FAP-targeted radiopharmaceuticals

Abstract

The invention relates to a targeted fibroblast activating protein radiopharmaceutical, in particular to a compound which is a compound as shown in a formula I or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound as shown in the formula I, the compounds can inhibit the expression of fibroblast activating protein FAP or diagnose and / or treat diseases characterized by overexpression of fibroblast activating protein. # imgabs0 #

Description

[0001] Priority Information

[0002] This invention claims the priority and rights of the patent application with the patent application number 202311721106.6 filed with the China National Intellectual Property Administration on December 13, 2023, and incorporates the entire text thereof by reference herein. Technical Field

[0003] This invention relates to the field of pharmaceutical technology. Specifically, this invention relates to FAP-targeted radiopharmaceuticals. Background Art

[0004] Fibroblast activation protein (FAP) is highly overexpressed on cancer-associated fibroblasts (CAFs), which are the main stromal components of solid tumors, and is generally not expressed in normal tissues and benign tumors. Tumor stromal CAFs can promote the growth and invasion of tumor cells and have become an important target for tumor intervention. The overexpression of the tumor biomarker molecule FAP is a significant feature of CAFs, and FAP is an important potential target for the diagnosis and treatment of CAF-targeted tumors. FAP is a type II transmembrane serine protease on tumor fibroblasts, exists on the cell surface in the form of a homodimer, belongs to the proline oligopeptidase family, and its enzymatic activity plays an important role in tumor growth and tissue remodeling. The surface-specific FAPα on CAFs can enhance the ability of tumor cells to invade along fibers, participate in tumor angiogenesis, etc. by promoting matrix reconstruction and participating in signal transduction pathways such as VEGF / AKT / ERK to form a tumor biological barrier and inhibit the function of effector T cells, thereby promoting tumor progression. The inducible high expression of FAP in the tumor stroma also depends on the malignant transformation of tumor tissues. There is a positive correlation between the high expression level of FAP and poor tumor prognosis. FAP has positive expression to varying degrees in a variety of sarcomas, melanomas, esophageal cancers, breast cancers, cholangiocarcinomas, lung cancers (FAP positive rate 97.3%), liver cancers, colorectal cancers, head and neck cancers, ovarian cancers, pancreatic cancers, neuroendocrine tumors, prostate cancers, pheochromocytomas, kidney cancers, thyroid cancers, adenoid cystic carcinomas, and gastric cancers. FAP is not expressed or is lowly expressed in normal tissues, especially in ovarian cancers, pancreatic cancers, etc. where FAP has high expression.

[0005] Antibody-drug conjugate (ADC) drugs are not conducive to clinical development due to poor permeability, long half-life, long non-target organ uptake and retention time, and relatively high toxicity. FAP-targeted antibody-conjugated drugs such as 131I-mAbF19 (liver metastasis of colon cancer) cannot be developed for tumor diagnosis and treatment due to disadvantages such as poor permeability and long circulating half-life. FAP-targeted small molecules and peptide inhibitors that have undergone structural modification and optimization screening have great development value advantages for cancer diagnosis and treatment if they can overcome the challenges of rapid clearance and insufficient tumor uptake and retention time. In the preclinical stage, many new progress has been made in the development of tumor-targeted FAPI structures (in terms of target-specific affinity and druggability), and new molecules that can be used as lead compounds are constantly emerging, providing new possibilities for tumor radio-diagnosis and treatment based on FAPI and its derivatives. Currently, FAP-targeted diagnostic small molecule conjugates at the preclinical and clinical stages 68 Ga]-FAPI-46, 177 Lu]-FAPI-46, and 225 Ac]-FAPI-46, etc., can be used for imaging diagnosis and targeted treatment of tongue squamous cell carcinoma, ovarian cancer, pancreatic cancer and other various malignant tumors. Small molecule peptide-targeted conjugates 68 Ga]-FAP-2286, etc., have entered preclinical and early clinical studies and have achieved comparable results to 68 Ga]-FAPI-46 in more than a dozen clinical malignant tumors, and are superior to 18 F]-FDG in the ability to detect imaging diagnosis lesions. 18 F]-labeled small molecule tracers 18 F]AIF-FAPI-74 and 18 F]AIF-NOTA-FAPI-04, etc., also show good specific targeting binding and clinical lesion detection advantages.

[0006] For the diagnosis and treatment of tumors, using structurally optimized and screened FAPI as a tumor-targeted small molecule carrier has become an advantageous choice in the field of anti-tumor diagnosis and treatment. Developing FAPI with better tumor selectivity and diagnostic drugs with higher imaging efficiency advantages has strong feasibility and great potential application value for the precise diagnosis and treatment of FAP-positive malignant solid tumors. Summary of the Invention

[0007] The present invention aims to solve at least one of the technical problems existing in the prior art to at least a certain extent.

[0008] Accordingly, in a first aspect of the present invention, the present invention provides a compound which is a compound represented by Formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by Formula I:

[0009]

[0010] Wherein, ring A is selected from a five-membered heteroalkyl optionally substituted by R 1 ; B is selected from -NR 2 -, -O-, -S- or -C 1～6 alkylene-; L 1 is selected from the structure or a bond; L 2 is selected from -NR 2 -, a -C 1 alkylene NH- optionally substituted by R 1～6 ((, a -NH-C 1 alkylene-NH- optionally substituted by R 1～6 or a bond; L 1 , L 2 are not both bonds at the same time; L 11 , L’ 11 are each independently selected from an amino acid chain optionally substituted by R 1 , a carbon chain optionally substituted by R 1 , a combination of an amino acid chain and a carbon chain optionally substituted by R 1 , a -C 1 alkylene-[NH-C(O)-CH 1～6 2 - optionally substituted by R t , a -C 1 alkylene-[NH-C(O)-CH 1～6 2 -NH- or a -C(O)-NH-C t alkylene optionally substituted by R 1 ; L 1～10 is selected from a -C 12 alkylene-NH- optionally substituted by R 1 , a C 1～6 alkylene optionally substituted by R 1 , a -C(O)-C 1～6 alkylene optionally substituted by R 1 or a bond; T or Z are each independently selected from a chelating agent, a fluorescent group or a radioactive group. 1～6 R

[0011] are each independently selected from -F, -Cl, -Br, -I, -CN, =O, an 1 optionally substituted by R​​3 Substituted C 1～6 alkyl, -OH, -COOH, -CH 2 OH, -CH 2 COOH, phenyl or tolyl; R 2 is independently selected from -H, -C 1-6 alkyl, -C 1-6 alkylene-, -CH 2 O-, cycloalkenyl, cycloheteroalkenyl, aryl or -C 1-6 cycloalkyl-; R 3 is selected from -F, -Cl, -Br, -I, -CN, =O, -OH or -COOH; t is selected from 1, 2, 3 or 4; when the said R 1 , R 2 or R 3 are multiple, the said R 1 , R 2 or R 3 can be the same or different.

[0012] It should be noted that when ring A is selected from a five-membered heteroalkyl substituted by R 1 , this five-membered heteroalkyl can be substituted by one or more R 1 simultaneously. When there are multiple R 1 substituting simultaneously, R 1 can be the same or different. When L 11 , L’ 11 or L 12 is selected from a specific structure substituted by R 1 , this specific structure can be substituted by one or more R 1 simultaneously. When there are multiple R 1 substituting simultaneously, R 1 can be the same or different.

[0013] In the present invention, the definitions of some substituents in the compound shown in Formula I can be described as follows, and the definitions of the unmentioned substituents are as described in any of the above schemes.

[0014] According to the embodiments of the present invention, the compound is a compound shown in Formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound shown in Formula II:

[0015]

[0016] Among them, ring A is selected from a five-membered heteroalkyl optionally substituted by R 1 ; B is selected from -NR 2 -, -O-, -S- or -C 1～6 alkylene-; L 11 is selected from optionally being substituted by R1 Substituted amino acid chain, optionally substituted by R 1 Substituted carbon chain, optionally substituted by R 1 Combination of substituted amino acid chain and carbon chain, optionally substituted by R 1 Substituted -C 1～6 Alkylene-[NH-C(O)-CH 2 t -, optionally substituted by R 1 Substituted -C 1～6 Alkylene-[NH-C(O)-CH 2 t -NH- or optionally substituted by R 1 Substituted -C(O)-NH-C 1～10 Alkylene; L 2 Selected from optionally substituted by R 1 Substituted -C 1～6 Alkylene-NH-; T is selected from a chelating agent or a fluorescent group.

[0017] R 1 Are each independently selected from -F, -Cl, -Br, -I, -CN, =O, optionally substituted by R 3 Substituted C 1～6 Alkyl, -OH, -COOH, -CH 2 OH, -CH 2 COOH, phenyl or tolyl; R 2 Selected from -H, -C 1-6 Alkyl, -C 1-6 Alkylene-, -CH 2 O-, cycloalkenyl, cycloheteroalkenyl, aryl or -C 1-6 Cycloalkyl-; R 3 Selected from -F, -Cl, -Br, -I, -CN, =O, -OH or -COOH; t is selected from 1, 2, 3 or 4; when the said R 1 , R 2 or R 3 are in plurality, the said R 1 , R 2 or R 3 can be the same or different.

[0018] According to an embodiment of the present invention, the compound is a compound represented by Formula III or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by Formula III:

[0019]

[0020] Among them, ring A is selected from optionally substituted by R 1 Substituted five-membered heteroalkyl; B is selected from -NR 2 ​​-O-,-S- or -C 1～6 alkylene-; L' 11 selected from an optionally R 1 substituted amino acid chain, an optionally R 1 substituted carbon chain, an optionally R 1 substituted combination of an amino acid chain and a carbon chain, an optionally R 1 substituted -C 1～6 alkylene-[NH-C(O)-CH 2 t -, an optionally R 1 substituted -C 1～6 alkylene-[NH-C(O)-CH 2 t -NH- or an optionally R 1 substituted -C(O)-NH-C 1～10 alkylene; L 12 selected from an optionally R 1 substituted -C 1～6 alkylene-NH-, an optionally R 1 substituted C 1～6 alkylene or an optionally R 1 substituted -C(O)-C 1～6 alkylene or a bond; L 2 selected from -NR 2 -, an optionally R 1 substituted -C 1～6 alkylene-NH- or an optionally R 1 substituted -NH-C 1～6 alkylene-NH-; T or Z are each independently selected from a chelating agent, a fluorescent group or a radioactive group, wherein one of T or Z is a fluorescent group.

[0021] R 1 are each independently selected from -F, -Cl, -Br, -I, -CN, =O, an optionally R 3 substituted C 1～6 alkyl, -OH, -COOH, -CH 2 OH, -CH 2 COOH, phenyl or tolyl; R 2 are each independently selected from -H, -C 1-6 alkyl, -C 1-6 alkylene-, -CH 2 O-, cycloalkenyl, cycloheteroalkenyl, aryl or -C 1-6 cycloalkyl-; R 3 is selected from -F, -Cl, -Br, -I, -CN, =O, -OH or -COOH; t is selected from 1, 2, 3 or 4; when the said R 1 、R​​2 or R 3 When there are multiple of them, the R 1 , R 2 or R 3 may be the same or different.

[0022] According to an embodiment of the present invention, the amino acid chain is selected from any combination of glycine or its derivative compounds, lysine or its derivative compounds, glutamic acid or its derivative compounds, serine or its derivative compounds, alanine or its derivative compounds, tyrosine or its derivative compounds, aspartic acid or its derivative compounds, and threonine or its derivative compounds.

[0023] According to an embodiment of the present invention, the carbon chain is -(CH 2 ) n -, and n is an integer between 0 and 20. n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

[0024] According to an embodiment of the present invention, one or more carbon atoms in the carbon chain can be arbitrarily replaced by O, N, or S.

[0025] According to an embodiment of the present invention, the ring A is selected from those optionally substituted by R 4 substituted R 4 is selected from -F, -Cl, -Br, -I, -CN. Among them, can be substituted by one or more R 4 When the R 4 are multiple, the R 4 may be the same or different.

[0026] According to an embodiment of the present invention, the B is selected from -NR 2 - or -O-, and R 2 is selected from -H or -C 1-6 alkyl. Among them, -C 1-6 alkyl can be methyl, ethyl, propyl, butyl, pentyl, hexyl.

[0027] According to an embodiment of the present invention, the L 11 is selected from an amino acid chain optionally substituted by R 1 , a -C 1 alkylene -[NH - C(O)-CH 1～6 2 optionally substituted by R t , a -C 1 alkylene -[NH - C(O)-CH 1～6 2 optionally substituted by R t ​​-NH-, R 1 Selected from =O, -C 1～6 alkyl, -OH, -COOH, -CH 2 OH, -CH 2 COOH. Wherein, when L 11 is selected from a specific structure substituted by R 1 , this structure can be substituted by one or more R 1 simultaneously. When the said R 1 is plural, the said R 1 can be the same or different.

[0028] According to an embodiment of the present invention, the said L 11 is selected from -C 1 alkylene-[NH-C(O)-CH 1～3 2 optionally substituted by R t , -C 1 alkylene-[NH-C(O)-CH 1～3 2 -NH-. t 11

[0029] According to an embodiment of the present invention, the said L' 11 is selected from -C 1 alkylene-[NH-C(O)-CH 1～6 2 optionally substituted by R t , -C 1 alkylene-[NH-C(O)-CH 1～6 2 -NH-, R t is selected from =O or -C 1 alkyl. Wherein, when L' 1～6 is selected from a specific structural formula substituted by R 11 , this structure can be substituted by one or more R 1 simultaneously. When the said R 1 is plural, the said R 1 can be the same or different. 1 11

[0030] According to an embodiment of the present invention, the said L' 11 is selected from -C 1 alkylene-[NH-C(O)-CH 1～3 2 optionally substituted by R t , -C 1 alkylene-[NH-C(O)-CH 1～3 2 ​​​​​​t -NH-.

[0031] According to an embodiment of the present invention, the L 12 is selected from -C 1～6 alkylene-NH-.

[0032] According to an embodiment of the present invention, the L 12 is selected from -C 1～4 alkylene-NH-.

[0033] According to an embodiment of the present invention, the L 2 is selected from -NR 2 -, -C 1～6 alkylene-NH-, -NH-C 1 optionally substituted by R 1～6 alkylene-NH-, R 2 is selected from -H or -C 1-6 alkyl, and R 1 is selected from -C 1～6 alkyl. Wherein, when L 2 is selected from -NH-C 1 alkylene-NH- substituted by R 1～6 -, -NH-C 1～6 alkylene-NH- can be substituted by one or more R 1 s, and when the R 1 s are multiple, the R 1 s can be the same or different.

[0034] According to an embodiment of the present invention, the ring A is selected from

[0035] According to an embodiment of the present invention, the B is selected from -N(CH 3 )- or -O-.

[0036] According to an embodiment of the present invention, the L 11 is selected from

[0037] According to an embodiment of the present invention, the L' 11 is selected from

[0038] According to an embodiment of the present invention, the L 12 is selected from

[0039] According to an embodiment of the present invention, the L 2 is selected from -NH-,

[0040] ​According to an embodiment of the present invention, the radioactive group is selected from wherein X is independently selected from 18 F, 124 I, 125 I, 131 I or 211 At, and n is independently an integer between 0, 1, 2, 3 or 4.

[0041] According to an embodiment of the present invention, the radioactive group is selected from

[0042] According to an embodiment of the present invention, the chelating agent is derived from 1,4,7,10-tetraazacyclododecane-N,N',N",N"-tetraacetic acid ( = DOTA), N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid ( = HBED-CC), 1,4,7-triazacyclononane-1,4,7-triacetic acid ( = NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazanon-1-yl)glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)glutaric acid (DOTAGA), 1,4,7-triazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9.3.1.]pentadec-1(15),11,13-triene-3,6,9-triacetic acid ( = PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A), p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B), 1-(2)-methyl-4-isothiocyanatobenzyl-DTPA (MX-DTPA), (R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine pentaacetic acid (p-SCN-Bn-CHX-A"-DTPA) or 6-hydrazinylpyridine-3-carboxylic acid (HYNIC).

[0043] According to an embodiment of the present invention, the chelating agent is selected from

[0044] According to an embodiment of the present invention, the fluorescent group is selected from anthocyanin fluorescent groups.

[0045] According to an embodiment of the present invention, the fluorescent group is derived from Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Cy7.5, sulfonated-Cy3, sulfonated-Cy5, sulfonated-Cy7 or ICG.

[0046] According to an embodiment of the present invention, the fluorescent group is selected from

[0047] According to an embodiment of the present invention, the compound is a compound represented by formula II-1 or II-2, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula II-1 or II-2:

[0048]

[0049]

[0050] wherein B is selected from -NR 2 -, -O-, -S- or -C 1～6 alkylene-; L 11 is selected from an amino acid chain optionally substituted by R 1 , a carbon chain optionally substituted by R 1 , a combination of an amino acid chain and a carbon chain optionally substituted by R 1 , -C 1 alkylene-[NH-C(O)-CH 1～6 2 t -, -C 1 alkylene-[NH-C(O)-CH 1～6 2 t -NH- or -C(O)-NH-C 1 alkylene optionally substituted by R 1～10 ; T is selected from a chelating agent or a fluorescent group.

[0051] R 1 is selected from -F, -Cl, -Br, -I, -CN, =O, C 3 alkyl optionally substituted by R 1～6 , -OH, -COOH, -CH 2 OH, -CH 2 COOH, phenyl or tolyl; R 2 is selected from -H, -C 1-6 ​​​​Alkyl, -C 1-6 Alkylene-, -CH 2 O-, cycloalkenyl, cycloheteroalkenyl, aryl or -C 1-6 Cycloalkyl-; R 3 Selected from -F, -Cl, -Br, -I, -CN, =O, -OH or -COOH; t is selected from 1, 2, 3 or 4; when the said R 1 , R 2 or R 3 is plural, the said R 1 , R 2 or R 3 can be the same or different.

[0052] According to an embodiment of the present invention, the compound is a compound shown in Formula III-1, III-2 or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound shown in Formula III-1, III-2:

[0053]

[0054] Wherein, B is selected from -NR 2 -, -O-, -S- or -C 1～6 Alkylene-; L’ 11 Selected from an amino acid chain optionally substituted by R 1 , a carbon chain optionally substituted by R 1 , a combination of an amino acid chain and a carbon chain optionally substituted by R 1 , -C 1 Alkylene-[NH-C(O)-CH 1～6 2 t -, -C 1 Alkylene-[NH-C(O)-CH 1～6 2 t -NH- or -C(O)-NH-C 1 Alkylene optionally substituted by R 1～10 ; L 2 Selected from -NR 2 -, -C 1 Alkylene-NH- optionally substituted by R 1～6 or -NH-C 1 Alkylene-NH- optionally substituted by R 1～6 ; T or Z are each independently selected from a chelating agent, a fluorescent group or a radioactive group, wherein one of T or Z is a fluorescent group.

[0055] R 1 Selected from -F, -Cl, -Br, -I, -CN, =O, optionally substituted by R​​​​3 Substituted C 1～6 alkyl, -OH, -COOH, -CH 2 OH, -CH 2 COOH, phenyl or tolyl; R 2 is selected from -H, -C 1-6 alkyl, -C 1-6 alkylene-, -CH 2 O-, cycloalkenyl, cycloheteroalkenyl, aryl or -C 1-6 cycloalkyl-; R 3 is selected from -F, -Cl, -Br, -I, -CN, =O, -OH or -COOH; t is selected from 1, 2, 3 or 4; when the said R 1 , R 2 or R 3 are multiple, the said R 1 , R 2 or R 3 can be the same or different.

[0056] In the second aspect of the present invention, the present invention provides a compound which is a compound represented by formula IV or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula IV:

[0057]

[0058] wherein, ring A is selected from optionally R'- 1 substituted

[0059] B is selected from -NR' 2 -, -O-;

[0060] L 13 is selected from optionally R'' 1 substituted -C 1～3 alkylene-[NH-C(O)-CH 2 t’ -NH-;

[0061] T is selected from a chelating agent, a fluorescent group or a radioactive group;

[0062] R' 1 is selected from -F, -Cl, -Br, -I, -CN; when the said R' 1 are multiple, the said R' 1 can be the same or different;

[0063] R'' 1 is selected from =O, methyl, ethyl, propyl, -OH, -COOH, -CH 2 OH, -CH 2 ​COOH; when said R” 1 is plural, said R” 1 can be the same or different;

[0064] R’ 2 is selected from -H, methyl, ethyl, propyl;

[0065] t’ is selected from 1, 2 or 3.

[0066] According to an embodiment of the present invention, L 13 is selected from -C 1 substituted by R” 1～3 alkylene - [NH - C(O) - CH 2 t’ -NH-, where R” 1 can be one or plural, when said R” 1 is plural, said R” 1 can be the same or different.

[0067] In a third aspect of the present invention, the present invention provides a compound, the structure of which is selected from one of the following;

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074] In a fourth aspect of the present invention, the present invention provides a compound, which is formed by complexing the compound described in the first aspect, the second aspect or the third aspect with M.

[0075] According to an embodiment of the present invention, said M is selected from at least one of radionuclides or non - radioactive elements.

[0076] According to an embodiment of the present invention, said radionuclide is selected from at least one of diagnostic radionuclides or therapeutic radionuclides.

[0077] According to an embodiment of the present invention, said diagnostic radionuclide is selected from 68 Ga, 18 F, 99m Tc, 89 Zr, 124 I, 76 Br, 43 Sc,​111 In, 45 Ti, 52 Mn, 59 Fe, 64 Cu, 94m Tc, 67 Ga, 71 / 72 / 74 As, 82m Rb or 86 Y.

[0078] According to an embodiment of the present invention, the therapeutic radionuclide is selected from 177 Lu, 90 Y, 131 I, 153 Sm, 67 Cu, 89 Sr, 166 Ho, 177 Yb, 47 Sc, 186 / 188 Re, 212 / 213 Bi, 149 Pm, 212 Pb, 211 At, 223 Ra, 225 Ac or 227 Th.

[0079] According to an embodiment of the present invention, the diagnostic radionuclide 18 F is formed by complexing with 18 F]AlF.

[0080] According to an embodiment of the present invention, the compound structure is selected from one of the following,

[0081]

[0082]

[0083] wherein, in formula IV, T is selected from chelating agents;

[0084] In formula V, T is selected from chelating agents and Z is selected from fluorescent groups;

[0085] In formula VI, Z is selected from chelating agents and T is selected from fluorescent groups.

[0086] According to an embodiment of the present invention, the compound structure is selected from one of the following,

[0087]

[0088]

[0089] In a fifth aspect of the present invention, there is provided a compound, the structure of which is selected from one of the following:

[0090]

[0091]

[0092]

[0093]

[0094] In a sixth aspect of the present invention, there is provided a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises: the compound described in the first, second, third, fourth or fifth aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

[0095] According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0096] In a seventh aspect of the present invention, there is provided the use of the compound described in the first, second, third, fourth or fifth aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition described in the sixth aspect, in inhibiting the expression of fibroblast activation protein.

[0097] In an eighth aspect of the present invention, there is provided the use of the compound described in the first, second, third, fourth or fifth aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition described in the sixth aspect, in the preparation of a reagent and / or drug for diagnosing and / or treating a disease characterized by overexpression of fibroblast activation protein.

[0098] According to an embodiment of the present invention, the diagnostic method is selected from optical imaging and / or radionuclide imaging.

[0099] According to an embodiment of the present invention, the diagnostic method is selected from fluorescence imaging, PET imaging and / or SPECT imaging.

[0100] According to an embodiment of the present invention, the treatment is selected from radiotherapy and / or fluorescence surgical navigation to assist surgery.

[0101] According to an embodiment of the present invention, the disease is selected from cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling or scar disease.

[0102] According to an embodiment of the present invention, the cancer is selected from breast cancer, gastric cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, liver cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary origin), thymic carcinoma, glioma, glioblastoma, astrocytoma, cervical cancer or prostate cancer.

[0103] According to an embodiment of the present invention, the cancer is selected from glioma, gastric cancer, breast cancer, colon cancer, lung cancer, head and neck cancer, liver cancer, pancreatic cancer or sarcoma.

[0104] In a ninth aspect of the present invention, the present invention provides a method for diagnosing and / or treating a disease characterized by overexpression of fibroblast activation protein. According to an embodiment of the present invention, the method includes administering to a patient a pharmaceutically acceptable dose of the compound described in the first aspect, second aspect, third aspect, fourth aspect or fifth aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition described in the sixth aspect.

[0105] According to an embodiment of the present invention, the diagnostic method is selected from optical imaging and / or radionuclide imaging.

[0106] According to an embodiment of the present invention, the diagnostic method is selected from fluorescence imaging, PET imaging and / or SPECT imaging.

[0107] According to an embodiment of the present invention, the treatment is selected from radiotherapy and / or fluorescence surgical navigation to assist surgery.

[0108] According to an embodiment of the present invention, the disease is selected from cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling or scar disease.

[0109] According to an embodiment of the present invention, the cancer is selected from breast cancer, gastric cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, liver cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary origin), thymic carcinoma, glioma, glioblastoma, astrocytoma, cervical cancer or prostate cancer.

[0110] According to an embodiment of the present invention, the cancer is selected from glioma, gastric cancer, breast cancer, colon cancer, lung cancer, head and neck cancer, liver cancer, pancreatic cancer or sarcoma.

[0111] In a tenth aspect of the present invention, there is provided the use of the compound according to the first, second, third, fourth or fifth aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition according to the sixth aspect, in the diagnosis and / or treatment of diseases characterized by overexpression of fibroblast activation protein.

[0112] According to an embodiment of the present invention, the method of diagnosis is selected from optical imaging and / or radionuclide imaging.

[0113] According to an embodiment of the present invention, the method of diagnosis is selected from fluorescence imaging, PET imaging and / or SPECT imaging.

[0114] According to an embodiment of the present invention, the treatment is selected from radiotherapy and / or fluorescence surgical navigation to assist surgery.

[0115] According to an embodiment of the present invention, the diseases are selected from cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling or scar disease.

[0116] According to an embodiment of the present invention, the cancers are selected from breast cancer, gastric cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, liver cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal cell carcinoma, neuroendocrine tumors, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic cancer, glioma, glioblastoma, astrocytoma, cervical cancer or prostate cancer.

[0117] According to an embodiment of the present invention, the cancers are selected from glioma, gastric cancer, breast cancer, colon cancer, lung cancer, head and neck cancer, liver cancer, pancreatic cancer or sarcoma.

[0118] In an eleventh aspect of the present invention, there is provided a method for imaging tissues overexpressing fibroblast activation protein. According to an embodiment of the present invention, the method includes administering to the tissue the compound according to the first, second, third, fourth or fifth aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition according to the sixth aspect, and imaging the tissue after administration.

[0119] According to an embodiment of the present invention, the imaging is performed by emission computed tomography or fluorescence imaging.

[0120] Advantageous effects:

[0121] The drug targeting fibroblast activation protein disclosed by the present invention can be used for diagnosing and / or treating diseases characterized by overexpression of fibroblast activation protein (FAP), and the drug also has the following advantages:

[0122] (1) It has a strong affinity for fibroblast activation protein (FAP);

[0123] (2) It has a strong specific binding to fibroblast activation protein (FAP);

[0124] (3) It has good specific targeting binding and clinical lesion detection for tumors, especially for diseases characterized by overexpression of fibroblast activation protein (FAP);

[0125] (4) It can diagnose primary tumors and their metastatic lesions, with clear imaging, thus effectively distinguishing tumors from normal tissues.

[0126] Additional aspects and advantages of the present invention will be partly given in the following description, partly will become obvious from the following description, or will be learned through the practice of the present invention.

[0127] Terms and Definitions

[0128] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination should fall within the scope recorded in the specification of this application.

[0129] Unless otherwise defined, all scientific and technical terms herein have the same meanings as those commonly understood by those skilled in the art to which the subject matter of the claims belongs. Unless otherwise specified, all patents, patent applications, and published materials cited throughout this text are incorporated herein by reference in their entirety. If there are multiple definitions for a term in this text, the definitions in this chapter shall prevail.

[0130] Unless otherwise specified or there is an obvious conflict in the context, the articles "a", "one (kind)", and "the" used herein are intended to include "at least one" or "one or more". Therefore, these articles used herein refer to articles for one or more (i.e., at least one) objects. For example, "a component" refers to one or more components, that is, there may be more than one component considered to be adopted or used in the implementation of the described embodiment.

[0131] It should be understood that the above summary and the following detailed description are exemplary and for explanatory purposes only, and do not impose any limitation on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that, unless clearly stated otherwise in the text, the singular forms used in this specification and the claims include the plural forms of the indicated things. It should also be noted that, unless otherwise stated, the use of "or" means "and / or". In addition, the terms "comprising" and other forms, such as "including", "containing", and "having", are not restrictive.

[0132] It should be noted that represents the same structure, and the ranges of the series of compounds represented by its two structures are the same.

[0133] Definitions of standard chemical terms can be found in reference works (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED.", Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR, and UV / VIS spectroscopy and pharmacological methods. Unless a specific definition is provided, the terms used in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation, and delivery, as well as the treatment of patients. For example, the instructions provided by the manufacturer for the kits can be utilized, or the reactions can be carried out and purification can be performed in a manner well-known in the art or as described in the present invention. Generally, the above-mentioned techniques and methods can be implemented according to the descriptions in a number of general and more specific documents cited and discussed in this specification, in a conventional manner well-known in the art. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0134] Generally speaking, the term "substituted" means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Unless otherwise indicated, a substituted group can have a substituent replacing at each substitutable position of the group. When more than one position in the given structural formula can be replaced by one or more substituents selected from a specific group, then the substituents can replace at each substitutable position either identically or differently.

[0135] The term "unsubstituted" means that the specified group does not carry a substituent.

[0136] As described in the present invention, the compounds of the present invention may optionally be substituted by one or more substituents, such as the compounds of the general formula above, or as in the specific examples, subclasses, and a class of compounds included in the present invention. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". Generally, the term "optionally", whether before or after the term "substituted", means that the hydrogen in the given structure is either unsubstituted or one or more hydrogen atoms are substituted by specific substituents. Unless otherwise indicated, an optional substituent group may have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be the same or different at each position.

[0137] In addition, it should be noted that unless otherwise explicitly indicated, in the present invention, the description methods "each... independently is", "... each independently is", and "... independently is" can be interchanged and should be understood in a broad sense. It can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can also mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0138] Unless otherwise specified, the solid wedge bond and the dashed wedge bond represent the absolute configuration of a stereocenter, and the solid straight bond and the dashed straight bond represent the relative configuration of a stereocenter.

[0139] In the chemical structure of the ligand or compound described in the present disclosure, the bond represents an unspecified configuration. If there are chiral isomers in the chemical structure, the bond can be or simultaneously include and both configurations. Although all the above structural formulas are drawn in certain isomeric forms for simplicity, the present disclosure may include all isomers, such as: tautomers, rotamers, geometric isomers, diastereomers, racemates, and enantiomers.

[0140] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when writing the structural formula from right to left. For example, CH 2 O is equivalent to OCH 2 . As used herein, represents the attachment site of the group.

[0141] The chapter headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and theses, are hereby incorporated by reference in their entirety.

[0142] Except as otherwise provided above, when used in the specification and claims of this application, unless otherwise specifically indicated, the following terms have the meanings set forth below.

[0143] As used herein, when used alone or as part of other substituents, the term "-acetylpiperazinyl" means

[0144] For the numerical ranges recited in the specification and claims of this application, when the numerical range is understood as "integers", it should be understood that the two endpoints of the range and each integer within the range are recited. For example, "integers from 1 to 6" should be understood to recite each of 0, 1, 2, 3, 4, 5, and 6. When the numerical range is understood as "numbers", it should be understood that the two endpoints of the range and each integer within the range and each decimal within the range are recited. For example, "numbers from 1 to 20" should be understood to recite not only each of the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, but also at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9, respectively.

[0145] When used alone or as part of other substituents, the term "alkyl" refers to a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. carbon atoms, such as C 1-6 alkyl, C 2-4 alkyl, C 3-4 alkyl, wherein the alkyl can be independently and optionally substituted by one or more substituents described in the present invention, and the substituents include but are not limited to deuterium, amino, hydroxy, cyano, F, Cl, Br, I, mercapto, nitro, oxo (=O), etc. Examples of alkyl include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 )) 2 ), n-butyl (n-Bu, -CH 2 CH 2CH 2 CH 3 )), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ) and so on. The terms "alkyl" and its prefix "alk-" are used herein to include both straight-chain and branched-chain saturated carbon chains.

[0146] When used alone or as part of another substituent, the term "alkylene" is understood to represent a straight-chain or branched-chain saturated, unsaturated or partially saturated divalent hydrocarbon group. For example, "C 1-10 alkylene" or "C 1- C 10 alkylene" represents a straight-chain or branched-chain divalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms, including but not limited to methylene, ethylene, propylene, 1-methylpropylene, butylene.

[0147] When used alone or as part of another substituent, the term "cycloalkyl" refers to a cyclic alkyl group. Examples of unsubstituted cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or bicyclic hydrocarbon groups such as the decahydronaphthalene ring. The cycloalkyl group can be substituted with one or more substituents. In some embodiments, the cycloalkyl group can be a cycloalkyl group fused to an aryl or heteroaryl ring group. The term "cycloalkyl" can be used interchangeably with the term "carbocyclic group".

[0148] When used alone or as part of another substituent, the term "heterocycloalkyl" refers to a cycloalkyl group in which one or more (in some embodiments 1 to 3) carbon atoms are replaced by heteroatoms such as, but not limited to, N, O, S and P. The term "m-n membered heterocycloalkyl" or "C m-n"Heterocycloalkyl" should be understood to represent a saturated, unsaturated or partially saturated ring having from m to n atoms, wherein the heteroatoms are selected from N, O, S, P, preferably selected from N, O or S. For example, the term "4-8 membered heterocycloalkyl" or "C 4 -C 8 heterocycloalkyl" should be understood to represent a saturated, unsaturated or partially saturated ring having from 4 to 8 atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, S, P, preferably selected from N, O or S. "4-10 membered heterocyclic group" means a saturated, unsaturated or partially saturated ring having from 4 to 10 atoms. In some embodiments, the heterocycloalkyl may be a heterocycloalkyl fused to an aryl group or a heteroaryl group. When a prefix such as 4-8 membered or 4-10 membered is used to denote a heterocycloalkyl, the number of carbons also means including heteroatoms. It includes monocyclic, bicyclic, tricyclic, spiro or bridged rings. Examples of heterocycloalkyl are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, etc. The term "heterocycloalkyl" may be used interchangeably with the term "heteroalkane ring".

[0149] When used alone or as part of another substituent, the term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group having from two to forty carbon atoms with at least one carbon-carbon sp2 double bond (e.g., C 2 -C 6 alkenyl, and for example C 2 -C 4 alkenyl), and includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. Examples of alkenyl include, but are not limited to, vinyl and allyl.

[0150] When used alone or as part of another substituent, the term "cycloalkenyl" is a cyclized alkenyl. C 4-6 cycloalkenyl is intended to include C 4 、C 5 and C 6 cycloalkenyl. Exemplary cycloalkenyl include, but are not limited to, cyclobutenyl, cyclopentenyl and cyclohexenyl.

[0151] When used alone or as part of other substituents, the term "aryl" can be used alone or as a major part of "aralkyl", "aralkoxy" or "aryloxyalkyl", and represents a monocyclic, bicyclic and tricyclic carbocyclic system containing a total of 6-14 membered rings, wherein at least one ring system is aromatic, each ring system contains 3-7 membered rings, and has one or more attachment points connected to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring", and the aromatic ring can include phenyl, naphthyl and anthracenyl. And the aryl can be substituted or unsubstituted, and the substituents can be, but are not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxyl-substituted alkyl-S(=O)-, hydroxyl-substituted alkyl-S(=O) 2 -, carboxyl-substituted alkoxy and the like.

[0152] In the present application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are within the scope of reliable medical judgment, suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, allergic reaction or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0153] The term "stereoisomer" refers to isomers generated by different arrangements of atoms in space in a molecule, including cis-trans isomers, enantiomers, diastereoisomers and conformational isomers.

[0154] Depending on the choice of raw materials and methods, the compounds of the present invention can exist in the form of one or a mixture of possible isomers, such as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereoisomer mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to the chiral center (or chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0155] When depicting the bonds to the chiral carbon in the formula of the present invention as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and both the enantiomerically pure compounds and mixtures resulting therefrom are included within the scope of this general formula. The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114 - 120. Wedge and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0156] The term "tautomer" refers to functional group isomers resulting from the rapid migration of an atom within a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in an equilibrium form, and attempting to isolate a single tautomer usually results in a mixture whose physical and chemical properties are consistent with those of a mixture of compounds. The position of the equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0157] The term "solvate" refers to a stoichiometric or non - stoichiometric solvent in which a compound of the present invention or its salt is included, bound by intermolecular non - covalent forces, and when the solvent is water, it is a hydrate.

[0158] The term "prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound of the present invention. The prodrugs of the present invention are prepared by modifying the functional groups in the compound, and this modification can be removed by conventional operations or in vivo to obtain the parent compound. Prodrugs include compounds formed by attaching a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to separately form a free hydroxyl group and a free amino group.

[0159] In the present application, a "pharmaceutical composition" refers to a preparation of a compound of the present invention and a medium commonly accepted in the art for delivering a bioactive compound to a mammal (such as a human). This medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and thereby exert its biological activity.

[0160] In the present application, a "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent that has been approved by the relevant government regulatory authorities for use in humans or livestock.

[0161] The term "excipient" refers to pharmaceutically inert ingredients. Non-limiting examples of the types of "excipients" include binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents, etc. Excipients can enhance the handling characteristics of pharmaceutical formulations, that is, make the formulations more suitable for direct compression by increasing fluidity and / or adhesiveness.

[0162] The term "treatment" refers to therapeutic treatment. When referring to a specific disease or disorder, treatment means: (1) alleviating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade that causes or gives rise to the disorder or (b) one or more biological manifestations of the disorder, (3) improving one or more symptoms, effects, or side effects associated with the disorder, or one or more symptoms, effects, or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.

[0163] The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0164] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has received administration of the compound or composition according to an embodiment of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.

[0165] The term "therapeutically effective amount" refers to the amount of a compound that is sufficient to effectively treat the diseases or disorders described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the disorder and its severity, and the age of the patient to be treated, and can be adjusted by those skilled in the art as needed. BRIEF DESCRIPTION OF THE DRAWINGS

[0166] The above and / or additional aspects and advantages of the present invention will become apparent and be readily understood from the description of the embodiments in conjunction with the following drawings, wherein:

[0167] Figure 1 is the LCMS spectrum of compound NYM052 according to an embodiment of the present invention;

[0168] Figure 2 is the HPLC spectrum of compound NYM052 according to an embodiment of the present invention;

[0169] Figure 3 is the NMR spectrum of compound NYM052 according to an embodiment of the present invention;

[0170] Figure 4 is the LCMS spectrum of compound NYM066 according to an embodiment of the present invention;

[0171] Figure 5 It is the HPLC chromatogram of compound NYM066 according to an embodiment of the present invention;

[0172] Figure 6 It is the LCMS chromatogram of compound NYM067 according to an embodiment of the present invention;

[0173] Figure 7 It is the HPLC chromatogram of compound NYM067 according to an embodiment of the present invention;

[0174] Figure 8 It is the LCMS chromatogram of compound NYM072 according to an embodiment of the present invention;

[0175] Figure 9 It is the HPLC chromatogram of compound NYM072 according to an embodiment of the present invention;

[0176] Figure 10 It is the LCMS chromatogram of compound NYM076 according to an embodiment of the present invention;

[0177] Figure 11 It is the HPLC chromatogram of compound NYM076 according to an embodiment of the present invention;

[0178] Figure 12 It is according to an embodiment of the present invention 68 Radioactive thin layer chromatography scanning result diagram of Ga-NYM052;

[0179] Figure 13 It is according to an embodiment of the present invention 68 Radioactive thin layer chromatography scanning result diagram of Ga-NYM066;

[0180] Figure 14 It is according to an embodiment of the present invention 68 Radioactive thin layer chromatography scanning result diagram of Ga-NYM067;

[0181] Figure 15 It is according to an embodiment of the present invention 68 PET / CT imaging result diagram of Ga-NYM052 in SJSA-1 mouse model;

[0182] Figure 16 It is according to an embodiment of the present invention 8 Uptake result diagram of Ga-NYM052 in different tissues in SJSA-1 mouse model;

[0183] Figure 17 It is the MIP diagram of a patient after injection of the PET tracer 18 F-FDG;

[0184] Figure 18Patient injection according to an embodiment of the present invention 68 MIP image after

[0185] Figure 19 In vivo fluorescence scanning imaging of NCI-N87 mouse model 1 after injection of NYM076 according to an embodiment of the present invention

[0186] Figure 20 In vivo fluorescence scanning imaging of NCI-N87 mouse model 2 after injection of NYM076 according to an embodiment of the present invention

[0187] Figure 21 LCMS spectrum of compound NYM077 according to an embodiment of the present invention

[0188] Figure 22 HPLC spectrum of compound NYM077 according to an embodiment of the present invention

[0189] Figure 23 According to an embodiment of the present invention 68 Radioactive thin layer chromatography scanning result image of

[0190] Figure 24 According to an embodiment of the present invention 18 Radioactive thin layer chromatography scanning result image of [ [

[0191] Figure 25 According to an embodiment of the present invention 68 PET / CT imaging result image of

[0192] Figure 26 According to an embodiment of the present invention 68 Uptake result image of

[0193] Figure 27 According to an embodiment of the present invention [ [ 18 PET / CT imaging result image of [ [

[0194] Figure 28 According to an embodiment of the present invention [ [ 18 Uptake result image of different tissues of [ [

[0195] Figure 29 According to an embodiment of the present invention 68 PET / CT imaging result image of

[0196] Figure 30 is according to the embodiments of the present invention 68 Uptake results of Ga-NYM052 in different tissues in the B-hFAP MC38 mouse model;

[0197] Figure 31 is according to the embodiments of the present invention 68 PET / CT imaging results of Ga-NYM052 in the A549 mouse model;

[0198] Figure 32 is according to the embodiments of the present invention 68 Uptake results of Ga-NYM052 in different tissues in the A549 mouse model;

[0199] Figure 33 is according to the embodiments of the present invention 68 PET / CT imaging results of Ga-NYM077 in the B-hFAP MC38 mouse model;

[0200] Figure 34 is according to the embodiments of the present invention 68 Uptake results of Ga-NYM077 in different tissues in the B-hFAP MC38 mouse model;

[0201] Figure 35 is according to the embodiments of the present invention 68 PET / CT imaging results of Ga-NYM067 in the B-hFAP MC38 mouse model;

[0202] Figure 36 is according to the embodiments of the present invention 68 Uptake results of Ga-NYM067 in different tissues in the B-hFAP MC38 mouse model; Detailed implementation manners

[0203] The embodiments of the present invention will be described in detail below. The following described embodiments are exemplary and are only used to explain the present invention, and should not be construed as a limitation to the present invention. For those not specified in the embodiments in terms of specific technologies or conditions, they shall be carried out according to the technologies or conditions described in the literature in this field or according to the product specifications. For reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchases.

[0204] Chemical abbreviations

[0205] DCM: Dichloromethane

[0206] DIEA: N,N-Diisopropylethylamine

[0207] MTBE: Methyl tert-butyl ether

[0208] DMF: N,N-Dimethylformamide

[0209] HATU: Polypeptide condensation reagent

[0210] TFA: Trifluoroacetic acid

[0211] ACN: Acetonitrile

[0212] AllocCl: Allyl chloroformate

[0213] ICG-OSu: Indocyanine green

[0214] Cy7-OSu: Cyanine fluorescent dye Cy7

[0215] THF: Tetrahydrofuran

[0216] Preparation of the compound in Example 1

[0217] 1. Molecular structure of NYM052

[0218] Preparation process:

[0219]

[0220] Dissolve compound 10 (1.00 g, 1.00 eq) in tetrahydrofuran (10 mL), add benzyl bromoacetate (1.13 g, 1.00 eq) and triethylamine (1.38 mL, 2.00 eq) thereto, and react with stirring at 20 °C for 12 hours. After the raw materials reacted completely, add 50 mL of ethyl acetate to dilute the reaction solution, wash it successively with 50 mL of 0.5 M sodium bicarbonate solution and 50 mL of brine solution, dry the organic phase with anhydrous sodium sulfate and then rotary evaporate to obtain the crude product. The crude product was separated by column chromatography to obtain compound 11 (1.5 g).

[0221]

[0222] Dissolve compound 11 (1.50 g, 1.00 eq) in methanol (20 mL), and add wet palladium-carbon (455 mg) thereto. React with stirring at 20 °C for 12 hours under a hydrogen atmosphere at 15 Psi pressure. After filtration, concentrate the filtrate under reduced pressure to obtain compound 12 (1.1 g, crude product).

[0223]

[0224] Compound 12 (600 mg, 1.00 eq) was dissolved in DMF (5 mL), and HATU (1.05 g, 1.20 eq), triethylamine (932 mg, 4.00 eq), and glycine benzyl ester hydrochloride (464 mg, 1.00 eq) were added thereto. The reaction was stirred at 20 °C for 12 hours. 50 mL of ethyl acetate was added to the reaction solution for dilution, and it was washed successively with 50 mL of 0.5 M sodium bicarbonate solution and 50 mL of brine solution. The organic phase was dried over anhydrous sodium sulfate and then concentrated by rotary evaporation to obtain the crude product. The crude product was separated and purified by column chromatography to obtain Compound 13 (900 mg).

[0225]

[0226] Compound 13 (900 mg, 1.00 eq) was dissolved in methanol (20 mL), and wet palladium on carbon (235 mg) was added thereto. The reaction was stirred at 20 °C for 12 hours under a hydrogen atmosphere at 15 Psi pressure. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product, and the crude product was prepared by reverse phase to obtain Compound 4A (500 mg).

[0227]

[0228] Compound 1 (2.00 g, 1.00 eq) was dissolved in methanol (40 mL), and thionyl chloride (5.66 g, 6.00 eq) was added thereto. The reaction solution was heated to 80 °C and stirred for 12 hours. After the reaction solution was concentrated and rotary evaporated, 50 mL of ethyl acetate was added for dilution, and it was washed successively with 50 mL of 0.5 M sodium bicarbonate solution and 50 mL of brine solution. The organic phase was dried over anhydrous sodium sulfate and then concentrated by rotary evaporation to obtain Compound 2 (1.5 g).

[0229]

[0230] Compound 2 (1.30 g, 1.00 eq) and Compound 2A (1.06 g, 1.20 eq) were dissolved in dioxane (5.0 mL), and Pd 2 (dba) 3 (447 mg, 488 μmol, 0.10 eq), XPhos (465 mg, 977 μmol, 0.20 eq), and cesium carbonate (3.18 g, 9.77 mmol, 2.00 eq) were added thereto. The reaction was stirred at 80 °C for 12 hours. 100 mL of ethyl acetate was added to the reaction solution for dilution, and it was washed successively with 50 mL of 0.5 M sodium bicarbonate solution and 50 mL of brine solution. The organic phase was dried over anhydrous sodium sulfate and then concentrated by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography to obtain Compound 3 (1.4 g).

[0231]

[0232] Compound 3 (450 mg, 1.00 eq) was dissolved in 33% hydrobromic acid acetic acid solution (9.0 mL), and the reaction was stirred at 60 °C for 12 hours. 50 mL of ethyl acetate was added to the reaction solution for dilution, and it was washed successively with 50 mL of 0.5 M sodium bicarbonate solution and 50 mL of brine solution. The organic phase was dried over anhydrous sodium sulfate and then concentrated by rotary evaporation to obtain the crude product.

[0233] The crude product was separated by column chromatography to obtain Compound 4 (230 mg).

[0234]

[0235] Compound 4A (350 mg, 1.00 eq) and Compound 4 (238 mg, 1.00 eq) were dissolved in DCM (2.0 mL) and pyridine (1.0 mL), and phosphorus oxychloride (338 mg, 2.00 eq) was added thereto. The reaction was stirred at 0 °C for 1 hour. The reaction solution was quenched with 20 mL of 0.5 M sodium bicarbonate solution, and the organic phase was washed with 50 mL of brine solution. The organic phase was dried over anhydrous sodium sulfate and then concentrated by rotary evaporation to obtain the crude product. The crude product was prepared by reverse phase to obtain Compound 5 (280 mg).

[0236]

[0237] Compound 5 (280 mg, 1.00 eq) was dissolved in tetrahydrofuran (4.00 mL) and water (2.00 mL), and lithium hydroxide (26.0 mg, 2.00 eq) was added thereto. The reaction was stirred at 20 °C for 12 hours. The reaction solution was directly prepared by reverse phase to obtain Compound 6 (140 mg).

[0238]

[0239] Compound 6 (110 mg, 1.00 eq) was dissolved in N,N-dimethylformamide (2.0 mL), and Compound 6A (237 mg, 3.00 eq), HATU (91.7 mg, 1.10 eq), and triethylamine (88.7 mg, 4.00 eq) were added thereto. The reaction was stirred at 25 °C for 12 hours. The reaction solution was directly prepared by reverse phase to obtain Compound 7 (140 mg).

[0240]

[0241] Compound 7 (140 mg, 1.00 eq) was dissolved in anhydrous acetonitrile (5.0 mL), and p-toluenesulfonic acid (158 mg, 4.00 eq) was added thereto. The reaction was stirred at 40 °C for 12 hours. The reaction solution was concentrated by rotary evaporation to obtain Compound 8, which was directly used for the next step.

[0242]

[0243] Compound 8 (119 mg, 1.00 eq) and compound 8A (103 mg, 1.20 eq) were dissolved in anhydrous N,N-dimethylformamide (2.0 mL). HATU (94.9 mg, 1.20 eq) and triethylamine (105 mg, 5.00 eq) were added thereto, and the reaction was stirred at 25 °C for 2 hours. The reaction solution was directly subjected to reverse-phase preparation to obtain compound 9 (90 mg).

[0244]

[0245] Compound 9 (70.0 mg, 1.00 eq) was dissolved in dichloromethane (1.00 mL). Trifluoroacetic acid (1.00 mL, 186 eq) was added thereto. The reaction was stirred at 20 °C for 12 hours. After the reaction solution was concentrated to dryness, it was directly subjected to reverse-phase preparation to obtain NYM052 (13.0 mg, 97.2% purity, trifluoroacetate).

[0246] LCMS: MS: [M+H] + = 858.4 (as Figure 1 shown)

[0247] HPLC: Purity: 97.2% (as Figure 2 shown)

[0248] 1 1H NMR: DMSO-d 6 , 400 MHz (as Figure 3 shown)

[0249] δ: 9.21 - 9.18 (m, 1H), 9.05 - 9.03 (m, 1H), 8.46 - 8.40 (m, 2H), 8.20 - 8.11 (m, 2H), 7.75 (d, J = 3.6 Hz, 1H), 7.61 (d, J = 4.4 Hz, 1H), 5.20 - 5.17 (m, 1H), 4.33 - 4.24 (m, 4H), 3.82 (brs, 2H), 3.49 - 3.47 (m, 5H), 3.24 (s, 3H), 3.20 - 3.06 (m, 8H), 2.94 - 2.81 (m, 8H), 2.62 - 2.60 (m, 6H), 2.37 (s, 2H), 1.48 (s, 4H)

[0250] 2. Molecular structure of NYM066

[0251]

[0252] Preparation process:

[0253]

[0254] At 0 °C, DIEA (5.91 mL, 3.00 eq) was added dropwise to a solution of compound 8a-1 (1.50 g, 1.00 eq, HCl) and compound 8a-2 (4.62 g, 1.50 eq) in DCM (15.0 mL), and the reaction was carried out at 20 °C for 0.5 h. The reaction solution was poured into 0.5 N HCl (100 mL), extracted with dichloromethane, the combined organic phases were washed with brine (30.0 mL), and dried over Na 2 SO 4 After drying, it was filtered and concentrated to obtain the crude product. The solid compound 8a-3 (1.60 g) was obtained by column chromatography.

[0255]

[0256] To a solution of compound 8a-3 (1.60 g, 1.00 eq) in ACN (30.0 mL) was added TsOH·H 2 O (4.21 g, 3.50 eq), and the reaction was carried out at 45 °C for 1 h. The reaction solution was dropped into MTBE (600 mL), and the reaction was carried out at 20 °C for 0.5 h. After filtration, the crude product of compound 8a (1.39 g) was obtained under vacuum drying.

[0257]

[0258] To a solution of compound 6 (200 mg, 1.00 eq) and compound 8a (202 mg, 1.55 eq, TsOH) in DMF (2.00 mL) were added HATU (152 mg, 1.00 eq) and DIEA (417 μL, 6.00 eq), and the reaction was carried out at 20 °C for 0.5 h. The reaction solution was diluted with DMF (2.00 mL) and then purified. Under TFA conditions, reverse-phase purification and lyophilization gave the solid compound 9a (230 mg).

[0259]

[0260] To a solution of compound 9a (195 mg, 1.00 eq) in ACN (4.00 mL) was added TsOH·H 2 O (233 mg, 4.00 eq), and the reaction was carried out at 45 °C for 1 h. The reaction solution was concentrated in vacuo to obtain the unpurified compound 10a (217 mg).

[0261]

[0262] To a solution of Compound 10a (217 mg, TsOH) and Compound 11a (153 mg, 1.20 eq) in DMF (0.20 mL) was added HATU (116 mg, 1.00 eq) and DIEA (320 μL, 6.00 eq), and the reaction was carried out at 20 °C for 0.5 h. The reaction solution was diluted with DMF (0.20 mL) and then purified. Under TFA conditions, after reverse-phase purification and lyophilization, Compound 12a (150 mg) was obtained.

[0263]

[0264] Compound 12a (150 mg, 1.00 eq) was dissolved in TFA (1.43 mL, 119 eq), triisopropylsilane (37.5 μL, 1.14 eq), and H 2 O (37.5 μL), and the reaction was carried out at 20 °C for 1 h. The reaction solution was evaporated to dryness. Under TFA conditions, after reverse-phase purification and lyophilization, Compound NYM066 (22.0 mg, 26.6 μmol, purity: 99.3%) was obtained.

[0265] LCMS: MS observed: [M+H] + = 822.4 (as Figure 4 shown)

[0266] HPLC: purity: 99.3% (as Figure 5 shown)

[0267] 3. Synthesis method of NYM067

[0268]

[0269] To a solution of Compound 1b (2.10 g, 1.00 eq) in DMF (50.0 mL) was added K 2 CO 3 (6.14 g, 4.00 eq) and Compound 2b (9.25 g, 3.50 eq), and the reaction was carried out at 60 °C for 12 h. The reaction solution was poured into H 2 O (150 mL), extracted with ethyl acetate, and the organic phase was washed with brine (100 mL). After drying with Na 2 SO 4 and filtered, and concentrated to obtain the crude product. Compound 3b (5.50 g) was obtained by column chromatography.

[0270]

[0271] To a solution of Compound 3b (5.50 g, 1.00 eq) in MeOH (55.0 mL) was added LiOH·H 2H solution of O (54.6 mL, 2.50 eq) was reacted at 20 °C for 1 h. The reaction solution was adjusted to pH 6.0 with 1N HCl, filtered, washed with H 2 O, and then washed with acetone. The crude product was slurried with MTBE (100 mL) at 20 °C for 30 min, filtered and dried to obtain solid compound 4b (2.80 g). 2 To a solution of compound 4b (400 mg, 1.00 eq) and compound 4b-1 (285 mg, 1.20 eq, TsOH) in DMF (8.00 mL), HATU (439 mg, 1.00 eq) and DIEA (1.01 mL, 5.00 eq) were added and reacted at 20 °C for 0.5 h. 30 mL of H

[0272]

[0273] O was added to the reaction solution, then extracted with ethyl acetate, and the organic phase was washed with brine. After drying with Na 2 O and filtered, the filtrate was concentrated to obtain the crude product. Compound 5b (410 mg) was obtained by column chromatography. 2 SO 4 To a solution of compound 5b (150 mg, 1.00 eq) in ACN (3.00 mL), TsOH·H

[0274]

[0275] O (237 mg, 4.00 eq) was added and reacted at 40 °C for 1 h. The reaction solution was concentrated to obtain the crude product of compound 6b (135 mg). 2 At 20 °C, TFA (25.0 mL, 16.9 eq) was added to a solution of compound A (4.07 mL 1.00 eq) in DCM (25.0 mL), and the mixture was stirred at 20 °C for 12 h. After concentration of the reaction solution, compound B (3.00 g, 11.2 mmol) was obtained.

[0276]

[0277] Compound B (3.00 g, 1.00 eq, TFA) was dissolved in DCM (70.0 mL), DIEA (19.0 mL, 10.0 eq) was added thereto, and AllocCl (1.79 mL 1.50 eq) was added at 0 °C. The reaction was stirred at 20 °C for 12 h. After concentration of the reaction solution under reduced pressure, it was purified by column chromatography to obtain the crude product of compound C (3.60 g).

[0278]

[0279]

[0280] ​

[0281] To a DMF (32.0 mL) solution of Compound C1 (2.50 g, 1.00 eq, HCl) and Compound C (3.25 g, 1.00 eq) was added K 2 CO 3 (5.71 g, 3.00 eq) and NaI (206 mg, 0.10 eq), and the reaction was carried out at 50 °C for 12 hours. The reaction solution was poured into H 2 O (150 mL), extracted with ethyl acetate, and the organic phase was washed with brine. Dried over Na 2 SO 4 and filtered, and concentrated to obtain the crude product. Purified by column chromatography to obtain Compound D (2.00 g)

[0282]

[0283] Compound D (2.00 g, 1.00 eq) was dissolved in a mixed solution of TFA (10.0 mL, 20.2 eq) and DCM (10.0 mL), and the reaction was carried out at 20 °C for 0.5 hour. The reaction solution was rotary evaporated to obtain the unpurified Compound E (1.63 g).

[0284]

[0285] Synthesis of peptide: The peptide was synthesized by standard Fmoc chemistry

[0286] 1) Weighed 1.30 mmol of 2-CTC resin (substitution degree Sub = 0.70 mmol / g) and Fmoc-Gly-OH (1.30 mmol, 1.00 eq) into the reaction column, added 60.0 mL of DCM, then dropped DIEA (5.20 mmol, 4.00 eq), adjusted nitrogen to make the resin bulge evenly. After reacting at 20 °C for 2 hours, MeOH (2.00 mL) was dropped into the reaction column, purged with nitrogen for 30 minutes, and the waste was discharged until no liquid flowed out. Added DMF for washing, and discharged the waste until no liquid flowed out.

[0287] 2) Deprotection: Added 20% piperidine / DMF (50.0 mL) (V:V) to the resin and purged with nitrogen for 15 minutes. The resin was washed with DMF and dried by suction to obtain the resin.

[0288] 3) Coupling of Amino Acids: Weigh compound E (2.60 mmol, 2.00 eq) and HATU (2.47 mmol, 1.90 eq) into the above resin. After adding 30.0 mL of DMF, add DIEA (5.20 mmol, 4.00 eq) dropwise into the reaction column, and adjust the nitrogen to make the resin bulge evenly. After reacting at 20 °C for 50 minutes, pump out the reaction solution, add DMF for washing, and drain the waste until no liquid flows out.

[0289] 4) Deprotection of Alloc (allyloxycarbonyl): Wash the resin with DMF and DCM. Add 50.0 mL of DCM and introduce nitrogen. Add PhSiH 3 (13.0 mmol, 10.0 eq), Pd(PPh 3 ) 4 (0.130 mmol, 0.100 eq) in sequence. Pump out the reaction solution, add DMF for washing, and drain the waste until no liquid flows out.

[0290] 5) Coupling of Amino Acids: Weigh NOTA(tBu) 2 (1.95 mmol, 1.50 eq). After adding 30.0 mL of DMF, add DIEA (1.95 mmol, 3.00 eq) dropwise into the above resin, and adjust the nitrogen to make the resin bulge evenly. Finally, add HATU (1.85 mmol, 1.42 eq) into the reaction column. After reacting at 20 °C for 50 minutes, pump out the reaction solution, add DMF for washing, and drain the waste until no liquid flows out.

[0291] 6) Contract the resin with MeOH (30.0 mL), drain the waste until no liquid flows out, and dry the resin with nitrogen for standby.

[0292] Peptide Cleavage: At room temperature, add the prepared cleavage solution (1% TFA / DCM, 60.0 mL) to the dried resin, and adjust the nitrogen to make the resin bulge evenly.

[0293] After cleaving at 20 °C for 30 minutes, cleave three times, filter, spin-dry the filtrate, and then add acetonitrile and water for lyophilization. Obtain peptide 1 (1.00 g).

[0294]

[0295] To a solution of compound 6b (135 mg, 1.00 eq, TsOH) and peptide 1 (300 mg, 2.00 eq) in DMF (2.00 mL) were added HATU (92.7 mg, 1.00 eq) and DIEA (255 μL, 6.00 eq), and the reaction was carried out at 20 °C for 0.5 h. The reaction solution was diluted with DMF and then purified. Under TFA conditions, after reverse-phase purification and lyophilization, compound 7b (60.0 mg, 61.3 μmol) was obtained.

[0296]

[0297] Compound 7b (60.0 mg, 1.00 eq) was dissolved in TFA (570 μL, 125 eq), triisopropylsilane (15.0 μL, 1.19 eq), and H 2 O (15.0 μL), and the reaction was carried out at 20 °C for 1 h. The reaction solution was evaporated to dryness. Under TFA conditions, after reverse-phase purification and lyophilization, compound NYM067 (25.0 mg, 27.9 μmol, purity 96.6%) was obtained.

[0298] LCMS: MS observed: [M+H] + = 866.4 (as Figure 6 shown)

[0299] HPLC: Epurity: 96.6% (as Figure 7 shown)

[0300] 4. Synthesis method of NYM072

[0301] Molecular structure:

[0302]

[0303] Preparation process:

[0304]

[0305] Compound 10a in the synthesis of compound NYM066 was used. To a solution of compound 10a (55.6 mg, 1.00 eq, TSOH) and ICG-OSu (78.2 mg, 1.00 eq) in DMF (0.50 mL) was added DIEA (98.7 μL, 6.00 eq), and the reaction was carried out at 20 °C for 0.5 h. The reaction solution was diluted with DMF (0.50 mL) and then purified. Under TFA conditions, after reverse-phase purification and lyophilization, NYM072 (12.0 mg, 9.19 μmol, purity: 95.7%) was obtained.

[0306] LCMS: MS observed: [M+H] += 1249.6 (as Figure 8 shown)

[0307] HPLC: purity: 95.7% (as Figure 9 shown)

[0308] 5. Synthesis method of NYM076

[0309] Molecular structure:

[0310]

[0311] Preparation process:

[0312]

[0313] Compound 10a in the synthetic compound NYM066 was used. DIEA (69.1 μL, 6.00 eq) was added to a solution of compound 10a (38.9 mg, 1.00 eq, TsOH) and Cy7-OSu (51.5 mg, 1.00 eq) in DMF (0.50 mL), and the reaction was carried out at 20 °C for 0.5 h. The reaction solution was diluted with DMF (0.50 mL) and then purified. Under TFA conditions, after reverse-phase purification and lyophilization, compound NYM076 (15.0 mg, 12.4 μmol, purity: 99.5%) was obtained.

[0314] LCMS: MS observed: [M+H] + = 1202.5 (as Figure 10 shown)

[0315] HPLC: purity: 99.5% (as Figure 11 shown)

[0316] 6. Synthesis method of NYM077

[0317] Molecular structure:

[0318]

[0319] Preparation process:

[0320]

[0321] POCl 3 (431 μL, 2.00 eq) was added dropwise to a solution of compound 5c (438 mg, 1.00 eq) and compound 4 (500 mg, 1.00 eq) in Py (5.00 mL) at 0 °C, and the reaction was carried out at 0 °C for 1 h. The reaction solution was poured into ice-cold NaHCO 3(20.0 mL), extracted with dichloromethane, and the organic phase was washed with brine (20.0 mL). Using Na 2 SO 4 After drying and filtration, the crude product was concentrated. Under the condition of TFA, after reverse-phase purification and lyophilization, compound 6c (440 mg) was obtained

[0322]

[0323] Compound 6c (400 mg, 1.00 eq) was dissolved in a mixed solution of TFA (400 μL, 5.22 eq) and DCM (4.00 mL), and the reaction was carried out at 20 °C for 1 h. The reaction solution was rotary evaporated to obtain the unpurified compound 7c (414 mg, TFA).

[0324]

[0325] Compound 1c (1.63 mL, 1.00 eq) was dissolved in N,N-dimethylformamide (20.0 mL), potassium carbonate (2.19 g, 2.00 eq), compound 1c (2.74 g, 1.20 eq, HCl) and sodium iodide (118 mg, 0.10 eq) were added thereto. The reaction was stirred at 70 °C for 30 h, quenched by adding 80.0 mL of water, extracted with ethyl acetate, the organic phases were combined, washed with 80.0 mL of saturated brine, dried over anhydrous sodium sulfate and rotary evaporated to obtain the crude product. The crude product was purified by reverse-phase preparation (trifluoroacetic acid) to obtain compound 2c (1.50 g, 3.55 mmol).

[0326]

[0327] Compound 2c (1.70 g, 1.00 eq) was dissolved in anhydrous methanol (17.0 mL), and Pd / C (170 mg, purity 10.0%, 3.97e-2 eq) was added under a nitrogen atmosphere. The reaction system was purged with hydrogen three times, and the reaction was carried out at 25 °C for 2 h under a hydrogen (15.0 Psi) atmosphere. The reaction solution was filtered through diatomaceous earth. Rotary evaporation gave the crude compound 3c (1.34 g), which was directly used in the next step.

[0328]

[0329] Compound 3c (1.34 g, 1.00 eq) was dissolved in tetrahydrofuran (10.5 mL) and water (3.50 mL). Potassium carbonate (1.11 g, 2.00 eq) and benzyl chloroformate (690 μL, 1.20 eq) were added thereto at 0 °C, and the reaction was stirred at 25 °C for 16 h. The reaction was quenched by adding 100 mL of 1 M HCl, extracted with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. The crude product was separated and purified by column chromatography to obtain compound 3c-1 (501 mg).

[0330]

[0331] To a solution of compound 3c-1 (450 mg, 1.00 eq) in DMF (5.00 mL) were added HOBt (261 mg, 2.00 eq), EDCI (185 mg, 1.00 eq), DIEA (1.01 mL, 6.00 eq) and compound 7c (414 mg, 1.07 eq), and the reaction was carried out at 20 °C for 1 h. The reaction solution was diluted with DMF (0.50 mL), and under TFA conditions, it was purified by reverse phase and freeze-dried to obtain compound 8c (510 mg).

[0332]

[0333] Compound 8c (510 mg, 1.00 eq) was dissolved in a mixed solution of TFA (510 μL, 9.91 eq) and DCM (5.00 mL), and the reaction was carried out at 20 °C for 1 h. The reaction solution was concentrated in vacuo to obtain unpurified compound 9c (519 mg, TFA).

[0334]

[0335] To a solution of compound 11a (575 mg, 2.00 eq) in DMF (5.00 mL) were added HATU (526 mg, 2.00 eq), DIEA (723 μL, 6.00 eq) and compound 9c (519 mg, 1.00 eq, TFA), and the reaction was carried out at 20 °C for 1 h. The reaction solution was diluted with DMF (0.50 mL) and then purified. Under TFA conditions, it was purified by reverse phase and freeze-dried to obtain compound 10c (150 mg, 145 μmol).

[0336]

[0337] In an N 2 atmosphere, to a solution of compound 10c (70.0 mg, 1.00 eq) in THF (1.40 mL) and H 2 O (0.14 mL) was added Pd / C (7.00 mg, 10% purity), and using H2 Replace 3 times, the reaction is carried out in H 2 (15 psi) atmosphere, react at 20 °C for 1 h. The reaction solution is filtered through diatomaceous earth, rinsed with THF (5.00 mL), and then concentrated by rotary evaporation. Under TFA conditions, after reverse-phase purification and lyophilization, compound 11c (68.0 mg) is obtained.

[0338]

[0339] To DCM (0.50 mL) containing compound 11c (68.0 mg, 1.00 eq, TFA), add DIEA (35.1 μL, 3.00 eq) and Boc 2 O (30.8 μL, 2.00 eq), and react at 20 °C for 12 h. The reaction solution is concentrated by rotary evaporation to obtain crude compound 12c (67.0 mg).

[0340]

[0341] At 0 °C, to MeOH (500 μL) containing compound 12c (67.0 mg, 1.00 eq), add LiOH·H 2 O (500 μL, 3.73 eq), and react at 0 °C for 1 h. The reaction solution is adjusted to pH = 8 with 1N HCl, and under TFA conditions, after reverse-phase purification and lyophilization, compound 13c (38.0 mg, TFA) is obtained.

[0342]

[0343] To a solution of compound 13c (38.0 mg, 1.00 eq, TFA) and compound 6a (39.2 mg, 6.00 eq) in DMF (0.40 mL), add HATU (15.8 mg, 1.20 eq) and DIEA (60.2 μL, 10.0 eq), and react at 20 °C for 0.5 h. The reaction solution is diluted with DMF (0.10 mL), and under TFA conditions, after reverse-phase purification and lyophilization, compound 14c (35.0 mg, TFA) is obtained.

[0344]

[0345] Compound 14c (35.0 mg, 1.00 eq, TFA) is dissolved in a solution of TFA (2.00 mL, 977 eq), triisopropylsilane (50.0 μL, 8.84 eq), and H 2 O (50.0 μL), react at 20 °C for 1 h, and concentrate the reaction solution by rotary evaporation. Under TFA conditions, after reverse-phase purification and lyophilization, compound NYM077 (11.0 mg, 12.0 μmol, purity: 96.7%) is obtained.

[0346] Observed by LCMS: [M+H] + = 888.4 (as Figure 21 shown)

[0347] HPLC: purity: 96.7% (as Figure 22 shown)

[0348] Method for radiolabeling compounds in Example 2

[0349] 1. 68 Synthesis of Ga-NYM052

[0350] Labeling process:

[0351] 1) 68 The Ga nuclide is obtained by eluting a germanium-gallium generator with a hydrochloric acid solution. The germanium-gallium generator is eluted with 5 mL of 0.1 M hydrochloric acid, and the eluate is collected.

[0352] 2) Take 3 mL of the above eluate (radioactivity is about 3 - 20 mCi), add 2.4 mL of sodium acetate / acetic acid buffer solution, and adjust the pH to 3 - 4.

[0353] 3) Add 60 μg of NYM052, heat to 100 °C and react for 10 min.

[0354] 4) Cool the reaction solution to room temperature.

[0355] 5) Take a sample, dilute the reaction solution with sterile injection water, add it to a pre-activated C18 column. After the liquid has drained, rinse the C18 column with sterile injection water and discard the effluent.

[0356] 6) Rinse the C18 column with 70% ethanol solution, collect the effluent, dilute it with physiological saline, and filter it through a 0.22 μm sterile filter membrane into a sterile vial to obtain 68 Ga-NYM052 solution.

[0357] Test using radio-thin layer chromatography 68 The radiochemical purity of Ga-NYM052, as Figure 12 shown, 68 The analysis result of the radio-thin layer chromatography scan purity of Ga-NYM052, and its radiochemical purity is 100%.

[0358] 2. 68 Synthesis of Ga-NYM066

[0359] Take 1 - 2 mL 68 GaCl 3A 0.1M hydrochloric acid solution (radioactivity about 5 - 15 mCi) is added with an equal volume of 0.15M sodium acetate / acetic acid buffer solution (pH 7.2), mixed well, 60 μg of NYM066 is added, and the mixture is reacted at 20 - 30 °C for 15 min. Samples are taken, the reaction solution is diluted with sterile injection water, added to a pre-activated C18 column. After the liquid has drained, the C18 column is rinsed with sterile injection water, the effluent is discarded, the C18 column is eluted with 70% anhydrous ethanol solution, the effluent is collected and the target product is eluted into a transfer bottle. All the product solution in the transfer bottle is aspirated with a syringe and filtered through a 0.22 μm sterile filter membrane into a sterile vial, thus obtaining the target product. 68 Ga-NYM066 sterile injection.

[0360] The radioactive chemical purity of the product is detected by radio thin layer chromatography, as Figure 13 shown. 68 The radio thin layer chromatography scanning purity analysis result of Ga-NYM066 shows that its radiochemical purity is 98.0%.

[0361] 3. 68 Synthesis of Ga-NYM067

[0362] Take 1 - 2 mL 68 GaCl 3 A 0.1M hydrochloric acid solution (radioactivity about 5 - 15 mCi) is added with an equal volume of 0.15M sodium acetate / acetic acid buffer solution (pH 7.2), mixed well, 60 μg of NYM067 is added, and the mixture is reacted at 20 - 30 °C for 15 min. Samples are taken, the reaction solution is diluted with sterile injection water, added to a pre-activated C18 column. After the liquid has drained, the C18 column is rinsed with sterile injection water, the effluent is discarded, the C18 column is eluted with 70% anhydrous ethanol solution, the effluent is collected and the target product is eluted into a transfer bottle. All the product solution in the transfer bottle is aspirated with a syringe and filtered through a 0.22 μm sterile filter membrane into a sterile vial, thus obtaining the target product. 68 Ga-NYM067 sterile injection.

[0363] The radioactive chemical purity of the product is detected by radio thin layer chromatography, as Figure 14 shown. 68 The radio thin layer chromatography scanning purity analysis result of Ga-NYM067 shows that its radiochemical purity is 97.8%.

[0364] 4. 68 Synthesis of Ga-NYM077

[0365] Add 1 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to a vial, then add 60 μL of NYM077 aqueous solution (containing 60 μg of NYM077). After thorough mixing, add 1 mL 68 GaCl 3 of 0.1 M hydrochloric acid solution. The reaction solution is reacted at 20 - 30 °C for 10 - 15 min, the reaction is terminated, and a sample is taken for detection. As Figure 23 shown: 68 The results of the radio-thin layer chromatography scanning purity analysis of Ga-NYM077, and its radiochemical purity is 99.8%.

[0366] 5. Synthesis of 18

[0367] Add 1.2 mL of ethanol, 100 μL of precursor aqueous solution (1 mg / ml), 27 μL of AlCl 3 aqueous solution (2 mM), and 5 μL of glacial acetic acid to a 10 ml reaction flask; then take a certain activity of fluorine water and add it to a pre-activated QMA column. Wash the QMA column with 5 ml of water for injection, and discard the effluent. Then elute with 0.6 mL of normal saline, and collect the eluate into the reaction flask. Place the reaction solution at 80 °C for 15 min. Transfer the reaction solution to a 30 ml vial, add 27 ml of water for injection for dilution, then add the diluted solution to a pre-activated C18 column, discard the effluent, and then wash the C18 column with 20 mL of sterile water for injection, and discard the effluent. Elute the C18 column with 1.5 mL of 70% ethanol solution, collect the effluent into the product bottle, and add 9 ml of normal saline for dilution to obtain the product solution. As shown in the appendix Figure 24 shown: The radiochemical purity measured by HPLC method is 97.7%.

[0368] Example 3 Affinity Test of NYM052

[0369] ​Detection of affinity using SPR: The equipment used was a Biacore 8K protein interaction system. The FAP protein (purchased from ACROBiosystems Inc, 200 μg) was coupled to the surface of a CM5 chip. The running buffer was: 50 mM Tris, 150 mM NaCl, 0.05% P20 (Tween20), 5% DMSO, pH 7.2 - 7.42. The sample to be tested, NYM052 molecule, was diluted, and samples with different concentrations were prepared and injected to measure the affinity between NYM052 and the FAP protein. The binding strength between the NYM052 molecule and the FAP protein was represented by the equilibrium dissociation constant KD (Kd / Ka) value, where Kd is the dissociation constant and Ka is the binding constant. The smaller the KD value, the higher the affinity of the compound for the protein. From the test results, the equilibrium dissociation constant KD value between the NYM052 molecule and the FAP protein was 0.276 ± 0.011 nM. The equilibrium dissociation constant KD value between the NYM052 molecule and the FAP protein was below the nM level. It can be seen that the NYM052 molecule has a strong affinity for the FAP protein.

[0370] Example 4 68 PET / CT scan tissue distribution and targeting experiment of Ga-NYM052 in SJSA1 model

[0371] The experimental animal SJSA-1 model was provided by Crown Bioscience (Taicang) Co., Ltd. It is a SJSA-1 subcutaneous ectopic xenograft tumor model established based on BALB / c nude mice. This model is a CDX mouse model constructed with human osteosarcoma cells.

[0372] Experimental procedure: Four of these animal models were selected, and each was given 100 μCi of the above 68 Ga-NYM052 drug. After pre-anesthetizing with an appropriate concentration of isoflurane / air mixed gas before scanning, the animals were placed in a MicroPET / CT imaging chamber (SNPC-303 type SuperNova, Pingsheng Medical Technology (Kunshan) Co., Ltd.), and anesthesia was maintained with an isoflurane / air mixed gas. MicroPET / CT scans were performed 1 h, 2 h, and 3 h after drug administration. After reconstruction by the equipment software, the scanned images were obtained, and the PMOD software was used to analyze the scanned images. The experimental results are as Figure 15 and Figure 16 and the data in Table 1. It can be seen that 68 the Ga-NYM052 drug can rapidly accumulate in large amounts at the tumor tissue site (indicated by the arrow) and still maintain high uptake at 3 hours; while the uptake in other non-specifically binding organs is low, and it is rapidly excreted through the kidneys, resulting in a high tumor-background ratio at 3 hours, producing high-contrast images with good imaging effects and clear imaging interfaces.

[0373] Table 1: Radioactivity of Different Tissues at Different Time Points

[0374]

[0375] Example 5 68 Ga-NYM052 B-hFAPMC38 Model PET / CT Scanning Tissue Distribution and Targeting Experiment

[0376] The experimental animal B-hFAP MC38 model was provided by Beijing Biocytogen Co., Ltd. It is a transgenic model constructed from MC38 mouse colon cancer cells, and human FAP is highly expressed on the surface of B-hFAP MC38 cells. A subcutaneous xenograft tumor model was established based on C57BL / 6 mice.

[0377] Experimental procedure: Three of these animal models were selected, and each was given 80 μCi of the above 68 Ga-NYM052 drug. After pre-anesthetizing with an appropriate concentration of isoflurane / air mixture before scanning, the animals were placed in a MicroPET / CT imaging chamber (SNPC-303 type SuperNova, Pingsheng Medical Technology (Kunshan) Co., Ltd.), and anesthesia was maintained using an isoflurane / air mixture. Dynamic 30-min, static 1-h, 2-h, and 3-h MicroPET / CT scans were performed after drug administration. After reconstruction by the equipment software, the scanned images were obtained, and the PMOD software was used to analyze the scanned images. The experimental results are shown in Figure 29 and Figure 30 , as well as the data in Table 2. It can be seen that 68 the Ga-NYM052 drug can rapidly accumulate at the tumor tissue site (indicated by the arrow), and maintain high uptake at 3 hours; and it is rapidly excreted through the kidneys, with low uptake in other non-specifically binding organs, so that a high tumor-background ratio can be obtained after 1 hour, producing high-contrast images with good imaging effects and clear imaging interfaces.

[0378] Table 2: Radioactivity of Different Tissues at Different Time Points

[0379]

[0380]

[0381] Example 6 68 Ga-NYM052 A549 Model PET / CT Scanning Tissue Distribution and Targeting Experiment

[0382] The experimental animal A549 model was provided by Hengjia Biotechnology (Suzhou) Co., Ltd. It is a subcutaneous xenograft tumor model established based on BALB / c nude mice, and this model is a CDX mouse model constructed from human non-small cell lung cancer cells.

[0383] Experimental procedure: Four of these animal models were selected, and each was given the above 68 Ga-NYM052 drug at 80 μCi. After pre-anesthetizing with a proper concentration of isoflurane / air mixture before scanning, the animals were placed in a MicroPET / CT imaging chamber (SNPC-303 type SuperNova, Pingsheng Medical Technology (Kunshan) Co., Ltd.), and anesthesia was maintained with the isoflurane / air mixture. MicroPET / CT scanning was performed 1 h after administration. After reconstruction by the equipment software, the scanned images were obtained, and the PMOD software was used to analyze the scanned images. The experimental results are as Figure 31 and Figure 32 , and the data in Table 3 show that 68 the Ga-NYM052 drug can be enriched at the tumor tissue site (indicated by the arrow), with low non-specific uptake in muscle and heart, and a high tumor-to-background ratio, enabling imaging diagnosis of tumors.

[0384] Table 3: Radioactivity of different tissues at different time points

[0385]

[0386] Example 7 68 Scientific research clinical trial of Ga-NYM052

[0387] Subject information: A 56-year-old female who had undergone "radical resection of sigmoid colon MT", and the pathology showed adenocarcinoma. The patient had experienced postoperative chemotherapy, targeted therapy, and immunotherapy before entering the experiment. At the same time, CEA and CA199 were progressively elevated. Subsequently, endoscopy showed appendiceal orifice lesions and submucosal elevation of the esophagus; chronic non-active gastritis. Enhanced CT later showed: After sigmoid colon MT surgery, no obvious recurrence was seen; multiple nodules and calcifications in both lungs; fibrotic foci in both lungs; bilateral pleural thickening; a lesion in segment S6 of the right lobe of the liver.

[0388] Experiment: The patient first underwent 18 whole-body PET / CT scanning 1 h after injection of 4.548 mCi of 18F-FDG. After a three-day interval, the patient was injected with 68 1.735 mCi of Ga-NYM052, and whole-body PET / CT scanning was performed 1 h later. The examination results are shown in Figure 17 and Figure 18 respectively, 68 The diagnostic results of Ga-NYM052 showed that multiple lesions appeared throughout the patient's body, and the tumor and metastatic lesions showed 68Ga-NYM052 has higher radioactivity uptake and lower background, resulting in higher contrast and better visibility of metastases. Tumors and metastases can be imaged quickly and clearly, enabling the detection of smaller tumor lesions. At the same time, compared with the commonly used PET tracer 18 F-FDG, 68 Ga-NYM052 has lower background uptake in the cardiac blood pool, liver, or kidneys.

[0389] Example 8 Fluorescence scanning experiment of NYM076 on the NCI-N87 model

[0390] The experimental animal NCI-N87 model was provided by Shanghai RunNuo Biotechnology Co., Ltd. It is an NCI-N87 tumor xenograft mouse model, which is a mouse model constructed with human gastric cancer cells.

[0391] Randomly select 2 of this animal model, administer 10 μg of the above NYM076 drug. During scanning, use an appropriate concentration of isoflurane / air mixed gas for pre-anesthesia and maintenance anesthesia. Perform in vivo fluorescence scanning imaging at 1 h, 2 h, 4 h, 6 h, and 8 h after drug administration. The scanning time is as Figure 19 and Figure 20 shown. The biodistribution of the NYM076 drug in the NCI-N87 tumor model mice shows that at 1 hour after injection, there is high fluorescence accumulation of NYM076 in the tumor; at 2 hours after injection, NYM076 is excreted from the body through metabolism in non-target organs in the body, and the fluorescence imaging at the tumor is more obvious and clear; until 8 hours after injection, there is still fluorescence imaging at the tumor, indicating that NYM076 has guiding significance for clinical fluorescence surgical navigation (the fluorescence at the tumor in the figure is indicated by a circle).

[0392] Example 9 68 PET / CT scanning tissue distribution and targeting experiment of Ga-NYM077 on the A549 model

[0393] The experimental animal A549 model was provided by Hengjia Biotechnology (Suzhou) Co., Ltd. It is an A549 subcutaneous ectopic transplantation tumor model established based on BALB / c nude mice, which is a CDX mouse model constructed with human lung adenocarcinoma cells.

[0394] Experimental procedure: Select 6 of this animal model, and administer the above 6880 μCi of Ga-NYM077 drug. After pre-anesthetizing with an appropriate concentration of isoflurane / air mixture before scanning, the animals were placed in a MicroPET / CT imaging chamber (SNPC-303 type SuperNova), and anesthesia was maintained using the isoflurane / air mixture. MicroPET / CT scan was performed 1 h after drug administration. After reconstruction by the device software, the scanned images were obtained. The PMOD software was used to analyze the scanned images, and the regions of interest (ROIs) of tissues such as brain, heart, lung, liver, stomach, kidney, muscle, intestine, and tumor were outlined. The radioactive counts and volumes of the tissues in the regions of interest were measured, and the percentage of injected dose per gram of tissue (%ID / g) was calculated. The experimental results are as Figure 25 and Figure 26 (the arrow points to the tumor), and the data in Table 4 show that 68 the Ga-NYM077 drug can rapidly accumulate at the tumor tissue site (the arrow indicates), with high uptake in the tumor one hour after injection. Meanwhile, the uptake amount at the tumor site is significantly higher than that in muscle, heart, and lung, showing good imaging effects. The imaging results indicate that 68 Ga-NYM077 can be specifically taken up at the tumor site as an imaging agent and has good application prospects.

[0395] Table 4: Radioactivity of different tissues at different time points

[0396]

[0397] Example 10 68 PET / CT scan tissue distribution and targeting experiment of Ga-NYM077 on B-hFAP MC38 model

[0398] The experimental animal B-hFAP MC38 model was provided by Beijing Biocytogen Co., Ltd. It is a transgenic model constructed from MC38 mouse colon cancer cells, and human FAP is highly expressed on the surface of B-hFAP MC38 cells. A subcutaneous ectopic tumor transplantation model was established based on C57BL / 6 mice.

[0399] Experimental procedure: Four of these animal models were selected, and each was given the above-mentioned 68 80 μCi of Ga-NYM077 drug. After pre-anesthetizing with an appropriate concentration of isoflurane / air mixture before scanning, the animals were placed in a MicroPET / CT imaging chamber (SNPC-303 type SuperNova, Pingsheng Medical Technology (Kunshan) Co., Ltd.), and anesthesia was maintained using the isoflurane / air mixture. Dynamic 30 min, static 1 h, 2 h, and 4 h MicroPET / CT scans were performed after drug administration. After reconstruction by the device software, the scanned images were obtained. The PMOD software was used to analyze the scanned images. The experimental results are asFigure 33 and Figure 34 , and the data in Table 5, it can be seen that 68 The Ga-NYM077 drug can rapidly accumulate in the tumor tissue site (indicated by the arrow), and maintain a high uptake at 4 hours; while the uptake in other non-specifically binding organs gradually decreases and is rapidly excreted through the kidneys, resulting in a high tumor-to-background ratio after 1 hour, producing a high-contrast image, showing good targeting, and a good imaging effect with a clear imaging interface.

[0400] Table 5: Radioactivity of different tissues at different time points

[0401]

[0402]

[0403] Example 11 18 PET / CT scan tissue distribution and targeting verification of [ [

[0404] The experimental animal A549 model was provided by Hengjia Biotechnology (Suzhou) Co., Ltd. It is an A549 subcutaneous ectopic xenograft tumor model established based on BALB / c nude mice, and this model is a CDX mouse model constructed with human lung adenocarcinoma cells.

[0405] Experimental procedure: Select 6 of these animal models, and give each 80 μCi of the above [ [ 18 F] AlF-NYM077 drug. After pre-anesthetizing with an appropriate concentration of isoflurane / air mixed gas before scanning, place the animals in a MicroPET / CT imaging chamber (SNPC-303 type SuperNova), and maintain anesthesia with the isoflurane / air mixed gas. Conduct a MicroPET / CT scan 1 h after administration. After reconstruction by the equipment software, obtain the scan images. Use PMOD software to analyze the scan images, outline the regions of interest of tissues such as the brain, heart, lungs, liver, stomach, kidneys, muscles, intestines, and tumors, measure the radioactive counts of the tissues in the regions of interest, and calculate the percentage of injected dose per gram of tissue (%ID / g).

[0406] The experimental results are as shown in Figure 27 and Figure 28 (the arrow points to the tumor), and the data in Table 6, it can be seen that [ [ 18 F] AlF-NYM077 drug can rapidly accumulate in large amounts in the tumor tissue site (indicated by the arrow). One hour after injection, there is a high uptake in the tumor, and at the same time, the uptake amount at the tumor site is significantly higher than that of other normal tissues, with a good imaging effect. The imaging results show that [ [ 18

F

[0407] Table 6: Radioactivity of different tissues at different time points

[0408]

[0409] Example 12 68 PET / CT scan tissue distribution and targeting verification of Ga-NYM067 on the B-hFAP MC38 model

[0410] The experimental animal B-hFAP MC38 model was provided by Beijing Biocytogen Co., Ltd. It is a transgenic model constructed from MC38 mouse colon cancer cells, and human FAP is highly expressed on the surface of B-hFAP MC38 cells. A subcutaneous xenograft tumor model was established based on C57BL / 6 mice.

[0411] Experimental procedure: Select 4 of this animal model, and give each of them 80 μCi of the above 68 Ga-NYM067 drug. After pre-anesthetizing with an appropriate concentration of isoflurane / air mixture before scanning, place the animal in the MicroPET / CT imaging chamber (SNPC-303 type SuperNova, Pingsheng Medical Technology (Kunshan) Co., Ltd.), and maintain anesthesia with the isoflurane / air mixture. Perform dynamic 30 min, static 1 h, and 2 h MicroPET / CT scans after administration. Obtain the scan images after reconstruction by the equipment software, and analyze the scan images using PMOD software. The experimental results are as Figure 35 and Figure 36 , as well as the data in Table 7. It can be seen that 68 the Ga-NYM067 drug can quickly accumulate at the tumor tissue site (indicated by the arrow) and still maintain high uptake at 2 hours; while the uptake in other non-specifically binding organs gradually decreases and is rapidly excreted through the kidneys, resulting in a higher tumor-to-background ratio after 1 hour, producing high-contrast images, showing good targeting, and having good imaging effect and clear imaging interface.

[0412] Table 7: Radioactivity of different tissues at different time points

[0413]

[0414]

[0415] In the description of this specification, the descriptions referring to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples", etc. mean that the specific features, structures, materials, or

[0416] characteristics are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, without contradiction, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0417] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound, which is a compound of formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula I: in, Ring A is selected from five-membered heterocycloalkyl groups optionally substituted by R1; B is selected from -NR2-, -O-, -S- or -C 1～6 Alkylene-; L1 is selected from the structure or key; L2 is selected from -NR2-, -C optionally substituted by R1 1～6 Alkylene-NH-, -NH-C optionally substituted by R1 1～6 Alkylene -NH- or bond; L1 and L2 are not keys at the same time; L 11 , L' 11 are independently selected from an amino acid chain optionally substituted by R1, a carbon chain optionally substituted by R1, a combination of an amino acid chain and a carbon chain optionally substituted by R1, a -C 1～6 Alkylene-[NH-C(O)-CH2] t -, -C optionally substituted by R1 1～6 Alkylene-[NH-C(O)-CH2] t -NH- or -C(O)-NH-C optionally substituted by R1 1～10 Alkylene; L 12 Selected from -C optionally substituted by R1 1～6 Alkylene-NH-, C optionally substituted by R1 1～6 Alkylene or -C(O)-C optionally substituted by R1 1～6 an alkylene group or a bond; R1 is independently selected from -F, -Cl, -Br, -I, -CN, =O, C optionally substituted by R3 1～6 Alkyl, -OH, -COOH, -CH2OH, -CH2COOH, phenyl or tolyl; when the R1 is multiple, the R1 may be the same or different; R2 is independently selected from -H, -C 1-6 Alkyl, -C 1-6 Alkylene-, -CH2O-, cycloalkenyl, cycloheteroalkenyl, aryl or -C 1-6 Cycloalkyl-; R3 is selected from -F, -Cl, -Br, -I, -CN, =O, -OH or -COOH; T or Z are independently selected from a chelator, a fluorescent group or a radioactive group; t is selected from 1, 2, 3 or 4.

2. The compound according to claim 1, characterized in that It is a compound represented by formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula II: Among them, L 11 is selected from an amino acid chain optionally substituted by R1, a carbon chain optionally substituted by R1, a combination of an amino acid chain and a carbon chain optionally substituted by R1, a -C 1～6 Alkylene-[NH-C(O)-CH2] t -, -C optionally substituted by R1 1～6 Alkylene-[NH-C(O)-CH2] t -NH- or -C(O)-NH-C optionally substituted by R1 1～10 Alkylene; L2 is selected from -C optionally substituted by R1 1～6 Alkylene-NH-; T is selected from a chelator or a fluorescent group.

3. The compound according to claim 1, characterized in that It is a compound represented by formula III or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula III: Among them, L' 11 is selected from an amino acid chain optionally substituted by R1, a carbon chain optionally substituted by R1, a combination of an amino acid chain and a carbon chain optionally substituted by R1, a -C 1～6 Alkylene-[NH-C(O)-CH2] t -, -C optionally substituted by R1 1～6 Alkylene-[NH-C(O)-CH2] t -NH- or -C(O)-NH-C optionally substituted by R1 1～10 Alkylene; L 12 Selected from -C optionally substituted by R1 1～6 Alkylene-NH-, C optionally substituted by R1 1～6 Alkylene or -C(O)-C optionally substituted by R1 1～6 an alkylene group or a bond; L2 is selected from -NR2-, -C optionally substituted by R1 1～6 Alkylene-NH- or -NH-C optionally substituted by R1 1～6 Alkylene-NH-; T or Z is independently selected from a chelating agent, a fluorescent group or a radioactive group, wherein one of T or Z is a fluorescent group.

4. The compound according to any one of claims 1 to 3, characterized in that The amino acid chain is selected from any combination of glycine or its derivatives, lysine or its derivatives, glutamic acid or its derivatives, serine or its derivatives, alanine or its derivatives, tyrosine or its derivatives, aspartic acid or its derivatives, and threonine or its derivatives; Optionally, the carbon chain is -(CH2) n -, n is selected from an integer between 0 and 20; Optionally, one or more carbon atoms in the carbon chain may be arbitrarily replaced by O, N or S.

5. The compound according to any one of claims 1 to 3, characterized in that The ring A is selected from the group consisting of R4 is selected from -F, -Cl, -Br, -I, -CN; when the R4 is multiple, the R4 can be the same or different; Optionally, B is selected from -NR2- or -O-, and R2 is selected from -H or -C 1-6 alkyl; Optionally, the L 11 is selected from an amino acid chain optionally substituted by R1, -C 1～6 Alkylene-[NH-C(O)-CH2] t -, -C optionally substituted by R1 1～6 Alkylene-[NH-C(O)-CH2] t -NH-, R1 is selected from =O, -C 1～6 Alkyl, -OH, -COOH, -CH2OH, -CH2COOH; when there are multiple R1s, the R1s may be the same or different; Optionally, the L' 11 Selected from -C optionally substituted by R1 1～6 Alkylene-[NH-C(O)-CH2] t -, -C optionally substituted by R1 1～6 Alkylene-[NH-C(O)-CH2] t -NH-, R1 is selected from =O or -C 1～6 Alkyl; when the R1 is multiple, the R1 may be the same or different; Optionally, the L 12 Selected from -C 1～6 Alkylene-NH-; Optionally, the L2 is selected from -NR2-, -C 1～6 Alkylene-NH-, -NH-C optionally substituted by R1 1～6 Alkylene-NH-, R2 is selected from -H or -C 1-6 Alkyl, R1 is selected from -C 1～6 alkyl.

6. The compound according to claim 5, characterized in that The ring A is selected from Optionally, B is selected from -N(CH3)- or -O-; Optionally, the L 11 Selected from Optionally, the L' 11 Selected from Optionally, the L 12 Selected from Optionally, the L2 is selected from -NH-, 7. The compound according to claim 2, characterized in that It is a compound represented by formula II-1 or II-2 or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula II-1 or II-2:

8. The compound according to claim 3, characterized in that It is a compound represented by formula III-1 or III-2 or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula III-1 or III-2:

9. A compound, characterized in that It is a compound represented by formula IV or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula IV: wherein ring A is selected from the group consisting of B is selected from -NR'2-, -O-; L 13 Selected from -C optionally substituted by R"1 1～3 Alkylene-[NH-C(O)-CH2] t’ -NH-; T is selected from a chelator, a fluorescent group or a radioactive group; R'1 is selected from -F, -Cl, -Br, -I, -CN; when there are multiple R'1, the R'1 can be the same or different; R"1 is selected from =O, methyl, ethyl, propyl, -OH, -COOH, -CH2OH, -CH2COOH; when the R"1 is multiple, the R"1 can be the same or different; R'2 is selected from -H, methyl, ethyl, propyl; t' is selected from 1, 2 or 3.

10. The compound according to any one of claims 1 to 9, characterized in that The chelating agent is derived from 1,4,7,10-tetraazacyclododecane-N,N',N",N",tetraacetic acid, N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)pentanedioic acid, 2-(4,7, 1,4,7-triazacyclononanephosphinic acid, 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid], 3,6,9,15-tetraazabicyclo[9.3.1.]pentadeca-1(15),11,13-triazacyclononanephosphinic acid, ene-3,6,9-triacetic acid, N'-{5-[acetyl (hydroxy) amino] pentyl}-N-[5-({4-[(5-aminopentyl) (hydroxy) amino] -4-oxobutyryl} amino) pentyl] -N-hydroxysuccinamide, diethylenetriamine pentaacetic acid, trans-cyclohexyl-diethylenetriamine pentaacetic acid, 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid, isobutylene thiocyanatobenzyl-DTPA, 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA, 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA, 1-(2)-methyl-4-isothiocyanatobenzyl-DTPA, [R]-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid or 6-hydrazinopyridine-3-carboxylic acid; Optionally, the chelating agent is selected from Optionally, the fluorescent group is selected from anthocyanin fluorescent groups; Optionally, the fluorescent group is derived from Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Cy7.5, sulfo-Cy3, sulfo-Cy5, sulfo-Cy7 or ICG.

11. A compound, the structure of which is selected from the following:

12. A compound, characterized in that The compound is formed by complexing the compound according to any one of claims 1 to 11 with M; Optionally, the M is selected from at least one of a radioactive nuclide or a non-radioactive element; Optionally, the radionuclide is selected from at least one of a diagnostic nuclide or a therapeutic nuclide; Optionally, the diagnostic nuclide is selected from 68 Ga, 18 F. 99 mTc, 89 Zr, 124 I. 76 Br, 43 Sc, 111 In, 45 Ti, 52 Mn, 59 Fe, 64 Cu, 94m Tc, 67 Ga, 71 / 72 / 74 As, 82m Rb or 86 Y; Optionally, the therapeutic nuclide is selected from 177 Lu, 90 Y. 131 I. 153 Sm, 67 Cu, 89 Sr. 166 Ho, 177 Yb, 47 Sc, 186 / 188 Re, 212 / 213 Bi, 149 Pm, 212 Pb, 211 At 223 Ra, 225 Ac or 227 Th; Optionally, the diagnostic nuclide 18 F is obtained by 18 F]AlF complex.

13. The compound according to claim 12, characterized in that Its structure is selected from the following: Wherein, in Formula IV, T is selected from a chelating agent; In Formula V, T is selected from a chelating agent, and Z is selected from a fluorescent group; In Formula VI, Z is selected from a chelating agent, and T is selected from a fluorescent group.

14. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: a compound according to any one of claims 1 to 13, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

15. Use of the compound according to any one of claims 1 to 13, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 14 in the preparation of an agent and / or a drug for diagnosing and / or treating a disease characterized by overexpression of fibroblast activation protein.

16. The use according to claim 15, characterized in that The diagnostic method is selected from optical imaging and / or nuclear imaging; Optionally, the diagnostic method is selected from fluorescence imaging, PET imaging and / or SPECT imaging; Optionally, the treatment is selected from radiotherapy and / or assisted surgery with fluorescent surgical navigation.

17. The use according to claim 15, characterized in that The disease is selected from cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling or scar disease; Optionally, the cancer is selected from breast cancer, stomach cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, liver cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumors, carcinogenic osteomalacia, sarcoma, cancer of unknown primary, thymic carcinoma, glioma, glioma, astrocytoma, cervical cancer or prostate cancer; Preferably, the cancer is selected from glioma, gastric cancer, breast cancer, colon cancer, lung cancer, head and neck cancer, liver cancer, pancreatic cancer or sarcoma.

18. A method for imaging tissue overexpressing fibroblast activation protein, characterized in that: The method comprises administering to the tissue the compound according to any one of claims 1 to 13, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition according to claim 14, and imaging the tissue after administration of the drug.

19. The method according to claim 18, characterized in that The imaging is performed by emission computed tomography or fluorescence imaging.

Images