (m, 2H), 0.38-0.32 (m, 2H).

[0180] Potassium carbonate (3.60 g, 26.0 mmol) was added to an acetone solution (20 mL) of intermediate 21-2 (2.00 g, 6.51 mmol). Under nitrogen protection, MeI (1.22 mL, 19.5 mmol) was added dropwise at 20 °C. The reaction mixture was heated to 60 °C and stirred for 12 hours under nitrogen protection. The mixture was filtered, and the filter cake was washed with ethyl acetate (5 mL x 3). The filtrates were combined and concentrated under reduced pressure. The residue was then subjected to rapid silica gel column chromatography (…). Purification was performed using 20.0 g of ethyl acetate / hexane (0–20%) at a rate of 120 mL / min to give a pale yellow solid intermediate 21-3 (550 mg, yield 25.2%). 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),8.37(d,J=9.2Hz,1H),8.00(s,1H),7.86-7.78(m,2H),7.69(d,J=9.2Hz,1H),3.98(s,3H),3.95(s,3H),2.11(br d,J=1.6Hz,1H),0.49-0.42(m,2H),0.38-0.32(m,2H).

[0181] Sodium hydroxide (197 mg, 4.92 mmol) was added to a mixed solution of intermediate 21-3 (550 mg, 1.64 mmol) in MeOH (4 mL) and water (1 mL). The mixture was heated to 60 °C and stirred for 12 hours. The solution was concentrated under reduced pressure, and the residue was acidified with 1 N hydrochloric acid to pH 2, precipitating a solid. The solid was collected by filtration, washed with water (3 mL), and dried under reduced pressure to give a white solid intermediate 21 (430 mg, yield 89.8%). 1 H NMR (400MHz, DMSO-d6) δ8.46 (s, 1H), 8.30 (d, J = 8.8Hz, 1H), 7.97 (br d,J=2.4Hz,1H),7.89-7.82(m,2H),7.66(d,J=9.2Hz,1H),3.97(s,3H),2.13(td,J=3.2,6.4Hz,1H),0.52-0.41(m,2H),0.39-0.31(m,2H).

[0182] Intermediate 22:

[0183] Under nitrogen protection, triethylamine (1.30 mL, 9.34 mmol) and DPPA (806 μL, 2.43 mmol) were added sequentially to a mixed solution of intermediate 21 (1.00 g, 3.11 mmol), toluene (10 mL), and tert-butanol (10 mL). The mixture was heated to 85 °C and stirred for 12 hours. The temperature was lowered to 20 °C, and the reaction was quenched with water (2 mL), precipitating a solid. The solid was filtered, and the filter cake was washed with ethyl acetate (5 mL). The filtrate was collected, and the aqueous phase was extracted with ethyl acetate (3 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to rapid silica gel column chromatography (…). Purification was performed using 12.0 g of ethyl acetate / hexane (0–30%) at a flow rate of 40 mL / min to obtain crude yellow oily intermediate 22-1 (360 mg).

[0184] Trifluoroacetic acid (1 mL) was added to a solution of crude intermediate 20-1 (360 mg) in dichloromethane (3.5 mL), and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Phenomenex Luna C1875*30 mm, 3 μm; [H2O(0.1% TFA)-ACN], 10%–40%) to give trifluoroacetate of yellow solid intermediate 22 (230 mg, yield 19.0%).

[0185] Intermediate 23:

[0186] At 0°C, triethylamine (46.8 mL, 336 mmol) and acetyl chloride (19.1 mL, 269 mmol) were added to a solution of 5-aminonaphthalene-1-sulfonic acid (50.0 g, 224 mmol) in dichloromethane (500 mL), and the mixture was stirred at 25°C for 12 hours. The mixture was filtered, and the filter cake was washed with dichloromethane (50 mL * 3) and dried under vacuum to obtain crude purple solid intermediate 23-1 (49.4 g). 1 H NMR (400MHz, DMSO-d6) δ9.93(br s,1H),8.71(br d,J=8.4Hz,1H),8.06(br d,J=4.0Hz,1H),7.98(br d,J=6.4Hz,1H),7.58(br d,J=2.0Hz,1H),7.50-7.43(m,2H),2.17(s,3H).

[0187] At 0°C, a solution of phosphorus pentachloride (58.2 g, 280 mmol) in dichloromethane (150 mL) was added dropwise to a solution of crude intermediate 23-1 (49.4 g) in dichloromethane (350 mL). The mixture was heated to 40°C and stirred for 12 hours. The reaction mixture was slowly poured into ice water (100 mL) to quench the reaction, and a solid precipitated. The mixture was filtered, and the filter cake was washed with dichloromethane (100 mL * 2). The filtrate was collected, and the aqueous phase was extracted with dichloromethane (100 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried in acetonitrile (50 mL) at 0°C for 30 minutes, filtered, and the filter cake was collected and dried under vacuum to give a grayish-purple solid intermediate 23-2 (12.0 g, yield 18.9%).

[0188] To a solution of intermediate 23-2 (5.00 g, 17.6 mmol) in dichloromethane (50 mL), N-Boc-ethylenediamine (3.33 mL, 21.2 mmol) and DIEA (9.21 mL, 52.9 mmol) were added sequentially, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to rapid silica gel column chromatography (…). Purification was performed using 40.0 g of ethyl acetate / hexane (0–100%; 80 mL / min) to give a yellow gelatinous intermediate 23-3 (1.71 g, yield 23.8%).

[0189] Intermediate 23-3 (1.71 g, 4.20 mmol) was added to hydrochloric acid (6 M, 17 mL), and the mixture was heated to 80 °C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was slurried at 20 °C in a hexane / ethyl acetate (5 / 1, 10 mL) mixture for 10 minutes. The mixture was filtered, and the filter cake was washed with hexane (10 mL) and dried under vacuum to give a white solid intermediate 23-4 hydrochloride (1.27 g).

[0190] Intermediate 23-4 hydrochloride (1.27 g, 4.20 mmol), (Boc)₂O (735 mg, 3.37 mmol), and sodium carbonate (2.23 g, 21.0 mmol) were added sequentially to water (13 mL). The resulting mixture was stirred at 25 °C for 12 hours. The mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL x 3), and the organic phases were combined. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried in dichloromethane (10 mL) at 25 °C for 10 minutes, filtered, and the filter cake was collected and dried under vacuum to give intermediate 23 (1.07 g, yield 69.6%) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ8.38(d,J=8.4Hz,1H),8.01(d,J=7.2Hz,1H),7.82(br t,J=6.0Hz,1H),7.76(d,J=8.4Hz,1H),7.49-7.42(m,1H),7.36(t,J=8.0Hz,1H),6.79(d,J=7.6Hz,1H),6.69(br t, J=5.6Hz, 1H), 5.98 (s, 2H), 2.89 (q, J=6.4Hz, 2H), 2.73 (q, J=6.4Hz, 2H), 1.31 (s, 9H).

[0191] Intermediate 24:

[0192] Under nitrogen protection and at 0°C, 8-bromo-1-naphthoic acid (1.00 g, 3.98 mmol) was added to chlorosulfonic acid (3 mL), and the mixture was heated to 60°C and stirred for 12 hours. The reaction mixture was slowly poured into ice water (10 mL), and a solid precipitated. The solid was filtered, and the filter cake was collected to give a yellow solid intermediate 24-1 (1.00 g, yield 71.9%). 1 H NMR (400MHz, DMSO-d6) δ9.06 (dd, J = 1.6, 8.4Hz, 1H), 7.89 (s, 2H), 7.71-7.57 (m, 2H).

[0193] To a DCM (30 mL) solution of intermediate 24-1 (1.00 g, 2.86 mmol), DIEA (1.49 mL, 8.58 mmol) and cyclopropylamine (237 μL, 3.43 mmol) were added sequentially, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (5 mL), washed with DCM (30 mL x 3), and the aqueous phase was collected and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex luna C18 100 x 40 mm, 5 μm; [H2O (0.2% FA)-ACN], 15%–45%) to give a white solid intermediate 24 (23.0 mg, yield 2.17%). 1 H NMR (400MHz, DMSO-d6) δ13.68-13.45(m,1H),8.80(br d,J=6.8Hz,1H),8.49(br s,1H),8.13(q,J=8.0Hz,2H),7.86-7.74(m,2H),2.11(tt,J=3.6,6.8Hz,1H),0.45-0.38(m,2H),0.30-0.23(m,2H).

[0194] Intermediate 25:

[0195] DIEA (965 μL, 5.54 mmol) and 5-(chlorosulfonyl)-1-naphthic acid (0.5 g, 1.85 mmol) were added to a DCM (5 mL) solution of 3-methoxypropylamine (165 mg, 1.85 mmol), and the mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (WePure Biotech XP tC). 18 Purified with [H2O(10mM NH4HCO3)-ACN] (1%–25%), yielding a colorless waxy intermediate 25 (384 mg, yield 64.3%). 1 H NMR (400MHz, DMSO-d6) δ9.11(d,J=8.4Hz,1H),8.68(d,J=8.4Hz,1H),8.11(d,J=7.2Hz,1H),8.00-7.82(m ,2H),7.71-7.58(m,2H),3.14(t,J=6.0Hz,2H),3.01(s,3H),2.83-2.79(m,2H),1.50(quin,J=6.4Hz,2H).

[0196] Intermediate 26:

[0197] Sodium hydroxide (40.3 mg, 1.01 mmol) was added to a mixed solution of intermediate 17 (240 mg, 504 μmol), water (1 mL), and methanol (1 mL), and the mixture was stirred at 80 °C for 12 hours. Sodium hydroxide (60.4 mg, 1.51 mmol) was then added to the reaction mixture, and stirring was continued at 80 °C for 14 hours. The reaction mixture was concentrated under reduced pressure to give crude yellow oily intermediate 26-1 (170 mg).

[0198] To a mixed solution of crude intermediate 26-1 (170 mg) in DCM (2 mL) and water (2 mL), (Boc)₂O (137 μL, 596 μmol) and TEA (138 μL, 993 μmol) were added, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (WePure Biotech XP tC18 150*40 mm, 7 μm; [H₂O(10 mM NH₄HCO₃)-ACN], 25%–45%) to give a yellow solid intermediate 26 (90.0 mg, yield 40.3%). 1H NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.12-8.03(m,1H),7.90(br s,2H),7.16(br t,J=7.6Hz,1H),3.64(br t,J=7.2Hz,2H),3.26(br s,4H),3.16(s,3H),2.33-2.23(m,6H),1.62-1.52(m,2H),1.47-1.41(m,2H),1.37(s,9H).

[0199] Intermediate 27:

[0200] Sodium tert-butoxide (548 mg, 5.71 mmol) and iodotrifluoromethane (3.35 g, 4.28 mmol) were added to a DMF (10 mL) solution of 6-methoxy-4-hydroxyquinoline (500 mg, 2.85 mmol). The mixture was degassed and purged with N2 three times, and then stirred for 14 hours at 25 °C under a green LED lamp (15 W). The reaction mixture was diluted with water (10 mL) and the pH was adjusted to 5 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (8 mL * 3), and the organic phases were combined and washed with brine (3 mL * 2). The mixture was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate, 5%–100%) to give a yellow solid intermediate 27-1 (190 mg, yield 27.4%). 1 H NMR (400MHz, DMSO-d6) δ12.48-12.31(m,1H),8.36(s,1H),7.62(d,J=9.2Hz,1H),7.54(d,J=2.8Hz,1H),7.42-7.35(m,1H),3.87-3.83(m,3H).

[0201] Phosphorus tribromide (33.4 mg, 123 μmol) was added to a DMF (1 mL) solution of intermediate 27-1 (120.0 mg, 493 μmol) at 0 °C under nitrogen protection. The mixture was stirred at 25 °C for 12 hours and then cooled to 0 °C. At 0 °C, the reaction mixture was slowly poured into a saturated sodium bicarbonate aqueous solution (2 mL), diluted with water (2 mL), extracted with ethyl acetate (2 mL * 3), and the combined organic phases were washed with brine (2 mL * 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (SiO2, n-hexane / EA = 3 / 1) to give a white solid intermediate 27-2 (70.0 mg, yield 46.3%). 1H NMR (400MHz, CDCl3) δ8.90(s,1H),8.10-8.04(m,1H),7.64-7.60(m,1H),7.55-7.50(m,1H),4.10-3.99(m,3H).

[0202] Under nitrogen protection, TEA (35.5 μL, 254 μmol) and Pd(dppf)Cl2·CH2Cl2 (10.4 mg, 12.7 μmol) were added sequentially to a methanol (2 mL) solution of intermediate 27-2 (26.0 mg, 84.9 μmol). The mixture was degassed and CO was replaced three times. The mixture was heated to 80 °C and stirred for 12 hours under a CO (50 psi) atmosphere. The reaction mixture was diluted with water (3 mL), extracted with ethyl acetate (2 mL * 3), and the combined organic phases were washed with brine (2 mL * 2). The mixture was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (SiO2, n-hexane / EA = 3 / 1) to give intermediate 27-3 (11.0 mg, yield 45.4%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ9.00 (s, 1H), 8.11 (d, J = 9.2Hz, 1H), 7.54 (dd, J = 2.8, 9.2Hz, 1H), 7.07 (d, J = 2.4Hz, 1H), 4.10 (s, 3H), 3.95 (s, 3H).

[0203] Sodium hydroxide (7.71 mg, 192 μmol) was added to a mixed solution of intermediate 27-3 (11.0 mg, 38.6 μmol) in methanol (0.5 mL) and water (0.5 mL). The mixture was heated to 70 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and 1 N hydrochloric acid was slowly added to adjust the pH to 5. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 100*30 mm, 10 μm; [H2O(10 mM NH4CO3)-ACN], 1%–30%) to give a white solid intermediate 27 (2.00 mg, yield 19.1%). 1 H NMR (400MHz, CD3OD) δ 8.83-8.80 (m, 1H), 7.99-7.94 (m, 1H), 7.54-7.49 (m, 1H), 7.43 (d, J = 2.8Hz, 1H), 3.99-3.89 (m, 3H).

[0204] Intermediate 28:

[0205] Following the synthesis method of intermediate 3, N-Boc-2,2-difluoro-propanediamine and 2,2-diethylmalonyl dichloride were used as raw materials to obtain white solid intermediate 28 hydrochloride. 1 H NMR (400MHz, DMSO-d6) δ 8.35 (br d, J = 3.6Hz, 3H), 4.05 (t, J = 16.4Hz, 2H), 3.55 (br t, J = 16.0Hz, 2H), 1.72 (q, J = 7.6Hz, 4H), 0.91 (t, J = 7.6Hz, 6H).

[0206] Intermediate 29:

[0207] Intermediate 27-3 (130 mg, 455 μmol) was added to hydrobromic acid (1 mL, 40.0%), and the mixture was heated to 130 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give crude yellow solid intermediate 29-1 (120 mg). MS (ESI) + ):m / z272.2[M+H] + .

[0208] Potassium carbonate (183 mg, 1.33 mmol) and intermediate 6-1 (176 mg, 442 μmol) were added to a DMF (3 mL) solution of crude intermediate 29-1 (120 mg, 442 μmol), and the mixture was heated to 60 °C and stirred for 12 hours. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (2 mL x 3), and the combined organic phases were washed with brine (2 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate, 5%–100%) to give crude yellow oily intermediate 29-2 (230 mg).

[0209] Sodium hydroxide (92.5 mg, 2.31 mmol) was added to a mixed solution of intermediate 29-2 (230 mg, 462 μmol) in methanol (2 mL) and water (2 mL), and the mixture was heated to 70 °C and stirred for 12 hours. The pH of the reaction mixture was adjusted to 7 with 1 N hydrochloric acid, filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by preparative HPLC (WePure Biotech XP tC18 150*40 mm, 7 μm; [H2O(10 mMNH4HCO3)-ACN], 15%–45%) to give a white solid intermediate 29 (11.0 mg, yield 5.0%). 1H NMR (400MHz, DMSO-d6) δ 8.35 (br d, J = 3.6Hz, 3H), 4.05 (t, J = 16.4Hz, 2H), 3.55 (brt, J = 16.0Hz, 2H), 1.72 (q, J = 7.6Hz, 4H), 0.91 (t, J = 7.6Hz, 6H).

[0210] Intermediate 30:

[0211] Potassium carbonate (204 mg, 1.48 mmol) was added to a DMF (1 mL) solution of 1-bromo-3-chloropropane (0.1 mL, 1.01 mmol) and intermediate 6-2 (100 mg, 492 μmol), and the mixture was heated to 60 °C and stirred for 12 hours. The reaction mixture was diluted with water (2 mL), extracted with ethyl acetate (1 mL x 3), and the combined organic phases were washed with brine (1 mL x 3). The mixture was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (hexane / ethyl acetate = 10 / 1) to give a yellow oily intermediate 30-1 (51.5 mg, yield 29.4%). MS (ESI) + ):m / z 356.1,358.1[M+H] + .

[0212] Lithium hydroxide hydrate (53.0 mg, 1.26 mmol) was added to a mixed solution of intermediate 30-1 (45.0 mg, 126 μmol) in methanol (0.5 mL) and water (0.5 mL), and the mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (WePure Biotech XP tC18100*30 mm, 7 μm; [H2O(10 mM NH4HCO3)-ACN], 1%–30%) to give a white solid intermediate 30-2 (9.00 mg, yield 25.5%). MS (ESI) was then used. + ):m / z280.0,282.0[M+H] + .

[0213] To a DMF (0.5 mL) solution of intermediate 30-2 (9.00 mg, 32.2 μmol), tert-butylpiperidine-4-carboxylic acid ester (17.9 mg, 96.5 μmol) and KI (6.41 mg, 38.6 μmol) were added, and the mixture was heated to 60 °C and stirred for 12 hours. The reaction mixture was purified by preparative HPLC (WePure Biotech XP tC18100*30 mm, 7 μm; [H2O(10 mM NH4HCO3)-ACN], 10%–40%) to give a white solid intermediate 30 (5.00 mg, yield 36.3%).1 H NMR(400MHz,DMSO-d6)δ8.43(s,1H),7.77-7.71(m,1H),7.23-7.18(m,2H),4.02(br t,J=6.0Hz,2H),3.19-3.10(m,4H),2.82-2.79(m,2H),2.30(s,3H),1.86(br d,J=1.6Hz,1H),1.76(br d,J=12.0Hz,2H),1.61-1.53(m,4H),1.39(s,9H).

[0214] Intermediate 31:

[0215] Sodium hydroxide (50.0 mg, 1.25 mmol) and water (0.1 mL) were added to a methanol (1 mL) solution of methyl 3-chloro-6-methoxyquinoline-4-carboxylate (100 mg, 397 μmol), and the mixture was heated to 70 °C and stirred for 2 hours. The reaction mixture was adjusted to pH 7 with 6N hydrochloric acid, concentrated under reduced pressure, and the residue was purified by preparative HPLC (WePure Biotech XP tC18100*30 mm, 7 μm; [H2O(10 mMNH4HCO3)-ACN], 1%–35%) to give a white solid intermediate 31 (60.0 mg, yield 63.5%). 1 H NMR (400MHz, DMSO-d6) δ8.53 (s, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.34 (dd, J = 2.8, 9.2 Hz, 1H), 7.17 (d, J = 2.8 Hz, 1H), 3.83 (s, 3H).

[0216] Intermediate 32:

[0217] Following the synthesis method of intermediate 30, using intermediate 29-1 as a starting material, a white solid intermediate 32 was obtained. MS(ESI) + ):m / z 483.3[M+H] + Intermediate 33:

[0218] Following the synthetic method for intermediate 30, intermediates 30-2 and 83 reacted to yield a white solid intermediate 33. MS(ESI) + ):m / z 774.4[M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.09(s,1H),8.82(d,J=2.4Hz,1H),8.40(d,J=8.8Hz,1H),8 .20(dd,J=2.4,8.8Hz,1H),4.40(q,J=7.2Hz,2H),2.46(s,3H),1.37(t,J=7.2Hz,3H).

[0219] Intermediate 34:

[0220] Intermediate 31-4 (200 mg, 794 μmol) was added to hydrobromic acid (2 mL, 40.0%), and the mixture was heated to 130 °C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to give crude intermediate 34-1 (177 mg) as a yellow solid. MS (ESI) + ):m / z223.9[M+H] + .

[0221] Potassium carbonate (328 mg, 2.37 mmol) and intermediate 6-1 (315 mg, 791 μmol) were added to a DMF (4 mL) solution of crude intermediate 34-1 (177 mg), and the mixture was heated to 60 °C and stirred for 12 hours. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (3 mL x 3), and the combined organic phases were washed with brine (3 mL x 2). The mixture was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol, 0%–9%) to give a yellow oily intermediate 34-2 (157 mg, yield 29.2%). MS (ESI) + ):m / z 676.3,678.4[M+H] + .

[0222] Sodium hydroxide (46.4 mg, 1.16 mmol) was added to a mixed solution of intermediate 34-2 (157 mg, 232 μmol) in methanol (1 mL) and water (1 mL), and the mixture was heated to 70 °C and stirred for 12 hours. The pH of the reaction mixture was adjusted to 5 with 1 N hydrochloric acid, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex luna C18 100*40 mm, 3 μm; [H2O(10 mM NH4HCO3)-ACN], 15%–45%) to give a white solid intermediate 34 (60.0 mg, yield 57.4%). MS (ESI) was then used. - ):m / z448.0,450.0[MH] - .

[0223] Intermediate 37:

[0224] N-methylpiperazine (200 mg, 2.00 mmol), methyl 3-chloro-6-bromo-4-carboxylate (300 mg, 998 μmol), Pd₂(dba)₃ (91.4 mg, 99.8 μmol), Xantphos (57.8 mg, 99.8 μmol), and Cs₂CO₃ (976 mg, 2.99 mmol) were added to dioxane (5 mL), the mixture was degassed under vacuum and purged with nitrogen three times, and then heated to 100 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Phenomenex Luna C1875*30 mm, 3 μm; [H₂O(10 mMNH₄HCO₃)-ACN], 25%–55%) to give a yellow solid intermediate 37-1 (113 mg, yield 35.4%). MS (ESI) was then used. + ):m / z 320.2,322.2[M+H] + .

[0225] Sodium hydroxide (70.7 mg, 1.77 mmol) was added to a mixed solution of intermediate 37-1 (113 mg, 353 μmol) in methanol (1 mL) and water (0.1 mL), and the mixture was heated to 70 °C and stirred for 2 hours. The reaction mixture was then purified directly by preparative HPLC (WePure Biotech XP tC18 100*30 mm, 7 μm; [H2O(10 mM NH4HCO3)-ACN], 10%–40%) to give a yellow solid intermediate 37 (107 mg, 99% yield). MS (ESI) + ):m / z 306.1,308.1[M+H] + .

[0226] Intermediate 38:

[0227] Following the synthetic method for intermediate 37, using methyl 3-chloro-6-bromo-4-carboxylate and N-(3-N-Boc-aminopropyl)-piperazine as starting materials, a white solid intermediate 38 was obtained. MS(ESI) + ):m / z449.2,451.2[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),7.85(d,J=9.2Hz,1H),7.67(dd,J=2.0,9.2Hz,1H),7.01(d,J=1.6Hz,1H),6.87(br s,1H),3.64-3.47(m,8H),3.09-3.00(m,4H),1.94-1.80(m,2H),1.39(s,9H).

[0228] Intermediate 39:

[0229] DIEA (9.59 g, 74.2 mmol) and N,N,N'-trimethyl-1,3-propanediamine (10.80 mL, 74.1 mmol) were added sequentially to 50 mL of THF containing 6.00 g (24.7 mmol) of 4-bromo-6-chloro-1,7-naphthidine. The mixture was pumped into a flow chemistry reactor and reacted at 240 °C for 0.5 h. LC-MS showed complete consumption of 4-bromo-6-chloro-1,7-naphthidine. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography. The sample was purified by chromatography (80.0 g; ethyl acetate / petroleum ether, 0-84%; 100 mL / min) to give a green oily intermediate 39-1 (1.53 g, yield 19.2%).

[0230] Intermediate 39-1 (695 mg, 2.15 mmol) was degassed three times with a mixture of DMA (10 mL) and methanol (10 mL) under N2 protection. Then, under N2 protection, diphenylcyclohexylphosphide palladium dichloromethane (176 mg, 215 μmol) and TEA (599 μL, 4.30 mmol) were added sequentially, followed by three degassed times with CO. The reaction was stirred for 12 hours under a CO (50 psi) atmosphere. LC-MS showed complete consumption of intermediate 39-1. The solution was diluted with water (10 mL), extracted with EtOAc (10 mL x 3), and the organic phases were combined. The solution was washed with brine (10 mL x 3), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to rapid silica gel column chromatography (…). 20.0 g; ethyl acetate / petroleum ether, 0-44%; 80 mL / min) was purified by chromatography to give a yellow oily intermediate 39-2 (587 mg, yield 84.4%).

[0231] To intermediate 39-2 (587 mg, 1.94 mmol), 10 mL of THF was added sequentially to water (2 mL) and lithium hydroxide (232 mg, 9.68 mmol), and the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Phenomenex Gemini C1875*40 mm, 5 μm; [H2O(10 mM NH4HCO3)-ACN], 20%–50%) to give a yellow solid intermediate 39 (246 mg, yield 44.0%). MS (ESI) was then used. + ):m / z289.2[M+H] + .

[0232] Intermediate 40-47:

[0233] Following the synthesis method of intermediate 3, intermediates 40 to 47 were synthesized from N-Boc-2-hydroxypropanediamine and malonyl dichloride with different substitutions at the 2-position.

[0234] Intermediate 48:

[0235] Following the synthesis method of intermediate 23-4, intermediate 23-2 and 3-methoxypropylamine were used as raw materials to obtain yellow solid intermediate 48 (96 mg).

[0236] Intermediate 49:

[0237] At 0°C, a solution of 1-nitronaphthalene (5.00 g, 28.9 mmol) in dichloromethane (25 mL) was slowly added to a solution of chlorosulfonic acid (16 mL, 241 mmol) in dichloromethane (16 mL). The mixture was heated to 55°C and stirred for 1 hour. The reaction mixture was cooled in an ice-water bath, and dichloromethane (160 mL) and ice water (160 mL) were added and stirred slowly for 5 min. After removing the aqueous layer, ice water (160 mL) was added and stirred slowly for 5 min. The mixture was allowed to stand and the organic phase was collected. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a black solid intermediate 49-1 crude product (10.0 g).

[0238] At 0°C, DIEA (18.3 mL, 105 mmol) and 8-aminooct-1-ol (5.59 g, 38.5 mmol) were added to a solution of crude intermediate 49-1 (9.50 g, 35.0 mmol) in 100 mL of dichloromethane. After the addition was complete, the ice bath was removed, and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to rapid silica gel column chromatography (…). Purification was performed using 120 g of ethyl acetate / petroleum ether (0–39%) at a flow rate of 100 mL / min to obtain a brown solid intermediate, 49-2 (4.70 g, yield 35.3%).

[0239] Under nitrogen protection at 0°C, TEA (3.44 mL, 24.7 mmol) and MsCl (1.68 mL, 21.7 mmol) were added to a solution of intermediate 49-2 (4.70 g, 12.4 mmol) in dichloromethane (60 mL). After the addition was complete, the ice bath was removed, and the reaction mixture was stirred at 25°C for 0.5 hours. The mixture was diluted with water (40 mL), extracted with dichloromethane (20 mL x 3), the organic phases were combined, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude brown oily intermediate 49-3 (5.60 g).

[0240] Potassium carbonate (5.06 g, 36.6 mmol) and crude intermediate 49-3 (5.60 g, 12.2 mmol) were added to a solution of N-Boc-piperazine (2.50 g, 13.4 mmol) in acetonitrile (70 mL). The mixture was heated to 80 °C and stirred for 12 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (15 mL x 3). The filtrates were combined and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography to give a brown oily intermediate 49-4 (3.40 g, yield 50.7%).

[0241] To a solution of intermediate 49-4 (3.40 g, 6.20 mmol) in ethanol (50 mL), a solution of iron powder (1.73 g, 31.0 mmol) and ammonium chloride (663 mg, 12.4 mmol) in water (10 mL) was added. The mixture was heated to 80 °C and stirred for 12 hours. The reaction mixture was filtered, and the filter cake was washed with methanol (20 mL x 3). The filtrate was concentrated under reduced pressure to give crude brown oily intermediate 49 (4.00 g).

[0242] Intermediate 50:

[0243] Following the synthetic method for intermediate 22, intermediate 21-1 and 3-methoxypropylamine were used as starting materials to obtain yellow solid intermediate 50. MS (ESI+): m / z 325.1 [M+H] + .

[0244] Intermediate 51:

[0245] Following the synthesis method of intermediate 20, using intermediate 24 as a raw material, a yellow solid intermediate 51 was obtained. MS(ESI) + ):m / z 341.0,343.0[M+H] + .

[0246] Intermediate 55:

[0247] To a solution of N-Fmoc-α-amino-4-quinoline propionic acid (87.7 mg, 0.20 mmol) in dichloromethane (1 mL), HCTU (82.7 mg, 0.20 mmol), HOBt (27.0 mg, 0.20 mmol), and DIEA (191.6 μL, 1.00 mmol) were added. The mixture was stirred at 0 °C for 20 min, and then O-(2-aminoethyl)-O'-(N-Boc-aminoethyl)hexaethylene glycol (93.7 mg, 0.20 mmol) was added. The mixture was heated to 20 °C and stirred for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (DCM / MeOH = 15 / 1) to give a colorless oily intermediate 55-1 (151.8 mg, yield 85.4%).

[0248] Hexahydropiperidine (0.2 mL) was added to a DMF (1 mL) solution of intermediate 55-1 (151.8 mg, 0.17 mmol), and the mixture was stirred at 20 °C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (WePure Biotech XP tC18100*30 mm, 7 μm; [H2O(10 mM NH4HCO3)-ACN], 10%–60%) to give a colorless oily intermediate 55 (87.5 mg, yield 77.2%). MS (ESI+): m / z 667.4 [M+H] + .

[0249] Intermediate 73:

[0250] Add N to 2 mL of DMF containing N-Boc-phenylalanine p-nitrophenol ester (289.8 mg, 0.75 mmol). ω N ω -Dimethylarginine (101.1 mg, 0.50 mmol) and triethylamine (174 μL, 1.25 mmol) were reacted at 25 °C with stirring for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (AcOH / MeOH / EA = 0.5 / 8 / 91.5) to give a pale yellow solid intermediate 73-1 (52.8 mg, yield 23.5%). MS (ESI) + ):m / z 450.3[M+H] + .

[0251] Intermediate 76:

[0252] Trifluoromethanesulfonic anhydride (1.20 mL, 7.17 mmol) was added dropwise to a solution of methyl 1,2-dihydro-3-methyl-1-oxo-4-isoquinoline carboxylate (1.30 g, 5.98 mmol) and pyridine (1.90 mL, 23.9 mmol) in dichloromethane (15 mL). A small amount of calcium hydride was added, and the mixture was stirred at 25 °C for 1 day. The reaction was quenched with NaOH aqueous solution (1 N, 25 mL), and the organic phase was collected. The aqueous phase was extracted with dichloromethane (15 mL * 3). The organic phases were combined, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 76-1 crude product (2.16 g).

[0253] 2,4-Dinitro-1-trifluoromethoxybenzene (1.40 mL, 9.01 mmol) was added to a solution of DMAP (549.0 mg, 4.49 mmol) in anhydrous acetonitrile (4 mL), and the mixture was stirred at 25 °C for 0.5 h. Then, a solution of crude intermediate 76-1 (2.12 g, 5.98 mmol) in anhydrous acetonitrile (1 mL) was added, and the mixture was heated to 80 °C and stirred overnight. The reaction mixture was cooled to room temperature, diluted with water (10 mL), extracted with methyl ether (10 mL x 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride aqueous solution and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (n-hexane / EA = 10 / 1) to give a brown oily intermediate 76-2 (203.2 mg, yield 12.1%).

[0254] Intermediate 76-2 (203.2 mg, 0.72 mmol) was added to a THF solution (1.25 mL) with 0.25 mL of water and 90.0 mg, 3.75 mmol of lithium hydroxide. The mixture was stirred at 25 °C for 6 h. The solution was diluted with 5.0 mL of water, and the pH was adjusted to approximately 5.0 with 1 N hydrochloric acid. The tetrahydrofuran was removed by concentration under reduced pressure. The residue was purified by preparative HPLC (WePure Biotech XP tC18100*30 mm, 7 μm; [H2O(10 mM NH4HCO3)-ACN], 10%–45%) to obtain a yellow solid intermediate 76 (91.2 mg, yield 46.5%). MS (ESI) was then used. + ):m / z272.1[M+H] + .

[0255] Intermediate 77:

[0256] Silver trifluoromethanesulfonate (1.28 g, 5.0 mmol) was added to a solution of methyl 1,2-dihydro-1-oxo-4-isoquinoline carboxylate (508 mg, 2.5 mmol) and DIPEA (871 μL, 5.0 mmol) in 1,2-dichloroethane (5.0 mL). The resulting suspension was cooled to 0 °C, and iodomethane (311 μL, 5.0 mmol) in 1,2-dichloroethane (1.0 mL) was added dropwise. The mixture was heated to reflux and stirred for 2 h. The reaction mixture was filtered through diatomaceous earth, washed with dichloromethane (15.0 mL), and the combined filtrates were washed with saturated NaHCO3 aqueous solution (10.0 mL) and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (n-hexane / EA = 10 / 1) to give a yellow oily intermediate 77-1 (203.1 mg, yield 37.4%).

[0257] To a solution of intermediate 77-1 (203.1 mg, 0.94 mmol) in THF (1.25 mL), water (0.25 mL) and lithium hydroxide (112.2 mg, 4.68 mmol) were added, and the mixture was stirred at 25 °C for 6 h. The solution was diluted with water (5.0 mL), and the pH was adjusted to approximately 5.0 with hydrochloric acid (1 N). Tetrahydrofuran was removed by concentration under reduced pressure. The residue was purified by preparative HPLC (WePure Biotech XP tC18100*30 mm, 7 μm; [H2O(10 mM NH4HCO3)-ACN], 10%–45%) to obtain a yellow solid intermediate 77 (119.3 mg, yield 62.8%). MS (ESI) was then used. + ):m / z204.1[M+H] + .

[0258] Intermediate 78:

[0259] Following the synthetic method for intermediate 77, using methyl 1,2-dihydro-1-oxo-4-isoquinoline carboxylate and bromocyclopropane as starting materials, a yellow solid intermediate 78 was obtained. MS(ESI) + ):m / z 230.1[M+H] + .

[0260] Intermediate 79:

[0261] To a solution of methyl 1,2-dihydro-1-oxo-4-isoquinoline carboxylate (101.6 mg, 0.5 mmol) and Na₂CO₃ (58.3 mg, 5.0 mmol) in acetonitrile (1.5 mL), TMSCF₂Br (100 μL, 0.6 mmol) was added, and the mixture was heated to 60 °C for 1 h. After the reaction mixture cooled to room temperature, it was diluted with dichloromethane (15 mL) and saturated sodium chloride aqueous solution (15 mL). The organic phase was collected, and the aqueous phase was extracted with dichloromethane (15 mL * 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (15 mL), and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (n-hexane / EA = 10 / 1) to give a yellow oily intermediate 79-1 (73.6 mg, yield 58.2%).

[0262] To a THF (1.25 mL) solution of intermediate 79-1 (76.6 mg, 0.29 mmol), water (0.25 mL) and lithium hydroxide (34.9 mg, 1.45 mmol) were added, and the mixture was stirred at 25 °C for 6 h. The solution was diluted with water (5.0 mL), and the pH was adjusted to approximately 5.0 with hydrochloric acid (1 N). Tetrahydrofuran was removed by concentration under reduced pressure. The residue was purified by preparative HPLC (WePure Biotech XPtC18100*30 mm, 7 μm; [H2O(10 mM NH4HCO3)-ACN], 10%–45%) to obtain a yellow solid intermediate 79 (45.2 mg, yield 65.0%). MS (ESI) was then used. + ):m / z240.0[M+H] + .

[0263] Intermediate 80:

[0264] Following the synthetic method for intermediate 17, using 5-bromo-3-chloro-8-methoxyisoquinoline and propylene glycol as starting materials, a yellow solid intermediate 80 was obtained. MS(ESI) + ):m / z 446.2[M+H] +

[0265] Intermediate 81 and Intermediate 82:

[0266] Following the synthesis method of intermediate 6, intermediate 6-2 and N-Boc-4-N'-[(3-tert-butyldimethylsiloxy)pentyl]-N'-[(2-toluenesulfonyloxy)ethyl]aminopiperidine were used as raw materials to obtain yellow solid intermediate 81.

[0267] Tetrabutylammonium fluoride (47.3 mg, 0.15 mmol) was added to a tetrahydrofuran (5 mL) solution of intermediate 81 (63.0 mg, 0.10 mmol), and the mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL * 3), and the organic phases were combined and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-film chromatography (SiO2, n-hexane / EA = 3 / 1) to give a yellow solid intermediate 82-1 (49.4 mg, yield 95.8%).

[0268] DMP (3.23 g, 153.5 μmol) was added to a mixed solution of intermediate 82-1 (49.4 mg, 95.8 μmol) in DCM (0.5 mL) and THF (0.5 mL), and the mixture was stirred at 25 °C for 4 hours. The solution was diluted with saturated sodium sulfite aqueous solution (20 mL), extracted with DCM (10 mL x 3), and the organic phases were combined. The mixture was washed with brine (10 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (SiO2, n-hexane / EA = 3 / 1) to give a yellow solid intermediate 82 (40.7 mg, yield 82.8%). MS (ESI) was then used. + ):m / z 514.3[M+H] + .

[0269] Intermediate 83:

[0270] DMF (5 drops) and oxaloyl chloride (4.33 mL, 50 mmol) were added sequentially to a tetrahydrofuran (50 mL) solution of piperidine-1,4-dicarboxylic acid monobenzyl ester (13.25 g, 50 mmol), and the reaction was carried out at 25 °C for 1.5 h. The mixture was concentrated under reduced pressure, and the residue was dispersed in toluene (50 mL) and concentrated again under reduced pressure. The resulting acyl chloride was dissolved in tetrahydrofuran (110 mL), and S-triphenylmethyl-cysteine ​​tert-butyl hydrochloride (22.80 g, 50 mmol) and DIEA (26.0 mL, 150 mmol) were added under ice bath. The ice bath was removed, and the mixture was stirred for 2 h. DMAP (240 mg, 1.90 mmol) was added, and the reaction was continued with stirring for 48 h. The reaction was quenched with hydrochloric acid (4 M, 50 mL), extracted with ethyl acetate (75 mL * 2), and the organic phase was washed with saturated NaHCO3 aqueous solution (50 mL) and saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (n-hexane / EA = 5 / 1) to give a colorless oily intermediate 83-1 (28.2 g, yield 84.8%).

[0271] Intermediate 83-1 (28.2 g, 42.4 mmol) was dissolved in ethyl acetate (100 mL), N2 was displaced, Pd / C (10%, 2.5 g) was added, H2 was displaced, and the reaction was carried out under hydrogen balloon for 18 h. The mixture was filtered, the filtrate was displaced with N2, Pd / C (10%, 2.5 g) was added, H2 was displaced, and the reaction was carried out under hydrogen balloon for 18 h, repeated once more. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (100 mL * 3), the filtrate was collected, and concentrated under reduced pressure to give colorless oily intermediate 83 (22.5 g, 100% yield). MS (ESI) + ):m / z 531.3[M+H] + .

[0272] Intermediate 84:

[0273] Following the synthesis method of intermediate 10, N-methylcyclopropane was used as a starting material to obtain white solid intermediate 84.

[0274] Intermediate 85:

[0275] To a solution of 8-aminoquinoline-4-carboxylic acid (200 mg, 1.06 mmol) in dichloromethane (2 mL), 3-[2-[(N-Boc-2-amino)ethoxy]ethoxy]propionic acid-N-hydroxysuccinimide ester (418 mg, 1.12 mmol) and DIEA (555 μL, 3.19 mmol) were added, and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (WePure Biotech XP tC18 100 mm * 30 mm, 7 μm; [H2O (10 mM NH4HCO3)-ACN], 5%–50%) to give a brown oily intermediate 85 (60.0 mg, yield 12.6%). MS: (ESI) + ):m / z 448.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.88(br d,J=4.4Hz,1H),8.62(d,J=7.2Hz,1H),8.28(d,J=8.4Hz,1H),7.72(br s,1H),7.54(t,J=8.4Hz,1H),7.27(br s,1H),6.74(br s,1H),3.78(t,J=5.6Hz,2H),3.58-3.55(m,2H),3.06-3.02(m,4H),2.78(t,J=6.0Hz,2H),2.27(t,J=6.4Hz,2H),1.35(s,9H).

[0276] Intermediate 93:

[0277] To a solution of 1-Boc-4-Cbz-2-aminomethylpiperidine (1.75 g, 5.0 mmol) in 1,4-dioxane (40 mL), an aqueous solution of Na₂CO₃ (1 M, 10 mL) and Fmoc-Cl (1.31 g, 5.1 mmol) were added, and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative rapid silica gel column chromatography (n-hexane / EA = 5 / 1) to give a white solid intermediate 93-1 (2.72 g, 95.1% yield).

[0278] Intermediate 93-1 (2.72 g, 4.76 mmol) was added to a THF (40 mL) suspension of Pd / C (793.3 mg, 0.71 mmol, 10%) at 25 °C under nitrogen protection. After displacing H2, the mixture was stirred for 12 hours under an H2 balloon. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with THF (20 mL * 2). The filtrates were combined and concentrated under reduced pressure to give a grayish-white solid intermediate 93 (2.0 g, yield 98.5%).

[0279] Synthesis of compound 20:

[0280] Quinoline-4-carboxylic acid (40.7 mg, 235 μmol), DIEA (63.4 mg, 490 μmol), and HATU (93.3 mg, 245 μmol) were added sequentially to a DMF (2 mL) solution of intermediate 3 hydrochloride (49.2 mg, 196 μmol). The mixture was stirred at 25 °C for 1 h. LC-MS showed that the quinoline-4-carboxylic acid completely consumed the intermediate. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Xbridge BEH C18 100*30 mm*10 μm; H2O (10 mM NH4HCO3)-ACN; 15–45%) to give a white solid compound 20 (29 mg, 39.7%). MS (ESI) + ):m / z 370.1[M+H] + . 1¹H NMR (400MHz, DMSO-d⁶) δ 8.98 (d, J = 4.4 Hz, 1H), 8.83 (br t, J = 5.6 Hz, 1H), 8.23–8.14 (m, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.81 (ddd, J = 1.2, 6.8, 8.4 Hz, 1H), 7.66 (ddd, J = 1.2, 7.0, 8.4 Hz, 1H), 7.59 (d, J = 4.4 Hz, 1H), 5.39 (d, J = 6.0 Hz, 1H), 4.05–3.92 (m, 1H), 3.46–3.33 (m, 4H), 1.69 (q, J = 7.6 Hz, 4H), 0.94 (t, J = 7.6 Hz, 6H). Synthesis of the compound:

[0281] Synthesis of Compound 1:

[0282] N-Boc-ethylenediamine (925 mg, 5.77 mmol) was dissolved in DMF (10 mL), cooled to 15 °C, and quinoline-4-carboxylic acid (1 g, 5.77 mmol), HATU (3.29 g, 8.66 mmol), and DIEA (1.49 g, 11.5 mmol) were added sequentially. The mixture was stirred at 15 °C for 12 hours, and LC-MS showed complete consumption of quinoline-4-carboxylic acid. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (10 mL * 3), and the combined organic layers were washed with saturated brine (10 mL * 3), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give crude compound 1-1 (2.74 g).

[0283] The crude compound 1-1 (1.5 g, 4.76 mmol) was added to HCl / EtOAc (4 M, 15.00 mL) at 15 °C and stirred for 12 hours. LC-MS showed that compound 1-1 was completely consumed. The mixture was filtered, the filter cake was collected and dried under vacuum, and the liquid was concentrated under reduced pressure and purified by column chromatography to obtain the crude compound 1-2 hydrochloride (1.18 g).

[0284] At 0°C, crude hydrochloride of compounds 1-2 (100 mg, 397 μmol), 2,2-diethylmalonyl dichloride (93.9 mg, 477 μmol), and TEA (121 mg, 1.19 mmol) were added sequentially to DCM (1 mL). The mixture was heated to 15°C and stirred for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Xbridge BEH C18 100*30 mm, 10 μm; [H2O(10 mM NH4HCO3)-ACN], 20%–50%) to give compound 1 (15.2 mg, yield 11.2%). MS (ESI+): m / z 340.1 M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.05-8.94(m,2H),8.15(d,J=8.4Hz,1H),8.08(d,J=8.4Hz,1H),7.82(t,J=7.6Hz,1H) ,7.65(t,J=7.6Hz,1H),7.51(d,J=4.4Hz,1H),3.63-3.46(m,4H),1.70(q,J=7.6Hz,4H),0.89(t,J=7.6Hz,6H).

[0285] Compound synthesis:

[0286] Synthesis of compound 3:

[0287] N-Boc-glycine (1.46 g, 8.32 mmol) and 5-amino-quinoline (1.79 g, 13.87 mmol) were dissolved in DCM (10 mL), followed by the addition of DIEA (2.42 mL, 13.87 mmol) and HATU (3.96 g, 10.40 mmol). The mixture was stirred at 25 °C for 10 hours, and LC-MS showed complete consumption of 5-amino-quinoline. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give a yellow oily compound 3-1 (1.7 g, yield 81.33%).

[0288] Compound 3-1 (600 mg, 1.99 mmol) was added to HCl / EtOAc (4 M, 3 mL) at 15 °C and stirred for 12 hours. LC-MS showed that the compound was completely consumed. The mixture was filtered, and the filter cake was washed with ethyl acetate (5 mL). The filter cake was then dried under vacuum to give a white solid compound 3-2 hydrochloride (350 mg, yield 73.96%).

[0289] Compound 3-2 hydrochloride (50 mg, 210 μmol) and DIEA (81.6 mg, 631 μmol) were dissolved in DCM (2 mL). The mixture was cooled to 0 °C, and a DCM (2 mL) solution of 2,2-diethylmalonyl dichloride (49.7 mg, 252 μmol) was added. The reaction mixture was heated to 15 °C and stirred for 1 hour. LC-MS showed that compound 3-2 was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (WePureBiotech XP tC18 150*40 mm, 7 μm; [H2O(10 mMNH4HCO3)-ACN], 20%–50%) to give a white solid compound 3 (6.8 mg, yield 9.18%). MS (ESI) + ):m / z 326.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.41(br s,1H),8.93(dd,J=1.6,4.0Hz,1H),8.52(d,J=8.4Hz,1H),7.89(d,J=7.6Hz,1H),7.82-7.70( m, 2H), 7.60 (dd, J = 4.0, 8.8Hz, 1H), 4.44 (s, 2H), 1.73 (q, J = 7.6Hz, 4H), 0.96 (t, J = 7.6Hz, 6H).

[0290] Compound synthesis:

[0291] Synthesis of compound 22:

[0292] At 0 °C, tert-butyl (chlorosulfonyl)methylcarbamate (524 mg, 2.28 mmol) and intermediate 13 (400 mg, 1.52 mmol) were dissolved in THF (2 mL), and N-methylmorpholine (0.52 mL, 4.62 mmol) was added. The ice bath was removed, the temperature was raised to 25 °C, and the reaction mixture was stirred for 18 hours. The reaction mixture was purified by silica gel column chromatography to give a yellow oily compound 22-1 (363 mg, yield 52.4%).

[0293] TFA (0.3 mL) was added to a DCM (1 mL) solution of compound 22-1 (363 mg, 0.80 mmol), and the mixture was stirred at room temperature for 3 hours. LC-MS showed that compound 22-1 was completely consumed. The solution was concentrated under reduced pressure to obtain crude compound 22-2 (372 mg).

[0294] Compound 22-2 (372 mg, 0.80 mmol) and DIEA (797 μL, 4.0 mmol) were dissolved in DCM (1 mL), cooled to 0 °C, and a DCM (1 mL) solution of 2,2-diethylmalonyl dichloride (189.2 mg, 0.96 mmol) was added. The reaction mixture was heated to 15 °C and stirred for 1 hour. LC-MS showed that compound 22-2 was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (WePureBiotech XP tC18 150*40 mm, 7 μm; [H2O (10 mM NH4HCO3)-ACN], 20%–50%) to give a white solid compound 22 (13 mg, yield 3.4%). MS (ESI) + ):m / z478.1[MH] - .

[0295] Synthesis of Compound 25

[0296] To a THF (1 mL) solution of quinoline-4-carboxylic acid (5.5 mg, 31.5 μmol), DIEA (16.5 μL, 94.5 μmol), intermediate 40 hydrochloride (8.0 mg, 27.5 μmol), and BOP-Cl (3.16 mg, 37.9 μmol) were added, and the mixture was stirred at 20 °C for 24 h. The reaction solution was diluted with water (1 mL), extracted with ethyl acetate (1 mL x 3), and the combined organic phases were washed with brine (1 mL x 2). The mixture was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (WePure Biotech XP tC18 150 x 30 mm, 7 μm; [H2O(10 mMNH4HCO3)-ACN], 50%–80%) to give a white solid compound 25 (3.9 mg, yield 32.4%). MS (ESI) was then used. + ):m / z410.1[M+H] + .

[0297] Synthesis of compound 41:

[0298] TFA (1.07 g, 9.42 mmol) was added to a DCM (2 mL) solution of compound 46 (160 mg, 255 μmol), and the mixture was stirred at 25 °C for 1 h. LC-MS showed that compound 46 was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Luna C1875*30 mm, 3 μm; [H2O (0.1% TFA)-ACN (0.1% TFA)], 1%–30%) to give a colorless oily compound 112 (140 mg). 1 H NMR (400MHz, DMSO-d6) δ9.16(td,J=2.0,4.0Hz,1H),8.78(t,J=5.6Hz,1H),8.70(s,1H),7.96( d,J=9.2Hz,1H),7.40(dd,J=2.8,9.2Hz,1H),7.12(d,J=2.4Hz,1H),5.73-4.93(m,1H),4.14(br t,J=5.6Hz,2H),3.99(br s,1H),3.45-3.30(m,11H),3.29-3.16(m,3H),2.41(s,3H),2.14(br dd, J=5.6, 8.0Hz, 2H), 1.70 (q, J=7.6Hz, 4H), 0.97-0.87 (m, 6H).

[0299] To a DCM (3 mL) solution of compound 112 (130 mg, 247 μmol), DIEA (129 μL, 741 μmol) and DOTA-p-nitrophenol ester (DOTA-ONp_1) (129 mg, 247 μmol) were added sequentially, and the mixture was stirred at 25 °C for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters xbridge 150*25 mm, 10 μm; [H2O(10 mM NH4HCO3)-ACN]; 10%–40%) to obtain the crude product. The crude product was purified by preparative HPLC (Waters xbridge 150*25 mm, 10 μm; [H2O(10 mM NH4HCO3)-ACN]; 15%–35%) to give a white solid compound 41 (15.3 mg, yield 6.67%). HRMS (ESI) - ):m / z 910.4705[MH] - . 1H NMR (400MHz, CD3OD) δ8.61(s,1H),7.94-7.89(m,1H),7.41(dd,J=2.8,9.2Hz,1H),7.28(d,J=2.4Hz,1H),4.29-4.2 2(m,2H),4.21-4.13(m,1H),3.97-3.55(m,12H),3.54-3.47(m,4H),3.46-3.35(m,6H),3.29-3.13(m,6H),3.13(br s,10H),2.53-2.44(m,3H),2.25(br s,2H),1.83-1.68(m,4H),1.09-0.96(m,6H).

[0300] Compound synthesis:

[0301] Synthesis of compound 27:

[0302] Intermediate 94 (437.5 mg, 1.00 mmol) was dissolved in DMF (2 mL). Intermediate 10 (291.3 mg, 1.00 mmol), HATU (570.2 mg, 1.50 mmol), and DIEA (350 μL, 2.00 mmol) were added sequentially under ice bath conditions. The ice bath was removed, and the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (5 mL), extracted with EtOAc (5 mL x 3), and the combined organic layers were washed with saturated brine (5 mL x 3), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain a crude brown solid compound 27-1 (720 mg).

[0303] Diethylamine (1 mL) was added to a solution of crude compound 27-1 (729 mg, 1.00 mmol) in dichloromethane (4 mL), and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (DCM / MeOH = 15 / 1) to give a yellow solid compound 27-2 (432.4 mg, yield 88.5%).

[0304] 2,2-Diethylmalonyl dichloride (209.3 mg, 1.06 mmol) and TEA (308 μL, 2.21 mmol) were added to a 2 mL solution of compound 27-2 (432.4 mg, 885 μmol) in DCM at 0 °C. The mixture was stirred and kept at this temperature for 12 hours. The solution was diluted with 5 mL of water, and the aqueous phase was extracted with 3 mL of DCM. The organic phases were combined and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude brown solid compound 27-3 (550 mg).

[0305] The crude compound 27-3 (550 mg) was dissolved in DCM (3 mL) and TFA (1 mL) was added. The mixture was stirred at 25 °C for 1 h. The solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Xbridge BEH C18 100*30 mm, 10 μm; H2O (10 mM NH4HCO3)-ACN; 20%–50%) to give compound 27 (44.4 mg, yield 9.8%). MS (ESI) was then used. + ):m / z 513.2M+H] + .

[0306] Synthesis of compound 80:

[0307] TFA (1.07 g, 9.42 mmol) was added to a DCM (2 mL) solution of compound 46 (160 mg, 255 μmol), and the mixture was stirred at 25 °C for 1 h. LC-MS showed that compound 46 was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Luna C1875*30 mm, 3 μm; [H2O (0.1% TFA)-ACN (0.1% TFA)], 1%–30%) to give a colorless oily compound 112 (140 mg).

[0308] To a DCM (3 mL) solution of compound 112 (130 mg, 247 μmol), DIEA (129 μL, 741 μmol) and NOA-p-nitrophenol ester (105 mg, 247 μmol) were added sequentially, and the mixture was stirred at 25 °C for 14 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters xbridge 150*25 mm, 10 μm; [H2O(10 mMNH4HCO3)-ACN], 10%–40%) to obtain the crude product. The crude product was purified by preparative HPLC (Waters xbridge 150*25 mm, 10 μm; [H2O(10 mMNH4HCO3)-ACN], 15%–35%) to give a white solid compound 41 (18.5 mg, yield 9.24%). MS (ESI) +):m / z 811.4[M+H] + .

[0309] Synthesis of compound 18:

[0310] Under N2 protection at 0°C, TEA (308 mg, 3.05 mmol) and triphosgene (360 mg, 1.21 mmol) were added to DCM (4 mL) containing intermediate 13 (400 mg, 1.52 mmol). The reaction mixture was heated to 25°C and stirred for 1 hour. LC-MS showed that intermediate 13 was completely consumed. N-Boc-ethylenediamine (293 mg, 1.83 mmol) was added, and the mixture was stirred at 25°C for 11 hours. The mixture was cooled to 0°C, quenched by slow addition of water (10 mL), and then stirred at 25°C for 15 minutes. The mixture was extracted with DCM (8 mL * 3), the organic phases were combined, washed with brine (8 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 3) to give a yellow solid compound 18-1 (280 mg). 1 HNMR(400MHz, DMSO-d6)δ8.71(s,1H),8.40-8.35(m,1H),8.31(d,J=8.4Hz,1H),8.26(d,J=2.0Hz,1H),8.22-8.18(m,1H),8.01(br d,J=7.6Hz,1H),7.71-7.65(m,1H),7.63-7.56(m,1H),6.88(br t,J=5.2Hz,1H),6.63-6.55(m,1H),3.19(q,J=6.0Hz,2H),3.09-3.02(m,2H) ,2.10-2.03(m,1H),1.39-1.38(m,9H),0.40-0.34(m,2H),0.27-0.22(m,2H).

[0311] Compound 18-1 (280 mg, 624 μmol) was added to HCl / EtOAc (4 M, 4 mL), and the mixture was stirred at 25 °C for 1 hour. LC-MS showed that compound 18-1 was completely consumed. The mixture was filtered, the filter cake was collected and dried under reduced pressure to give crude yellow solid compound 18-2 hydrochloride (200 mg).

[0312] The crude product of compound 18-2 hydrochloride (200 mg, 574 μmol) and TEA (239 μL, 1.72 mmol) were dissolved in DCM (2 mL). At 0 °C, the above solution was added to a DCM (2 mL) solution of 2,2-diethylmalonyl dichloride (169 mg, 861 μmol), and the reaction was stirred for 0.5 h. LC-MS showed complete consumption of compound 18-2. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (SiO2, DCM / MeOH = 20 / 1). The crude product was then purified by preparative HPLC (Phenomenex luna C18 100*40 mm, 5 μm; [H2O (0.2% FA)-ACN], 30%–60%) to give a white solid compound 18 (8.7 mg, yield 3.18%). MS (ESI) + ):m / z473.1[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.80(s,1H),8.34(t,J=9.6Hz,2H),8.27(d,J=2.0Hz,1H),8.22-8.17(m,1H),7.92(d,J=7.6H z,1H),7.69(dd,J=7.6,8.4Hz,1H),7.60(t,J=8.4Hz,1H),6.64(s,1H),3.48-3.42(m,2H),3.41-3.36(m,2H),2.06(br dd,J=3.6,5.6Hz,1H),1.67(q,J=7.6Hz,4H),0.88(t,J=7.6Hz,6H),0.40-0.34(m,2H),0.27-0.22(m,2H).

[0313] Compound synthesis:

[0314] Synthesis of compound 24:

[0315] Under nitrogen protection, compound 77 (20.0 mg, 50.7 μmol) and ammonium formate (20.0 mg, 317 μmol) were added sequentially to a THF (1 mL) suspension of Pd / C (20.0 mg, 18.8 μmol, 10%), and the mixture was stirred at 20 °C for 2 hours. The reaction mixture was filtered, the filter cake was washed with THF (2 mL), the filtrates were combined and concentrated under reduced pressure, and the residue was subjected to preparative HPLC (Waters Xbridge BEH C). 18Purified by [H2O(10mM NH4HCO3)-ACN] (30%–60%), yielding a white solid compound 24 (1.20 mg, yield 6.1%). MS (ESI) + ):m / z 369.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.07-9.01(m,1H),8.85(br t,J=5.6Hz,1H),8.28-8.21(m,1H),8.15(d,J=8.4Hz,1H),7.91-7.85(m,1H),7.75-7.70 (m,1H),7.66(d,J=4.0Hz,1H),3.30-3.19(m,5H),1.80-1.74(m,4H),1.04-0.97(m,6H).

[0316] Synthesis of compound 131:

[0317] A solution of compound 45 (33.0 mg, 60.4 μmol) in dichloromethane (1 mL) was added with 0.3 mL of trifluoroacetic acid, and the mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Phenomenex Luna C1875*30 mm, 3 μm; [H2O(0.1% TFA)-ACN], 5%–35%) to give a white solid compound 131-1 trifluoroacetate (9.80 mg, yield 29.0%).

[0318] To a DMF (0.1 mL) solution of compound 131-1 (2.00 mg, 3.57 μmol), N-Boc-N',N”-Boc-L-arginine (1.69 mg, 3.57 μmol), HCTU (2.21 mg, 5.35 μmol), HOBt (48.2 μg, 0.38 μmol), and DIEA (1.86 μL, 10.7 μmol) were added sequentially, and the mixture was stirred at 20 °C for 12 hours. The mixture was diluted with water (0.5 mL), extracted with ethyl acetate (0.2 mL x 2), and the organic phases were combined. The mixture was washed with brine (0.1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude yellow oily compound 131-2 (3.00 mg).

[0319] A solution of crude compound 131-2 (3.00 mg) in dichloromethane (0.1 mL) was added to trifluoroacetic acid (0.03 mL), and the mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Welch Ultimate C18 120*30 mm, 5 μm; [H2O(0.1% TFA)-ACN], 15%–45%) to give a grayish-white solid compound 131 (0.18 mg, yield 7.0%). MS (ESI) was then used. + ):m / z603.4[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.52(br d,J=7.6Hz,1H),8.49-8.42(m,1H),8.38(d,J=8.4Hz,1H),8.20-8.12(m,2H),8.10-7.95(m,2H),7.73(q,J=7.6Hz,3H),7.48-7.4 0(m,1H),7.34-6.71(m,3H),4.44(s,2H),3.68-3.56(m,1H),3.20-3.02(m,4H),2.88-2.75(m,2H),1.73(q,J=7.6Hz,4H),1.63(br d, J=4.4Hz, 2H), 1.50-1.35 (m, 2H), 0.96 (t, J=7.6Hz, 6H).

[0320] Synthesis of compound 82:

[0321] To a DCM (1 mL) solution of compound 112 (8.50 mg, 16.2 μmol), DIEA (8.45 μL, 48.5 μmol) and disulfo-cy5 NHS ester (12.6 mg, 16.2 μmol) were added sequentially. The mixture was stirred at 25 °C for 1 h. LC-MS showed that the disulfo-cy5 NHS ester was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters xbridge 150*25 mm, 10 μm; [H2O(10 mM NH4HCO3)-ACN], 15%–45%) to give a blue solid compound 82 (1.20 mg, yield 6.05%). MS (ESI-): m / z 1148.4816 [MK] - . 1H NMR(400MHz,CD3OD)δ8.59(s,1H),8.40-8.23(m,2H),7.95(br d,J=5.2Hz,5H),7.44-7.27(m,3H),7.27-7.21(m,1H),6.72(s,1H),6.42-6.26(m,2H),4 .25-4.21(m,2H),4.19-4.13(m,3H),3.65(s,3H),3.63-3.50(m,4H),3.46-3.34(m,6H), 3.05-2.65(m,4H),2.53-2.46(m,3H),2.44-2.32(m,2H),2.24-2.11(m,2H),1.92-1.84( m,2H),1.80-1.72(m,16H),1.69-1.60(m,2H),1.43-1.35(m,2H),1.04(t,J=7.6Hz,6H).

[0322] Synthesis of compound 93:

[0323] TFA (1.07 g, 9.42 mmol) was added to a 2 mL solution of compound 143 (155 mg, 160 μmol) in dichloromethane, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Luna C1875*30 mm, 3 μm; [H2O(0.1% TFA)-ACN(0.1% TFA)], 1%–30%). The resulting oily substance was dissolved in 1 mL of acetonitrile, and triethylamine (48.1 μL, 346 μmol) and DOTA-maleimide (61 mg, 115 μmol) were added sequentially, and the mixture was stirred at 25 °C for 5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters xbridge 150*25 mm, 10 μm; [H2O(10 mMNH4HCO3)-ACN], 10%–40%) to obtain the crude product. The crude product was purified by preparative HPLC (Waters xbridge 150*25mm, 10μm; [H2O(10mM NH4HCO3)-ACN]; 15%–35%) to give a white solid compound 41 (12.8 mg, yield 6.68%). MS (ESI) - ):m / z 599.8[M+2H] 2+ .

[0324] Experimental Example 1: Pure Protein Level FAP Enzyme Activity Assay

[0325] Compound IC 50 Human FAP, DPP4 protein (Shanghai Kaika Biotechnology), and DPP2 (MCE) were used for assays. First, a mixture of proteins and a series of compounds was incubated at room temperature for 1 h. The reaction system consisted of FAP (2 μg / mL, 100 mM Tris buffer, 100 mM NaCl, pH 7.4), DPP4 (0.25 μg / mL, 100 mM Tris buffer, pH 8.0), and DPP2 (2 μg / mL, 100 mM Tris buffer, 100 mM NaCl, pH 6.0), with a total volume of 50 μL. Next, 50 μL of substrate working solution containing 2.5 mM of substrate H-Gly-Pro-pNA was added, and the mixture was incubated at 37°C for 0.5 h. The reaction system contained 1% DMSO. The absorbance at 405 nm was measured using a Multiskan FC microplate. IC50 50 The GraphPad Prism fitting was used, and the results are shown in Table 1. In addition, the kinetic parameters of some compounds were tested using this method, and the affinity of the compounds for FAP and the kinetic properties of covalent bond formation were compared. The results are shown in Table 2.

[0326] Table 1 Inhibition rate of compounds

[0327] Table 2 Kinetic parameters of compounds

[0328] The results showed that the compounds had excellent FAP enzyme activity inhibitory activity and good selectivity for DPP2 and DPP4. The Kinact / Ki kinetic parameters of compounds 20, 11, 17, and 41 were also tested using this method.

[0329] This invention uses an enzyme activity assay to test and compare the TDI effect of compounds 20, 11, and 17. The assay results, using IC50 values ​​at different incubation times, showed that... 50 The covalent irreversible binding value between the compound and FAP was used to characterize the relationship between the compound and FAP. The experimental results are shown in Table 3.

[0330] Table 3 IC50 of compounds at different incubation times 50 data

[0331] Example 2: Identification of modified peptides by fingerprinting

[0332] A certain concentration of DMSO stock solution was added to 1 μg of human FAP protein solution, and the volume was adjusted to 20 μL using 100 mM Tris buffer (pH 7.4) and 100 mM NaCl. The mixture was incubated at room temperature for 1 h. After the reaction, the protein and excess compound were separated using a Zeba desalting centrifuge column (Thermo Scientific). Subsequently, 6 M urea, 1% SDS, and 10 mM DTT were added to denature the protein, and the mixture was incubated at 37°C for 0.5 h. Then, 20 mM IAA was added for blocking, and the mixture was incubated at 35°C for 0.5 h; followed by 20 mM DTT and incubation at 37°C for 0.5 h. After these steps, the protein was enriched using the SP3 method. A 1:1 mixture of two carboxyl magnetic beads was added to the protein, mixed well, and then 25 μL of ethanol was added. The mixture was shaken in an EP tube and incubated at room temperature for 10 min. The magnetic beads were then separated using a magnetic rack, the supernatant was removed, and the mixture was washed three times with 80% ethanol solution to recover the magnetic beads. Magnetic beads were placed in a mixed enzyme solution of LysC and Trypsin (NH4HCO3) and digested overnight at 37°C. Following magnetic separation, the supernatant was recovered and quenched with 1% formic acid. The peptide solution was desalted using a C18 column, evaporated to dryness, reconstituted, and then analyzed for peptide mass using a high-resolution mass spectrometer (Thermo Fisher, Orbitrap Exploris 480). Mass spectrometry data were used for library search and quantitative analysis using Thermo Proteome Discoverer 2.5.

[0333] This invention further utilizes peptide fingerprinting analysis to generate specific peptide sequences from FAP protein after enzymatic digestion. Biomolecular mass spectrometry is then used to analyze the quality of the peptide mixture, and database searches are combined to identify the proteins in the sample. The peptide with increased molecular weight of compound 20 is accurately identified. Secondary spectroscopy further confirms that compound 20 modifies the amino acid residues of FAP protein Ser-624, as shown in Figure 1, indicating that the compound of this invention can form a stable, irreversible covalent bond with FAP protein Ser-624.

[0334] Experimental Example 3: Selectivity Assessment of FAP Binding Activity at Pure Protein Level

[0335] The binding activity of fluorescent molecule 82 to FAP, DPP-4, and HSA (human serum albumin) at the pure protein level was tested using the fluorescent gel method.

[0336] A certain concentration of DMSO stock solution was added to the pure protein solution, and the volume was adjusted to 20 μL using 100 mM Tris buffer (pH 7.4) and 100 mM NaCl. The final concentration of each protein was 0.25 μM. The mixture was thoroughly mixed and incubated at room temperature for 1 h. 5X Loading Buffer was added, and the reaction was quenched at 95 °C for 5 min. The samples were separated by 10% SDS-PAGE at 150 V for approximately 1 h. The fluorescent bands on the gel were visualized using Chemi-Doc imaging, and then stained with Coomassie blue, as shown in Figure 2.

[0337] At the pure protein level, 82 fluorescent molecules labeled only FAP protein, indicating that the compounds of this invention have high selectivity for binding to FAP.

[0338] Experiment 4: Imaging assessment of FAP-highly expressing cells using fluorescent molecule 82

[0339] Table 4 Cell Culture and Preparation of Test Compounds

[0340] As shown in Table 4, the cell lines to be tested were placed in DMEM medium containing 10% heat-inactivated FBS (fetal bovine serum), 100 U / mL penicillin, and 100 g / mL streptomycin, and cultured in a cell culture incubator at 37°C and 5% CO2. The medium was changed every two days. After the cells reached 80% confluence, they were digested with trypsin, passaged, and kept in a good logarithmic growth phase.

[0341] 1) Cell transfection:

[0342] Seed cells in 6cm dishes; when cell density reaches 60%-80%, use Neofect. TM The FAP plasmid was transfected using the transfection reagent. Cells were digested 36 hours after transfection with the FAP plasmid, and the cells were reseeded and incubated overnight.

[0343] 2) Detection method:

[0344] Prepare serum-free DMEM high-glucose medium containing compound 82 (0, 100 nM, 1 μM). Wash cells with PBS and serum-free medium respectively. Add medium containing the probe to the cells and incubate for 1 h. Add Hoechst for nuclear staining. Remove the medium after staining, wash with PBS 2-3 times, and take pictures using a fluorescence microscope.

[0345] The results, as shown in Figure 3, indicate that the compound of the present invention can be applied to the imaging of FAP-related disease lesions, thereby diagnosing FAP-related diseases.

[0346] Experiment 5: Assessment of FAP binding activity in live cells and detection of the inhibitory effect of the compound on fluorescent molecule 82-labeled FAP.

[0347] Table 5 Cell culture and preparation of test compounds

[0348] As shown in Table 5, the cell lines to be tested were placed in a culture medium containing 10% heat-inactivated FBS (fetal bovine serum), 100 U / mL penicillin, and 100 g / mL streptomycin, and cultured in a cell culture incubator at 37°C and 5% CO2. The medium was changed every two days. After the cells reached 80% confluence, they were digested with trypsin, passaged, and kept in a good logarithmic growth phase.

[0349] All samples were dissolved in DMSO.

[0350] 1) Detection method:

[0351] U87MG cells in logarithmic growth phase at 1*10 6 Cells were seeded per well in 12-well cell culture plates and cultured for 24 h. Cells were washed with PBS and serum-free medium, respectively. Serum-free medium containing the test sample (concentrations shown in the table) was prepared and added to the cells. Cells were then incubated for another 1 h. Cells were washed again with serum-free medium, and serum-free medium containing compound 82 (final concentration 5 μM) was added. Cells were then incubated for another 1 h. The cell culture dishes were then placed on ice and washed twice with cold PBS. PBS was then added to scrape off the cells and collect them.

[0352] The obtained cells were added to cell lysis buffer [PBS (Thermo Fisher Scientific), 1% IGEPEAL-CA-630 (Sigma-Aldrich), 0.2% SDS (Sigma-Aldrich), 1% EDTA-free protease inhibitor mixture (Sigma-Aldrich), 0.1% Benzonase (Beyotime)], and after sonication, were centrifuged at 4°C using a benchtop centrifuge (20000g, 30min). The supernatant was collected, and the protein concentration was adjusted to 2 mg / mL with cell lysis buffer. 20 μL of the protein solution was added to 5X Loading Buffer, and the reaction was quenched at 95°C for 5 min. The samples were separated by 10% SDS-PAGE, electrophoresis was performed at 150V for approximately 1 h, and the fluorescent bands on the gel were visualized using Chemi-Doc imaging scanning. The gel was then stained with Coomassie blue, and the results are shown in Figure 4.

[0353] The relative occupancy of the sample is calculated using the following formula:

[0354] Inhibition rate (%) = 100 - (target band signal of sample group / target band signal of blank group) * 100, and the results are shown in Table 6.

[0355] Table 6. Relative occupancy of compounds in FAP cells

[0356] This invention tested the inhibitory effect of the compound on FAP protein labeled by fluorescent molecule 82 in living cells at the cellular level. The results showed that the compound exhibited a significant inhibitory effect on FAP labeled by fluorescent molecule 82 even at a low concentration (100 nM), indicating that the compound of this invention has excellent affinity for binding FAP.

Claims

1. A compound of Formula I: ###0001### or a metal complex thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or an optical isomer thereof, or a stereoisomer thereof. W is selected from CR1or N; R1, R2, R3are each independently selected from the group consisting of hydrogen, halogen, -CN, -NR8R9, C 1-8 alkyl, C 2-8 unsaturated alkyl or -OR 13 wherein R1, R2, R3have one selected from wherein R6, R7are each independently selected from the group consisting of hydrogen, halogen, C 2-4 unsaturated alkyl or C 1-4 alkyl, wherein C 1-4 alkyl or C 2-4 unsaturated alkyl optionally substituted by one or more substituents selected from the group consisting of halogen, dimethylsulfone, C 2-4 unsaturated alkyl or C 1-4 alkyl; or R6, R7form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered carbocyclic ring or the 3- to 6-membered heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of O or halogen, wherein the 3- to 6-membered heterocyclic ring contains 1 to 2 atoms optionally selected from O, S, N; L is selected from -NHCO-, -NHSO2-, -NR 10 CONH-, -CONHCO-, -NR 14 CSNH-, or R 10 , R 14 is selected from hydrogen, C 1-8 alkyl or C 2-8 unsaturated alkyl; M is selected from C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 2-4 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl or C 2-4 unsaturated alkyl is optionally substituted by one or more of halogen, O, C 3-5 cycloalkyl, hydroxyl, -NH2or -N3, wherein C 3-5 cycloalkyl is optionally substituted by one or more of halogen, O or hydroxyl, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; R4, R5are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, C 1-8 alkyl, C 2-8 alkenyl, -OR 15 or -NR 11 R 12 wherein C 1-8 alkyl or C 2-8 alkenyl is optionally substituted with one or more halogen, O, hydroxyl, R 11 , R 12 ; R8, R9, R 11 , R 12 , R 13 , R 15 are each independently selected from L2is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted with one or more halogen, O, hydroxyl; K1is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 16 or a bond; L3is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) a or a bond, a = 1-10, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted with one or more halogen, O, hydroxyl; K2is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 17 , AA or a bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 、 AA or a bond; L4, L5are independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) b or a bond, b = 1 to 10, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl optionally substituted by one or more halogen, O, hydroxyl; K4is selected from NR 28 , carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxy, S, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; X, Y, Z are each independently selected from CH, N, CSO2NR 19 R 26 , CNHCOR 27 , CNHCOR 21 , COR 20 , COR 19 , COR 20 , COR 21 , COR 27 are each independently selected from L6is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl is optionally substituted with one or more halogen, NR 22 R 23 , O, hydroxyl, C 1-6 alkyl or C 2-6 unsaturated alkyl, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl; K5 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 29 or a bond; L7is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) d or a bond, d = 1 to 10, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxy, C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, O, hydroxy; K6is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 30 , AA or a bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 、 AA or a bond; L8, L9, L 10 each independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) e , e = 1 to 10 or a bond, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl, NR 24 R 25 , C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, O, hydroxyl; K8, K9 are each independently selected from NR 32 , carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, S, hydroxy, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; wherein R 16 , R 17 , R 18 , R 28 , R 29 , R 30 , R 31 , R 32 are each independently selected from H, C 1-3 alkyl or C 2-3 unsaturated alkyl, R 22 , R 23 , R 24 , R 25 are independently selected from H, C 1-3 alkyl, C 2-3 unsaturated alkyl, R 26 H, C 1-6 alkyl, C 2-6 unsaturated alkyl, C 3-6 cycloalkyl, wherein AA is selected from the group consisting of an amino acid residue, said amino acid being selected from the group consisting of glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; ring A1, ring A2 are independently selected from the group consisting of a naphthalene ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a benzo 5- to 9-membered heteroaromatic ring, wherein the naphthalene ring, the benzene ring, the pyridine ring, the pyrimidine ring, the pyrazine ring or the benzo 5- to 9-membered heteroaromatic ring can be substituted by halogen, CN, nitro, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl.

2. The compound according to claim 1, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or an optical isomer thereof, or a stereoisomer thereof, wherein, The compound of formula I is represented by formula I-1: R2 and R3 are each independently selected from hydrogen, halogen, -CN, -NR8R9, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl or -OR 13 R6 and R7 are each independently selected from hydrogen, halogens, and C. 2-4 Unsaturated alkyl or C 1-4 Alkyl, wherein C 1-4 Alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, dimethyl sulfone, C 2-4 Unsaturated alkyl or C 1-4 Alkyl group; or R6, R7 forming a 3- to 6-membered carbon ring or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered carbon ring or the 3- to 6-membered heterocycle is optionally substituted by one or more of the following substituents: O or halogen, wherein the 3- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, N; L is selected from -NHCO-, -NHSO2-, -NR 10 CONH-, -CONHCO-, -NR 14 CSNH-, or R 10 , R 14 is selected from hydrogen, C 1-8 alkyl or C 2-8 unsaturated alkyl; M is selected from C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 2-4 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl or C 2-4 unsaturated alkyl is optionally substituted by one or more of halogen, O, C 3-5 cycloalkyl, hydroxyl, -NH2 or -N3, wherein C 3-5 cycloalkyl is optionally substituted by one or more of halogen, O or hydroxyl, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; R4, R5are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, C 1-8 alkyl, C 2-8 unsaturated alkyl, -OR 15 or -NR 11 R 12 wherein C 1-8 alkyl or C 2-8 unsaturated alkyl is optionally substituted by one or more halogen, O, hydroxyl, R 11 , R 12 ; R8, R9, R 11 , R 12 , R 13 , R 15 each is independently selected from L2is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted by one or more halogen, O, hydroxyl; K1is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 16 or a bond; L3is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) a or a bond, a = 1 to 10, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted by one or more halogen, O, hydroxyl; K2is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 17 , AA or a bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 、 AA or a bond; L4, L5are independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) b or a bond, b = 1 to 10, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl optionally substituted by one or more halogen, O, hydroxyl; K4is selected from NR 28 , carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxy, S, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; X, Y, Z are each independently selected from CH, N, CSO2NR 19 R 26 , CSO2R 27 , CNHCOR 21 , COR 20 wherein R 19 , R 20 , R 21 , R 27 are each independently selected from L6is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl is optionally substituted with one or more halogen, NR 22 R 23 , O, hydroxyl, C 1-6 alkyl or C 2-6 unsaturated alkyl; wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl; K5is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 29 or a bond; L7is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) d or a bond, d = 1 to 10, wherein C 1-8 alkyl is optionally substituted by one or more halogen, O, hydroxy, C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogen, O, hydroxy; K6is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 30 , AA or a bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 、 AA or a bond; L8, L9, L 10 each independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) e , e = 1 to 10 or a bond, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl, NR 24 R 25 , C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, O, hydroxyl; K8, K9 are each independently selected from NR 32 , carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxy, S, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; wherein R 16 , R 17 , R 18 , R 28 , R 29 , R 30 , R 31 , R 32 are each independently selected from H, C 1-3 alkyl or C 2-3 unsaturated alkyl, R 22 , R 23 , R 24 , R 25 are independently selected from H, C 1-3 alkyl, C 2-3 unsaturated alkyl, R 26 H, C 1-6 alkyl, C 2-6 unsaturated alkyl, C 3-6 cycloalkyl, wherein AA is selected from the group consisting of an amino acid residue, said amino acid being selected from the group consisting of glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; ring A1, ring A2 are independently selected from the group consisting of a naphthalene ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a benzo 5- to 9-membered heteroaromatic ring, wherein the naphthalene ring, the benzene ring, the pyridine ring, the pyrimidine ring, the pyrazine ring or the benzo 5- to 9-membered heteroaromatic ring can be substituted by halogen, CN, nitro, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl.

3. The compound of claim 2, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or an optical isomer thereof, or a stereoisomer thereof, wherein, The compound of formula I-1 is represented by formula I-1-1, formula I-1-2, or formula I-1-3: R2 and R3 are each independently selected from hydrogen, halogen, -CN, -NR8R9, and C. 1-8 Alkyl, C 2-8 Unsaturated alkyl or -OR 13 R6 and R7 are each independently selected from hydrogen, halogens, and C. 2-4 Unsaturated alkyl or C 1-4 Alkyl, wherein C 1-4 Alkyl or C 2-4 The unsaturated alkyl group may optionally be substituted with one or more of the following substituents: halogen, dimethyl sulfone, C 2-4 Unsaturated alkyl or C 1-4 Alkyl group; or R6, R7 forming a 3- to 6-membered carbon ring or a 3- to 6-membered heterocycle, wherein the 3- to 6-membered carbon ring or the 3- to 6-membered heterocycle is optionally substituted by one or more of the following substituents: O or halogen, wherein the 3- to 6-membered heterocycle contains 1 to 2 atoms optionally selected from O, S, N; L is selected from -NHCO-, -NHSO2-, -NR 10 CONH-, -CONHCO-, -NR 14 CSNH-, or R 10 , R 14 is selected from hydrogen, C 1-8 alkyl or C 2-8 unsaturated alkyl; M is selected from C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 2-4 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl or C 2-4 unsaturated alkyl is optionally substituted by one or more of halogen, O, C 3-5 cycloalkyl, hydroxyl, -NH2or -N3, wherein C 3-5 cycloalkyl is optionally substituted by one or more of halogen, O or hydroxyl, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; R4, R5are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, C 1-8 alkyl or C 2-8 unsaturated alkyl, -OR 15 or -NR 11 R 12 wherein C 1-8 alkyl or C 2-8 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl; V is selected from O, NR 33 , SO2NR 26 , SO2, NHCO, CO or a bond; L2is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted with one or more halogen, O, hydroxyl; K1is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 16 or a bond; L3is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) a or a bond, a = 1-10, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted with one or more halogen, O, hydroxyl; K2is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 17 ​ AA or a bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 、 AA or a bond; L4, L5are independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) b or a bond, b = 1 to 10, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl optionally substituted by one or more halogen, O, hydroxyl; K4is selected from NR 28 , carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl optionally substituted by one or more halogen, O, S, hydroxy, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl optionally substituted by one or more halogen, O, S, hydroxy, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; L6is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted by one or more halogen, NR 22 R 23 , O, hydroxy, C 1-6 alkyl or C 2-6 unsaturated alkyl, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl optionally substituted by one or more halogen, O, hydroxy; K5is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 29 or a bond; L7is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) d or a bond, d = 1 to 10, wherein C 1-8 alkyl is optionally substituted with one or more halogen, O, hydroxy, C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, O, hydroxy; K6is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 30 , AA or a bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 、 AA or a bond; L8, L9, L 10 each independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) e , e = 1 to 10 or a bond, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl, NR 24 R 25 , C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, O, hydroxyl; K8, K9 are each independently selected from NR 32 , carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxy, S, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; wherein R 16 , R 17 , R 18 , R 28 , R 29 , R 30 , R 31 , R 32 are each independently selected from H, C 1-3 alkyl or C 2-3 unsaturated alkyl, R 22 , R 23 , R 24 , R 25 are independently selected from H, C 1-3 alkyl, C 2-3 unsaturated alkyl, R 26 H, C 1-6 alkyl, C 2-6 unsaturated alkyl, C 3-6 cycloalkyl, wherein AA is selected from the group consisting of an amino acid residue, said amino acid being selected from the group consisting of glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; ring A1, ring A2 are independently selected from the group consisting of a naphthalene ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a benzo 5- to 9-membered heteroaromatic ring, wherein the naphthalene ring, the benzene ring, the pyridine ring, the pyrimidine ring, the pyrazine ring or the benzo 5- to 9-membered heteroaromatic ring can be substituted by halogen, CN, nitro, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl; R8, R9, R 11 , R 12 , R 13 , R 15 , R 33 are each independently selected from X, Y, Z are each independently selected from CH, N, CSO2NR 34 R 35 , CSO2R 36 , CNHCOR 37 , COR 38 wherein R 34 , R 36 , R 37 , R 38 are each independently selected from L 11 , L 13 independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl or a bond, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted with one or more halogen, NR 39 R 40 , O, hydroxyl, C 1-4 alkyl or C 2-4 unsaturated alkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl; K 10 , K 12 independently selected from carbonyl, sulfonyl, O, S, NR 41 or a bond; L 12 , L 14 are independently selected from C 1-4 alkyl, C 2-4 unsaturated alkyl, (OCH2CH2) f or a bond, f = 1 to 3, wherein C 1-4 alkyl or C 2-4 unsaturated alkyl is optionally substituted by one or more halogen, O, hydroxy; K 11 , K 13 are independently selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 42 , AA, COO, CONH, SO3, SO2NH or a bond; J, T are independently selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl optionally substituted with one or more halogen, O, hydroxyl, S, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl optionally substituted with one or more halogen, O, S, hydroxyl, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; R 35 selected from H, C 1-6 alkyl, C 2-6 unsaturated alkyl, C 3-6 cycloalkyl; R 39 , R 40 each independently selected from H, C 1-3 alkyl or C 2-3 unsaturated alkyl, R 41 , R 42 are independently selected from H, C 1-3 alkyl or C 2-3 unsaturated alkyl; wherein AA is selected from an amino acid residue, said amino acid is selected from glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; ring A3 is independently selected from a naphthalene ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a benzo 5- to 9-membered heteroaromatic ring, wherein said naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring or benzo 5- to 9-membered heteroaromatic ring can be substituted with halogen, CN, nitro, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl.

4. The compound of claim 1, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or an optical isomer thereof, or a stereoisomer thereof, wherein, The compound of formula I is represented by formula I-2: W is selected from CR1or N; R1, R2are each independently selected from the group consisting of hydrogen, halogen, -CN, -NR8R9, C 1-8 alkyl, C 2-8 alkyl, C 13 alkyl, C 2-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 2-4 alkyl, C 2-4 alkyl, C 1-4 alkyl; or R6, R7form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered carbocyclic ring or the 3- to 6-membered heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of O or halogen, wherein the 3- to 6-membered heterocyclic ring contains 1 to 2 atoms optionally selected from O, S, N; L is selected from -NHCO-, -NHSO2-, -NR 10 CONH-, -CONHCO-, -NR 14 CSNH-, or R 10 , R 14 is selected from hydrogen, C 1-8 alkyl or C 2-8 unsaturated alkyl; M is selected from C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 2-4 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl or C 2-4 unsaturated alkyl is optionally substituted by one or more of halogen, O, C 3-5 cycloalkyl, hydroxyl, -NH2 or -N3, wherein C 3-5 cycloalkyl is optionally substituted by one or more of halogen, O or hydroxyl, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; R4, R5are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, C 1-8 alkyl, C 2-8 unsaturated alkyl, -OR 15 or -NR 11 R 12 wherein C 1-8 alkyl or C 2-8 unsaturated alkyl is optionally substituted by one or more halogen, O, hydroxyl, R 11 , R 12 ; R8, R9, R 11 , R 12 , R 13 , R 15 are each independently selected from L2is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted with one or more halogen, O, hydroxyl; K1is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 16 or a bond; L3is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) a or a bond, a = 1-10, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted with one or more halogen, O, hydroxyl; K2is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 17 , AA or a bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 、 AA or a bond; L4, L5are independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) b or a bond, b = 1 to 10, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl optionally substituted by one or more halogen, O, hydroxyl; K4is selected from NR 28 , carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxy, S, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; X, Y, Z are each independently selected from CH, N, CSO2NR 19 R 26 , CNHCOR 27 , COR 21 , COR 20 wherein R 19 , R 20 , R 21 , R 27 are each independently selected from L6is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl is optionally substituted with one or more halogen, NR 22 R 23 , O, hydroxyl, C 1-6 alkyl or C 2-6 unsaturated alkyl, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl; K5 is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 29 or a bond; L7is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) d or a bond, d = 1 to 10, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxy, C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, O, hydroxy; K6is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 30 ,, AA or a bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 、 AA or a bond; L8, L9, L 10 each independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) e , e = 1 to 10 or a bond, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl, optionally substituted with one or more halogen, O, hydroxyl, NR 24 R 25 , C 1-6 alkyl, wherein C 1-6 alkyl optionally substituted with one or more halogen, O, hydroxyl; K8, K9 are each independently selected from NR 32 , carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, S, hydroxy, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; wherein R 16 , R 17 , R 18 , R 28 , R 29 , R 30 , R 31 , R 32 are each independently selected from H, C 1-3 alkyl or C 2-3 unsaturated alkyl, R 22 , R 23 , R 24 , R 25 are independently selected from H, C 1-3 alkyl, C 2-3 unsaturated alkyl, R 26 H, C 1-6 alkyl, C 2-6 unsaturated alkyl, C 3-6 cycloalkyl, wherein AA is selected from the group consisting of an amino acid residue, said amino acid being selected from the group consisting of glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; ring A1, ring A2 are independently selected from the group consisting of a naphthalene ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a benzo 5- to 9-membered heteroaromatic ring, wherein the naphthalene ring, the benzene ring, the pyridine ring, the pyrimidine ring, the pyrazine ring or the benzo 5- to 9-membered heteroaromatic ring can be substituted by halogen, CN, nitro, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl.

5. The compound of claim 4, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or an optical isomer thereof, or a stereoisomer thereof, wherein, The compound of formula I-2 is represented by formula I-2-1, formula I-2-2, or formula I-2-3: W is selected from CR1or N; R1, R2are each independently selected from the group consisting of hydrogen, halogen, -CN, -NR8R9, C 1-8 alkyl, C 2-8 alkyl, C 13 unsaturated alkyl or -OR 2-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 2-4 alkyl, C 2-4 alkyl, C 1-4 alkyl; or R6, R7form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered carbocyclic ring or the 3- to 6-membered heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of O or halogen, wherein the 3- to 6-membered heterocyclic ring contains 1 to 2 atoms optionally selected from O, S, N; L is selected from -NHCO-, -NHSO2-, -NR 10 CONH-, -CONHCO-, -NR 14 CSNH-, or R 10 , R 14 is selected from hydrogen, C 1-8 alkyl or C 2-8 unsaturated alkyl; M is selected from C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 2-4 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl or C 2-4 unsaturated alkyl is optionally substituted by one or more of halogen, O, C 3-5 cycloalkyl, hydroxyl, -NH2 or -N3, wherein C 3-5 cycloalkyl is optionally substituted by one or more of halogen, O or hydroxyl, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; R4, R5are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, C 1-8 alkyl, C 2-8 alkyl, -OR 15 or -NR 11 R 12 , wherein C 1-8 alkyl or C 2-8 alkyl is optionally substituted with one or more halogen, O, hydroxyl; V is selected from the group consisting of O, NR 33 , SO2NR 26 , SO2, NHCO, CO; L2is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted by one or more halogen, O, hydroxyl; K1is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 16 or a bond; L3is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) a or a bond, a = 1 to 10, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted by one or more halogen, O, hydroxyl; K2is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 17 , AA or a bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 、 AA or a bond; L4, L5are independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) b or a bond, b = 1 to 10, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl optionally substituted by one or more halogen, O, hydroxyl; K4is selected from NR 28 , carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl optionally substituted with one or more halogen, O, S, hydroxy, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl optionally substituted with one or more halogen, O, S, hydroxy, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; L6is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted with one or more halogen, NR 22 R 23 , O, hydroxy, C 1-6 alkyl or C 2-6 unsaturated alkyl, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl optionally substituted with one or more halogen, O, hydroxy; K5is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 29 or a bond; L7is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) d or a bond, d = 1 to 10, wherein C 1-8 alkyl is optionally substituted by one or more halogen, O, hydroxy, C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogen, O, hydroxy; K6is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 30 , AA or a bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 、 AA or a bond; L8, L9, L 10 each independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) e , e = 1 to 10 or a bond, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted by one or more halogen, O, hydroxyl, NR 24 R 25 , C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogen, O, hydroxyl; K8, K9 are each independently selected from NR 32 , carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, S, hydroxy, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; wherein R 16 , R 17 , R 18 , R 28 , R 29 , R 30 , R 31 , R 32 are each independently selected from H, C 1-3 alkyl or C 2-3 unsaturated alkyl, R 22 , R 23 , R 24 , R 25 are independently selected from H, C 1-3 alkyl, C 2-3 unsaturated alkyl, R 26 H, C 1-6 alkyl, C 2-6 unsaturated alkyl, C 3-6 cycloalkyl, wherein AA is selected from the group consisting of an amino acid residue, said amino acid being selected from the group consisting of glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; ring A1, ring A2 are independently selected from the group consisting of a naphthalene ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a benzo 5- to 9-membered heteroaromatic ring, wherein the naphthalene ring, the benzene ring, the pyridine ring, the pyrimidine ring, the pyrazine ring or the benzo 5- to 9-membered heteroaromatic ring can be substituted by halogen, CN, nitro, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl; R8, R9, R 11 , R 12 , R 13 , R 15 , R 33 are each independently selected from the group consisting of X, Y, Z are each independently selected from CH, N, CSO2NR 34 R 35 , CSO2R 36 , CNHCOR 37 , COR 38 , wherein R 34 , R 36 , R 37 , R 38 are each independently selected from L 11 , L 13 is independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl or a bond, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted with one or more halogen, NR 39 R 40 , O, hydroxyl, C 1-4 alkyl or C 2-4 unsaturated alkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl; K 10 , K 12 is independently selected from carbonyl, sulfonyl, O, S, NR 41 or a bond; L 12 , L 14 are independently selected from C 1-4 alkyl, C 2-4 unsaturated alkyl, (OCH2CH2) f or a bond, f = 1 to 3, wherein C 1-4 alkyl or C 2-4 unsaturated alkyl is optionally substituted by one or more halogen, O, hydroxyl; K 11 , K 13 are independently selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 42 , AA, COO, CONH, SO3, SO2NH or a bond; J, T are independently selected from H, nitro, nitrile, halogen, hydroxy, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl optionally substituted by one or more halogen, O, hydroxy, S, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl optionally substituted by one or more halogen, O, S, hydroxy, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; R 35 selected from H, C 1-6 alkyl, C 2-6 unsaturated alkyl, C 3-6 cycloalkyl; R 39 , R 40 each independently selected from H, C 1-3 alkyl or C 2-3 unsaturated alkyl, R 41 , R 42 are independently selected from H, C 1-3 alkyl or C 2-3 unsaturated alkyl; wherein AA is selected from an amino acid residue, said amino acid being selected from glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; ring A3 is independently selected from a naphthalene ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a benzo 5- to 9-membered heteroaromatic ring, wherein said naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring or benzo 5- to 9-membered heteroaromatic ring can be substituted with halogen, CN, nitro, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl.

6. The compound of claim 1, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or an optical isomer thereof, or a stereoisomer thereof, wherein, The compound of formula I is represented by formula I-3: W is selected from CR1or N; R1, R3are each independently selected from the group consisting of hydrogen, halogen, -CN, -NR8R9, C 1-8 alkyl, C 2-8 alkyl, C 13 alkyl, C 2-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 2-4 alkyl, C 2-4 alkyl, C 1-4 alkyl; or R6, R7form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered carbocyclic ring or the 3- to 6-membered heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of O or halogen, wherein the 3- to 6-membered heterocyclic ring contains 1 to 2 atoms optionally selected from O, S, N; L is selected from -NHCO-, -NHSO2-, -NR 10 CONH-, -CONHCO-, -NR 14 CSNH-, or R 10 , R 14 is selected from hydrogen, C 1-8 alkyl or C 2-8 unsaturated alkyl; M is selected from C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 2-4 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl or C 2-4 unsaturated alkyl is optionally substituted by one or more of halogen, O, C 3-5 cycloalkyl, hydroxyl, -NH2or -N3, wherein C 3-5 cycloalkyl is optionally substituted by one or more of halogen, O or hydroxyl, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; R4, R5are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, C 1-8 alkyl, C 2-8 alkenyl, -OR 15 or -NR 11 R 12 , wherein C 1-8 alkyl or C 2-8 alkenyl is optionally substituted with one or more halogen, O, hydroxyl, R 11 , R 12 ; R8, R9, R 11 , R 12 , R 13 , R 15 are each independently selected from the group consisting of L2is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted with one or more halogen, O, hydroxyl; K1is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 16 or a bond; L3is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) a or a bond, a = 1-10, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted with one or more halogen, O, hydroxyl; K2is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 17 , AA or a bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 、 AA or a bond; L4, L5are independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) b or a bond, b = 1 to 10, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl optionally substituted by one or more halogen, O, hydroxyl; K4is selected from NR 28 , carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxy, S, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; X, Y, Z are each independently selected from CH, N, CSO2NR 19 R 26 , CSO2R 27 , CNHCOR 21 , COR 20 , wherein R 19 , R 20 , R 21 , R 27 are each independently selected from L6is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl is optionally substituted with one or more halogen, NR 22 R 23 , O, hydroxyl, C 1-6 alkyl or C 2-6 unsaturated alkyl, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl; K5is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 29 or a bond; L7is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) d or a bond, d = 1 to 10, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl is optionally substituted by one or more halogen, O, hydroxy, C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogen, O, hydroxy; K6is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 30 , AA or a bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 、 AA or a bond; L8, L9, L 10 each independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) e , e = 1 to 10 or a bond, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted by one or more halogen, O, hydroxyl, NR 24 R 25 , C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogen, O, hydroxyl; K8, K9 are each independently selected from NR 32 , carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxy, S, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; wherein R 16 , R 17 , R 18 , R 28 , R 29 , R 30 , R 31 , R 32 are each independently selected from H, C 1-3 alkyl or C 2-3 unsaturated alkyl, R 22 , R 23 , R 24 , R 25 are independently selected from H, C 1-3 alkyl, C 2-3 unsaturated alkyl, R 26 selected from H, C 1-6 alkyl, C 2-6 unsaturated alkyl, C 3-6 cycloalkyl, wherein AA is selected from an amino acid residue, said amino acid being selected from glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; ring A1, ring A2are independently selected from a naphthalene ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a benzo 5- to 9-membered heteroaromatic ring, wherein the naphthalene ring, the benzene ring, the pyridine ring, the pyrimidine ring, the pyrazine ring or the benzo 5- to 9-membered heteroaromatic ring can be substituted with halogen, CN, nitro, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl.

7. The compound of claim 6, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or an optical isomer thereof, or a stereoisomer thereof, wherein, The compounds of formula I-3 are represented by formula I-3-1, formula I-3-2 or formula I-3-3: W is selected from CR1or N; R1, R3are each independently selected from the group consisting of hydrogen, halogen, -CN, -NR8R9, C 1-8 alkyl, C 2-8 alkyl, C 13 alkyl, C 2-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 2-4 alkyl, C 2-4 alkyl, C 1-4 alkyl; or R6, R7form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered carbocyclic ring or the 3- to 6-membered heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of O or halogen, wherein the 3- to 6-membered heterocyclic ring contains 1 to 2 atoms optionally selected from O, S, N; L is selected from -NHCO-, -NHSO2-, -NR 10 CONH-, -CONHCO-, -NR 14 CSNH-, or R 10 , R 14 is selected from hydrogen, C 1-8 alkyl or C 2-8 unsaturated alkyl; M is selected from C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 2-4 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl or C 2-4 unsaturated alkyl is optionally substituted with one or more of halogen, O, C 3-5 cycloalkyl, hydroxyl, -NH2 or -N3, wherein C 3-5 cycloalkyl is optionally substituted with one or more of halogen, O or hydroxyl, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; R4, R5are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, C 1-8 alkyl, C 2-8 unsaturated alkyl, -OR 15 or -NR 11 R 12 wherein C 1-8 alkyl or C 2-8 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl; V is selected from O, NR 33 , SO2NR 26 , SO2, NHCO, CO; L2is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted with one or more halogen, O, hydroxyl; K1is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 16 or a bond; L3is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) a or a bond, a = 1-10, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl optionally substituted with one or more halogen, O, hydroxyl; K2is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 17 , AA or a bond; K3 is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 、 AA or key; L4 and L5 are independently selected from C. 1-6 Alkyl, C 2-6 Unsaturated alkyl groups, (OCH2CH2) b OR key, b = 1 to 10, where C 1-6 Alkyl, C 2-6 The unsaturated alkyl group is optionally substituted with one or more halogens, O, or hydroxyl groups; K4 is selected from NR. 28 Carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Unsaturated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxy, S, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; L6is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl is optionally substituted with one or more halogen, NR 22 R 23 , O, hydroxyl, C 1-6 alkyl or C 2-6 unsaturated alkyl, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl; K5is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 29 or a bond; L7is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) d or a bond, d = 1 to 10, wherein C 1-8 alkyl is optionally substituted with one or more halogen, O, hydroxy, C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, O, hydroxy; K6is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 30 ,, AA or a bond; K7 is selected from carbonyl, thiocarbonyl, NR 31 、 AA or a bond; L8, L9, L 10 each independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) e , e = 1 to 10 or a bond, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted by one or more halogen, O, hydroxyl, NR 24 R 25 , C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogen, O, hydroxyl; K8, K9 are each independently selected from NR 32 , carbonyl, thiocarbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; U is selected from H, nitro, nitrile, halogen, hydroxyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxy, S, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; wherein R 16 , R 17 , R 18 , R 28 , R 29 , R 30 , R 31 , R 32 are each independently selected from H, C 1-3 alkyl or C 2-3 unsaturated alkyl, R 22 , R 23 , R 24 , R 25 are independently selected from H, C 1-3 alkyl, C 2-3 unsaturated alkyl, R 26 H, C 1-6 alkyl, C 2-6 unsaturated alkyl, C 3-6 cycloalkyl, wherein AA is selected from the group consisting of an amino acid residue, said amino acid being selected from the group consisting of glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; ring A1, ring A2 are independently selected from the group consisting of a naphthalene ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a benzo 5- to 9-membered heteroaromatic ring, wherein the naphthalene ring, the benzene ring, the pyridine ring, the pyrimidine ring, the pyrazine ring or the benzo 5- to 9-membered heteroaromatic ring can be substituted by halogen, CN, nitro, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl; R8, R9, R 11 , R 12 , R 13 , R 15 , R 33 are each independently selected from X, Y, Z are each independently selected from CH, N, CSO2NR 34 R 35 , CSO2R 36 , CNHCOR 37 , COR 38 wherein R 34 , R 36 , R 37 , R 38 are each independently selected from L 11 , L 13 independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl or a bond, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted with one or more halogen, NR 39 R 40 , O, hydroxyl, C 1-4 alkyl or C 2-4 unsaturated alkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl; K 10 , K 12 independently selected from carbonyl, sulfonyl, O, S, NR 41 or a bond; L 12 , L 14 are independently selected from C 1-4 alkyl, C 2-4 unsaturated alkyl, (OCH2CH2) f or a bond, f = 1 to 3, wherein C 1-4 alkyl or C 2-4 unsaturated alkyl is optionally substituted by one or more halogen, O, hydroxy; K 11 , K 13 are independently selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 42 , AA or a bond; J, T are independently selected from H, nitro, nitrile, halogen, hydroxy, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, wherein C 1-4 alkyl is optionally substituted with one or more halogen, O, hydroxy, S, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein the 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N; R 35 is selected from H, C 1-6 alkyl, C 2-6 unsaturated alkyl, C 3-6 cycloalkyl; R 39 , R 40 are each independently selected from H, C 1-3 alkyl or C 2-3 unsaturated alkyl, R 41 , R 42 are independently selected from H, C 1-3 alkyl or C 2-3 unsaturated alkyl; wherein AA is selected from an amino acid residue, said amino acid is selected from glycine, phenylalanine, arginine, N ω ,N ω -dimethylarginine, citrulline, tryptophan, histidine, leucine, valine, alanine, glutamic acid, aspartic acid, proline, lysine or isoleucine; ring A3 is independently selected from a naphthalene ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a benzo 5- to 9-membered heteroaromatic ring, wherein said naphthalene ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring or benzo 5- to 9-membered heteroaromatic ring can be substituted with halogen, CN, nitro, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl.

8. The compound of claim 1, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or an optical isomer thereof, or a stereoisomer thereof, wherein, R6, R7are each independently selected from the group consisting of H, fluorine, chlorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, wherein the R6, R7form a 3- to 6-membered carbocyclic ring, selected from the group consisting of: when R6, R7form a 3- to 6-membered heterocyclic ring, selected from the group consisting of:

9. The compound of claim 1, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or an optical isomer thereof, or a stereoisomer thereof, wherein, R4, R5are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, -OR 15 , 11 R 12 , 11 -COR 11 , 11 -CH=CHR 11 , 12 -COR 12 , 12 -CH=CHR 12 or -C≡CR 11 ; R 12 , R 15 are each independently selected from the group consisting of L2is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl or a bond, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl; K1is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 16 or a bond; L3is selected from C 1-8 alkyl, C 2-8 unsaturated alkyl, (OCH2CH2) a or a bond, a = 1 to 10, wherein C 1-8 alkyl, C 2-8 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl; K2is selected from carbonyl, thiocarbonyl, sulfonyl, O, S, NR 17 , AA or a bond; K3is selected from carbonyl, thiocarbonyl, sulfonyl, NR 18 , AA or a bond; L4, L5are independently selected from C 1-6 alkyl, C 2-6 unsaturated alkyl, (OCH2CH2) b or a bond, b = 1 to 10, wherein C 1-6 alkyl, C 2-6 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxyl; K4is selected from NR 28 , carbonyl, sulfonyl, S, O, COO, CONH, SO3, SO2NH or a bond; Q is selected from H, nitro, nitrile, halogen, hydroxyl, C 1-4 alkyl, C 2-4 unsaturated alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-4 alkyl, C 2-4 unsaturated alkyl is optionally substituted with one or more halogen, O, hydroxy, S, phenyl, naphthyl, wherein C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more halogen, O, S, hydroxy, wherein 4-6 membered heterocycle contains 1-2 atoms optionally selected from O, S, N.

10. The compound of claim 1, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or an optical isomer thereof, or a stereoisomer thereof, wherein, Ring A1is selected from: Ring A2is selected from:

11. The compound of any one of claims 1-10, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or an optical isomer thereof, or a stereoisomer thereof, wherein, The compound is selected from any of the following compounds:

12. A pharmaceutical composition comprising a compound or salt or metal complex of any one of claims 1-11, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

13. The compound or salt or metal complex of any one of claims 1-12, solvate, metabolite, co-crystal or prodrug thereof, or use of the foregoing in the manufacture of a medicament for the diagnosis and / or treatment of a disease mediated by FAP.

14. The use according to claim 13, wherein the disease is selected from rheumatoid arthritis, non-alcoholic fatty liver, atherosclerosis, myocardial infarction, liver fibrosis, lung fibrosis, kidney fibrosis, sarcoma, glioblastoma, ovarian cancer, breast cancer, cervical cancer, lung cancer, pancreatic cancer, mesothelioma, skin cancer, colorectal cancer, bladder cancer, gastric cancer, endometrial cancer or thyroid cancer.

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