FAP-targeting compound and preparation method therefor

Abstract

Disclosed in the present invention are a FAP-targeting compound and a preparation method therefor. By means of a meticulously designed molecular structure containing a plurality of variable substituents, the compound can precisely target fibroblasts in tumor stroma, thereby providing a new approach for cancer treatment. The Z group of the compound can be flexibly replaced by a radioactive agent, fluorescent agent or contrast agent, thus broadens the application range for tumor diagnosis and treatment. In the preparation method, starting from a starting material, a high-purity and high-yield FAP-targeting compound is ultimately obtained via a plurality of efficient reaction steps. Such compound has good metabolic stability and pharmacokinetic properties, which reduce the side effects of medications and increase the therapeutic effect. The diverse substituents and linker arms of the compound further optimize the physicochemical properties and improve the overall therapeutic effect. When combined with a pharmaceutical carrier, the compound achieves efficient delivery to tumor tissues and reduces non-target side effects, which provides a precise and effective personalized treatment regimen for cancer patients, and significantly improves the therapeutic effect and the quality of life of patients.

Description

A FAP-targeting compound and a preparation method thereof TECHNICAL FIELD

[0001] The present application relates to the technical field of radiopharmaceutical chemistry and clinical and medical technology, and particularly relates to a FAP-targeting compound and a preparation method thereof. BACKGROUND

[0002] Fibroblast activation protein plays an important role in the occurrence and development of tumors. FAP is a kind of antigen molecule specifically expressed on the surface of CAFs secreted by tumor-related fibroblasts, and is a type II serine protease with dipeptidyl peptidase activity and endopeptidase activity. In the tumor stroma, CAFS stably express FAP in large quantities, and play an important role in promoting tumor growth, invasion, metastasis and immunosuppression, and CAF overexpression FAP promotes the development and metastasis of tumors through mechanisms such as extracellular matrix remodeling, intracellular signal transduction, angiogenesis, epithelial-mesenchymal transition and immunosuppression.

[0003] In view of the wide and high expression of FAP in tumor tissues and the important physiological role, FAP has become a high-potential target for tumor diagnosis and treatment. Radionuclide-labeled fibroblast activation protein inhibitors (FAPI) derived from quinoline skeleton have made important progress in the field of precise tumor imaging. At present, dozens of PET / CT imaging agents based on this have been developed, such as 68Ga-labeled FAPI-02, FAPI-46, 18F-Al-labeled FAPI-74, etc., and have been widely used in clinical non-clinical trials. However, the above FAPI probes have the problems of high concentration in liver and kidney tissues and high background value in animal models and subjects, which greatly limits their clinical application.

[0004] Therefore, there is still a great optimization space for FAPI probes, and it is necessary to provide a FAP-targeting compound and a preparation method thereof to overcome the defects of low tumor uptake and high background value of the above FAPI probes. SUMMARY

[0005] The present application overcomes the shortcomings of the prior art and provides a FAP-targeting compound and a preparation method thereof.

[0006] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows: a FAP-targeting compound and a preparation method thereof, comprising: a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof.

[0007] wherein, X 1 is CR X1a R X1b ;

[0008] X 2R is CR X2a R X2b S, O or -S(=O)2;

[0009] R is CR 3 R X3a R X3b ;

[0010] R X1a R X1b R X2a R X2b R X3a R X3b R X4 are each independently H, halo, alkyl, alkenyl, alkynyl, -OR, cycloalkyl or heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl being optionally substituted with 1, 2 or 3 R x ;

[0011] or R X1a and R X1b are joined together to form a cycloalkyl, heterocyclyl or alkylidene, the cycloalkyl, heterocyclyl or alkylidene being optionally substituted with 1, 2 or 3 R x ;

[0012] or R X2a and R X2b are joined together to form a cycloalkyl, heterocyclyl or alkylidene, the cycloalkyl, heterocyclyl or alkylidene being optionally substituted with 1, 2 or 3 R x ;

[0013] or R X3a and R X3b are joined together to form a cycloalkyl, heterocyclyl or alkylidene, the cycloalkyl, heterocyclyl or alkylidene being optionally substituted with 1, 2 or 3 R x ;

[0014] or R X1a and R X2a are joined together to form a cycloalkyl or heterocyclyl, the cycloalkyl or heterocyclyl being optionally substituted with 1, 2 or 3 R x ;

[0015] or R X1a and R X3a are joined together to form a cycloalkyl or heterocyclyl, the cycloalkyl or heterocyclyl being optionally substituted with 1, 2 or 3 R x ;

[0016] or R X1a and R X4 are joined together to form a cycloalkyl or heterocyclyl, the cycloalkyl or heterocyclyl being optionally substituted with 1, 2 or 3 R x ;

[0017] or R X2a are linked together to form a cycloalkyl or heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 R X3a x substituents;

[0018] or R X2a are linked together to form a cycloalkyl or heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 R X4 x substituents;

[0019] or R X3a are linked together to form a cycloalkyl or heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 R X4 x substituents;

[0020] Ring A is heterocyclyl;

[0021] R A , R B are each independently halogen, alkyl, alkenyl, alkynyl, -OR, cycloalkyl or heterocyclyl, which alkyl, alkenyl, alkynyl, -OR, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 OH, CN, halogen or alkyl;

[0022] n, m are each independently 0, 1, 2, 3 or 4;

[0023] R 1 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0024] or one R A is linked together with R 1 to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, which cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1, 2 or 3 R 1a substituents;

[0025] L 1 , L 2 , L 3 , L 4 are each independently a single bond, O, S, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, which alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1, 2 or 3 R L substituents;

[0026] Z is a radioactive moiety, a chelator, a fluorescent dye or a contrast agent;

[0027] ​​​R is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 1, 2 or 3 alkyl, OH, halo, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0028] R 1a , R x , and R L are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 1, 2 or 3 alkyl, OH, halo, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0029] p is independently 1, 2 or 3.

[0030] said "alkyl" is a carbon, hydrogen, oxygen, nitrogen and heteroatom with one single bond connecting a carbon atom of the molecular backbone.

[0031] In one preferred embodiment of the present application, the compound of formula (I) has a structure as shown in formula (I-1) or formula (I-2):

[0032] In one preferred embodiment of the present application, ring A is a 3-12 membered heterocyclyl,

[0033] Optionally, ring A is

[0034] Optionally, R A is independently halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR, C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with 1, 2 or 3 OH, CN, halo or C 1-6 alkyl;

[0035] Optionally, R A is independently halo, methyl, ethyl, fluoromethylene or hydroxymethylene;

[0036] Optionally, n is 0, 1, 2 or 3;

[0037] Optionally, n is 0 or 1;

[0038] Optionally, is # represents a bond to L 1 is connected.

[0039] In one preferred embodiment of the application, R X1a , R X1b , R X2a , R X2b , R X3a , R X3b , R X4 are each independently H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl being optionally substituted with 1, 2, or 3 R x ;

[0040] Optionally, R x is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl being optionally substituted with 1, 2, or 3 C 1-6 alkyl, OH, halogen, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl;

[0041] Optionally, R X1a and R X1b are each independently selected from H, halogen, or C 1-6 alkyl;

[0042] Optionally, X 1 is CH2;

[0043] Optionally, X 2 is CR X2a R X2b , S, O, S(=O), or S(=O)2;

[0044] Optionally, X 2 is CR X2a R X2b or S;

[0045] Optionally, X 2 is S;

[0046] Optionally, X 2 is CRX2a R X2b and R X2a and R X2b are each independently selected from H, halo or C 1-6 alkyl;

[0047] optionally, X 2 is CF2;

[0048] optionally, R X3a and R X3b are each independently selected from H, halo or C 1-6 alkyl;

[0049] optionally, X 3 is CH2or C(CH3)2;

[0050] optionally, R X4 is H, halo or C 1-6 alkyl;

[0051] optionally, R X4 is H;

[0052] optionally, R X1a and R X1b are joined together to form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl or C 2-6 alkylidene, cycloalkyl, heterocyclyl or alkylidene optionally substituted with 1, 2 or 3 R x ;

[0053] optionally, R X2a and R X2b are joined together to form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl or C 2-6 alkylidene, cycloalkyl, heterocyclyl or alkylidene optionally substituted with 1, 2 or 3 R x ;

[0054] optionally, R X3a and R X3b are joined together to form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl or C 2-6 alkylidene, cycloalkyl, heterocyclyl or alkylidene optionally substituted with 1, 2 or 3 R x ;

[0055] optionally, R X1a and R X2a are joined together to form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, cycloalkyl or heterocyclyl optionally substituted with 1, 2 or 3 R x ;

[0056] optionally, RX1a with R X3a together to form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2, or 3 R x substituents;

[0057] optionally, one R X1a is linked together with R X4 to form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2, or 3 R x substituents;

[0058] optionally, one R X2a is linked together with R X3a to form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2, or 3 R x substituents;

[0059] optionally, one R X2a is linked together with R X4 to form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2, or 3 R x substituents;

[0060] optionally, one R X3a is linked together with R X4 to form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2, or 3 R x substituents;

[0061] optionally, is

[0062] optionally, is

[0063] In a preferred embodiment of the application, R 1 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;

[0064] optionally, one R A is linked together with R 1 to form a C 3-6cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally substituted with 1, 2 or 3 R 1a substituted;

[0065] R 1a are each independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally substituted with 1, 2 or 3 R 1-6 alkyl, OH, halo, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, aryl or 5-6 membered heteroaryl;

[0066] Optionally, m is 0 or 1.

[0067] In one preferred embodiment of the present application, Z is a radioactive moiety;

[0068] Optionally, Z is a fluorescent dye, said fluorescent dye is a xanthene, acridine, oxazine, cyanine, styryl dye, coumarin, porphyrin, metal ligand- complex, fluorescent protein, nanocrystal, perylene, boron dipyrromethene or phthalocyanine, as well as conjugates and combinations of these classes of dyes;

[0069] Optionally, Z is a chelator, chelator is 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), triethylenetetramine (TETA), iminodiacetic acid, diethylenetriamine-N,N,N',N',N"-pentaacetic acid (DTPA), bis-(carboxymethylimidazole)glycine or 6-hydrazinopyridine-3-carboxylic acid (HYNIC);

[0070] Optionally, Z is a contrast agent comprising a paramagnetic agent;

[0071] Optionally, the radioactive moiety comprises 18 F, 51 Cr, 67 Ga, 68 Ga, 111 In, 99m Tc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 88Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101 Rh, 119 Sb, 128 Ba, 123 I, 124 I, 131 I, 197 Hg, 211 At, 151 Eu, 153 Eu, 169 Eu, 201 Tl, 203 Pb, 212 Pb, 64 Cu, 67 Cu, 188 Re, 186 Re, 198 Au, 225 Ac, 227 Th and 199 Ag.

[0072] Optionally, Z is selected from one of the following structures:

[0073] In one preferred embodiment of the application, L 1 , L 2 , L 3 , L 4 are each independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with 1, 2, or 3 R L ;

[0074] Optionally, L 1 , L 2 , L 3, L 4 are each independently a single bond, O, S, C(R La )(R Lb ), N(R Lc ), C(=O), S(=O), S(=O)2, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally substituted with 1, 2 or 3 R L , R La , R Lb and R Lc are each independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, which alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1, 2 or 3 C 1-6 alkyl, OH, halogen, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;

[0075] optionally, L 1 , L 2 , L 3 , L 4 are each independently a single bond, O, S, CH2, CH2CH2, NH, CH=CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl or piperidinyl, which CH2, CH2CH2, NH, CH=CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl or piperidinyl is optionally substituted with 1, 2 or 3 methyl, ethyl, halogen or OH;

[0076] optionally, is

[0077] optionally, is

[0078] In one preferred embodiment of the present application, the pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is one of the compounds in Table 1.

[0079] A method for preparing a FAP-targeting compound of the present application comprises the following steps:

[0080] S1: B-1 is synthesized to B-2 by reacting with thionyl chloride and methanol;

[0081] S2: B-2 is synthesized into B-3 through Buchwald coupling reaction;

[0082] S3: B-3 is synthesized into B-4 through hydrolysis under alkaline conditions;

[0083] S4: B-4 is synthesized into B-6 through condensation reaction and deprotection under acidic conditions, respectively;

[0084] S5: B-6 is finally obtained into the final product B through two-step substitution reaction or condensation reaction.

[0085] In one preferred embodiment of the present application, the pharmaceutical composition comprises at least one compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

[0086] In one preferred embodiment of the present application, the use in the preparation of a medicament for the diagnosis or treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in an animal or human subject, wherein the disease characterized by overexpression of FAP is selected from the group consisting of cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and scarring.

[0087] The present application solves the defects in the background art and has the following beneficial effects:

[0088] (1) The present application provides, through its molecular structure comprising multiple variable substituents (such as RX1a to RX3b, RA, RB, etc.), a high selectivity and affinity for FAP. This property enables the compounds to accurately target and act on FAP-expressing cells or tissues, such as fibroblasts in the tumor stroma, opening up new avenues for cancer treatment. At the same time, the Z group in the compounds can be flexibly replaced with radioactive moieties, chelating agents, fluorescent dyes or contrast agents as needed, greatly broadening their application fields, whether for precise positioning and radiotherapy of tumor lesions, as fluorescent probes for early diagnosis and intraoperative navigation, or as contrast agents to enhance the accuracy of imaging examinations, all of which exhibit significant advantages. In addition, the compounds also have excellent metabolic stability and pharmacokinetic properties, which help to reduce drug side effects and improve treatment effectiveness, bringing more treatment options and hope to cancer patients.

[0089] (2) In the present application, by adjusting the ring A, RA, RX series of substituents, and X1, X2, X3 and other groups, the high selectivity and affinity of FAP are realized, and the drug can accurately and effectively target the fibroblasts in the tumor microenvironment, laying a solid foundation for precise treatment of cancer; secondly, the Z group in the compound has high flexibility, which can be selectively replaced by radioactive parts, fluorescent dyes or chelating agents, etc., thereby widening its application range in tumor treatment and diagnosis. For example, as a radiopharmaceutical, it can achieve accurate positioning and radiotherapy of tumor lesions; as a fluorescent probe, it can be used for early cancer diagnosis, intraoperative navigation and efficacy evaluation; the application of chelating agents helps to combine with radioisotopes, enhance the stability and therapeutic effect of the drug; in addition, the metabolic stability and pharmacokinetic properties of the compound in vivo are excellent, ensuring the effective distribution and long-acting effect of the drug in vivo, while reducing unnecessary side effects and improving the tolerance and quality of life of patients. The diversified substituents and connection modes further optimize the physical and chemical properties of the drug, such as solubility, stability, etc., thereby improving the overall efficacy of the drug.

[0090] (3) In the present application, based on the in-depth design of the targeted FAP compound, especially the diversified selection of the connecting arms L1, L2, L3, L4, the compound realizes a significant breakthrough in the field of cancer treatment and diagnosis. These connecting arms not only cover different lengths of alkyl, alkenyl, alkynyl, and various cycloalkyl, heterocyclyl, aryl and heteroaryl groups, providing rich molecular conformation and high flexibility and stability in vivo, but also introducing diversified functional groups through RL and its variant substituents on them, further optimizing the solubility, metabolic stability and targeting of the compound. In addition, the application of simple connecting arms such as single bond, O, S, CH2, etc. not only reduces the synthesis difficulty and cost, but also maintains the high affinity and selectivity of the compound to FAP. Finally, the pharmaceutical composition formed by combining such targeted FAP compound with a pharmaceutically acceptable carrier not only improves the bioavailability and safety of the compound, but also realizes efficient delivery to tumor tissue and reduces non-target tissue side effects, providing more precise and effective personalized treatment options for cancer patients, significantly improving treatment effect and patient quality of life.

[0091] (4) In the present application, the preparation method of the FAP-targeting compound, which starts from the starting material B-1, first realizes the synthesis of the key intermediate B-2 by using the reaction of thionyl chloride and methanol, lays a solid foundation for the subsequent coupling reaction. Subsequently, B-2 is successfully converted into B-3 through Buchwald coupling reaction, which not only improves the diversity of the product, but also ensures the efficiency and selectivity of the reaction; in the next step, B-3 undergoes hydrolysis reaction under alkaline conditions to generate B-4 with higher reactivity, which provides for the subsequent functional modification. B-4 then undergoes condensation reaction and deprotection process under acidic conditions, and the fine control of these steps ensures the structural integrity and purity of the target compound B-6, which lays a good foundation for the synthesis of the final product; finally, B-6 is successfully converted into the final product B with FAP-targeting activity through two-step substitution reaction or condensation reaction. This preparation method not only shortens the synthesis route and improves the synthesis efficiency of the product, but also reduces the generation of by-products by accurately controlling the reaction conditions, and improves the purity and yield of the product. BRIEF DESCRIPTION OF DRAWINGS

[0092] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, a brief introduction will be given below to the drawings needed to be used in the embodiments or prior art description. Obviously, the drawings described below are only some embodiments described in the present application, and other drawings can also be obtained by those skilled in the art without any creative effort on the basis of these drawings.

[0093] Figure 1 is the MS spectrum of compound 1 of the optional embodiment of the present application;

[0094] Figure 2 is the MS spectrum of compound 2 of the optional embodiment of the present application;

[0095] Figure 3 is the MS spectrum of compound 3 of the optional embodiment of the present application; 18 Radio-HPLC spectrum of F-Al-compound 1;

[0096] Figure 4 is the MS spectrum of compound 4 of the optional embodiment of the present application; 18 Radio-HPLC spectrum of F-Al-compound 2;

[0097] Figure 5 is the MS spectrum of compound 5 of the optional embodiment of the present application; 18 F-Al-compound 1 imaging diagram;

[0098] Figure 6 is the MS spectrum of compound 6 of the optional embodiment of the present application; 18 F-Al-compound 2 imaging diagram;

[0099] Figure 7 is the MS spectrum of compound 7 of the optional embodiment of the present application; 18 F-Al-FAPI-74 imaging diagram. DETAILED DESCRIPTION

[0100] The technical solutions in the embodiments of the present application will be apparently and completely described in combination with the accompanying drawings of the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments of the present application, all the other embodiments obtained by those of ordinary skill in the art without creative work belong to the protection scope of the present application.

[0101] In the following description, a large number of specific details are set forth in order to facilitate a thorough understanding of the present application, however, the present application can also be implemented in other manners different from those described herein, and therefore, the protective scope of the present application is not limited to the specific embodiments disclosed below.

[0102] In the description of the present application, it is understood that the term "heterocyclyl" refers to a 3- to 24-membered partially saturated or fully saturated ring group consisting of 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon and sulfur, including monocyclic, fused ring, bridged ring, spiro ring and combinations thereof. Examples of heterocycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. Examples of heterocycloalkyl groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-morpholinyl, 3-morpholinyl, 1,8-diazo-spiro-[4,5]decyl, 1,7-diazo-spiro-[4,5]decyl, 1,6-diazo-spiro-[4,5]decyl, 2,8-diazo-spiro[4,5]decyl, 2,7-diazo-spiro[4,5]decyl, 2,6-diazo-spiro[4,5]decyl, 1,8-diazo-spiro-[5,4]decyl, 1,7-diazo-spiro-[5,4]decyl, 2,8-diazo-spiro-[5,4]decyl, 2,7-diazo-spiro[5,4]decyl, 3,8-diazo-spiro[5,4]decyl, 3,7-diazo-spiro[5,4]decyl, 1-azo-7,11-dioxa-spiro[5,5]undecyl, 1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

[0103] For those of ordinary skill in the art, the specific meanings of the above-mentioned terms in the present application can be understood through specific circumstances.

[0104] The present application provides a kind of targeting FAP compound, comprising: compound of formula (I), pharmaceutically acceptable salt or stereoisomer thereof;

[0105] Wherein, X 1 For CR X1a R X1b ;

[0106] X 2 For CR X2a R X2b S, O or-S (= O) 2;

[0107] X 3 For CR X3a R X3b ;

[0108] R X1a , R X1b , R X2a , R X2b , R X3a , R X3b , R X4 Respectively independently H, halogen, alkyl, alkenyl, alkynyl, -OR, cycloalkyl or heterocyclyl, and the alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl are optionally substituted by 1, 2 or 3 R x Substituted;

[0109] Or R X1a And R X1b Link together, form cycloalkyl, heterocyclyl or alkylidene, and the cycloalkyl, heterocyclyl or alkylidene are optionally substituted by 1, 2 or 3 R x Substituted;

[0110] Or R X2a And R X2b Link together, form cycloalkyl, heterocyclyl or alkylidene, and the cycloalkyl, heterocyclyl or alkylidene are optionally substituted by 1, 2 or 3 R x Substituted;

[0111] Or R X3a And R X3b Link together, form cycloalkyl, heterocyclyl or alkylidene, and the cycloalkyl, heterocyclyl or alkylidene are optionally substituted by 1, 2 or 3 R x Substituted;

[0112] Or R X1a And R X2a Link together, form cycloalkyl or heterocyclyl, and the cycloalkyl or heterocyclyl are optionally substituted by 1, 2 or 3 R x Substituted;

[0113] Or R X1a And R X3atogether form a cycloalkyl or heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 R x substituted;

[0114] or R X1a together with R X4 together form a cycloalkyl or heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 R x substituted;

[0115] or R X2a together with R X3a together form a cycloalkyl or heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 R x substituted;

[0116] or R X2a together with R X4 together form a cycloalkyl or heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 R x substituted;

[0117] or R X3a together with R X4 together form a cycloalkyl or heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 R x substituted;

[0118] Ring A is heterocyclyl;

[0119] R A , R B are each independently halogen, alkyl, alkenyl, alkynyl, -OR, cycloalkyl or heterocyclyl, which alkyl, alkenyl, alkynyl, -OR, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 OH, CN, halogen or alkyl;

[0120] n, m are each independently 0, 1, 2, 3 or 4;

[0121] R 1 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0122] or one R A together with R 1 forms a cycloalkyl, heterocyclyl, aryl or heteroaryl, which cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1, 2 or 3 R 1a substituted;

[0123] L 1 , L 2 , L 3 , L 4each independently is a single bond, O, S, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1, 2, or 3 R L substituted;

[0124] Z is a radioactive moiety, a chelator, a fluorescent dye, or a contrast agent;

[0125] R is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1, 2, or 3 alkyl, OH, halo, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0126] R 1a , R x , and R L each independently is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1, 2, or 3 alkyl, OH, halo, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0127] p independently is 1, 2, or 3;

[0128] The "alkylidene" is a carbon, hydrogen, oxygen, nitrogen, and heteroatom group with two single bonds connecting carbon atoms of the molecular backbone.

[0129] wherein the compound of Formula (I) has a structure as shown in Formula (I-1) or Formula (I-2):

[0130] wherein ring A is a 3-12 membered heterocyclyl,

[0131] Optionally, ring A is

[0132] Optionally, R A independently is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, which C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 OH, CN, halo, or C 1-6 alkyl;

[0133] Optionally, R Aindependently halogen, methyl, ethyl, fluoromethylene or hydroxymethylene;

[0134] Optionally, n is 0, 1, 2 or 3;

[0135] Optionally, n is 0 or 1;

[0136] Optionally, is # represents a bond to L 1 .

[0137] wherein R X1a , R X1b , R X2a , R X2b , R X3a , R X3b , R X4 are each independently H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl being optionally substituted with 1, 2 or 3 R x ;

[0138] Optionally, R x is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 1, 2 or 3 C 1-6 alkyl, OH, halogen, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;

[0139] Optionally, R X1a and R X1b are each independently selected from H, halogen or C 1-6 alkyl;

[0140] Optionally, X 1 is CH2;

[0141] Optionally, X 2 is CR X2a R X2b , S, O, S(=O) or S(=O)2;

[0142] optionally X 2 is CR X2a R X2b or S;

[0143] optionally X 2 is S;

[0144] optionally X 2 is CR X2a R X2b and R X2a and R X2b are each independently selected from H, halo or C 1-6 alkyl;

[0145] optionally X 2 is CF2;

[0146] optionally R X3a and R X3b are each independently selected from H, halo or C 1-6 alkyl;

[0147] optionally X 3 is CH2or C(CH3)2;

[0148] optionally R X4 is H, halo or C 1-6 alkyl;

[0149] optionally R X4 is H;

[0150] optionally R X1a and R X1b are joined together to form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl or C 2-6 alkylidene, cycloalkyl, heterocyclyl or alkylidene is optionally substituted with 1, 2 or 3 R x ;

[0151] optionally R X2a and R X2b are joined together to form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl or C 2-6 alkylidene, cycloalkyl, heterocyclyl or alkylidene is optionally substituted with 1, 2 or 3 R x ;

[0152] optionally R X3a and R X3b are joined together to form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl or C 2-6 alkylidene, cycloalkyl, heterocyclyl or alkylidene is optionally substituted with 1, 2 or 3 R x ;

[0153] Optional, R X1a With R X2a Connected together, forming C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, optionally surrounded by 1, 2 or 3 R groups. x replace;

[0154] Optional, R X1a With R X3a Connected together, forming C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, optionally surrounded by 1, 2 or 3 R groups. x replace;

[0155] Optional, R X1a With R X4 Connected together, forming C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, optionally surrounded by 1, 2 or 3 R groups. x replace;

[0156] Optional, R X2a With R X3a Connected together, forming C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, optionally surrounded by 1, 2 or 3 R groups. x replace;

[0157] Optional, R X2a With R X4 Connected together, forming C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, optionally surrounded by 1, 2 or 3 R groups. x replace;

[0158] Optional, R X3a With R X4 Connected together, forming C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, optionally surrounded by 1, 2 or 3 R groups. x replace;

[0159] Choose any location for

[0160] Choose any location for

[0161] Among them, R 1 For H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;

[0162] optionally, one R A is connected together to form a C 1 ; 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 C 1a ;

[0163] optionally, R 1a are each independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 C 1-6 alkyl, OH, halogen, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, aryl, or 5-6 membered heteroaryl;

[0164] optionally, m is 0 or 1.

[0165] wherein Z is a radioactive moiety;

[0166] optionally, Z is a fluorescent dye, the fluorescent dye is a xanthene, acridine, oxazine, cyanine, styryl dye, coumarin, porphyrin, metal ligand- complex, fluorescent protein, nanocrystal, perylene, boron dipyrromethene, or phthalocyanine, as well as conjugates and combinations of these classes of dyes;

[0167] optionally, Z is a chelator, the chelator is 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), triethylenetetramine (TETA), iminodiacetic acid, diethylenetriamine-N,N,N',N',N"-pentaacetic acid (DTPA), bis-(carboxymethylimidazole)glycine, or 6-hydrazinopyridine-3-carboxylic acid (HYNIC);

[0168] optionally, Z is a contrast agent comprising a paramagnetic agent;

[0169] optionally, the radioactive moiety comprises 18 F, 51 Cr, 67 Ga, 68 Ga, 111 In, 99m Tc, 186 Re, 188Re, 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 88 Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101 Rh, 119 Sb, 128 Ba, 123 I, 124 I, 131 I, 197 Hg, 211 At, 151 Eu, 153 Eu, 169 Eu, 201 Tl, 203 Pb, 212 Pb, 64 Cu, 67 Cu, 188 Re, 186 Re, 198 Au, 225 Ac, 227 Th and 199 Ag;

[0170] Optionally, Z is selected from one of the following structures:

[0171] wherein L 1 , L 2 , L 3 , L 4 are each independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl, optionally substituted with 1, 2, or 3 RL substituted;

[0172] L 1 , L 2 , L 3 , L 4 are each independently a single bond, O, S, C(R La )(R Lb ), N(R Lc ), C(=O), S(=O), S(=O)2, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally substituted with 1, 2 or 3 R L , R La , R Lb and R Lc are each independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, which alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1, 2 or 3 C 1-6 alkyl, OH, halogen, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;

[0173] L 1 , L 2 , L 3 , L 4 are each independently a single bond, O, S, CH2, CH2CH2, NH, CH=CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl or piperidinyl, which CH2, CH2CH2, NH, CH=CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl or piperidinyl is optionally substituted with 1, 2 or 3 methyl, ethyl, halogen or OH;

[0174] optionally,

[0175] optionally,

[0176] a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is one of the compounds in Table 1;

[0177] ​​The pharmaceutical composition comprises at least one compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

[0178] A FAP-targeting compound, a pharmaceutically acceptable salt or a stereoisomer thereof, the compound being selected from the following (Table 1):

[0179] The present application provides a preparation method of a FAP-targeting compound, comprising the following steps:

[0180] S1: B-1 is synthesized to B-2 by reacting with thionyl chloride and methanol;

[0181] S2: B-2 is synthesized to B-3 by Buchwald coupling reaction;

[0182] S3: B-3 is synthesized to B-4 by hydrolysis under alkaline conditions;

[0183] S4: B-4 is synthesized to B-6 by condensation reaction and deprotection under acidic conditions, respectively;

[0184] S5: B-6 is finally synthesized to the final product B by two-step substitution reaction or condensation reaction.

[0185] The pharmaceutical composition comprises at least one compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

[0186] Use in the preparation of a medicament for the diagnosis or treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in an animal or human subject, wherein the disease characterized by overexpression of FAP is selected from the group consisting of cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and scarring.

[0187] General materials and test methods:

[0188] The synthesis of the compounds of the present application is illustrated in the following schemes, methods and examples. The starting materials are either commercially available or can be prepared according to known procedures in the art or as described herein. The compounds of the present application can be illustrated by the specific examples shown below. However, these specific examples should not be construed as being the only way(s) in which the present application can be practiced. These examples further illustrate the preparation of the compounds of the present application. Those skilled in the art will readily understand that known variations of the conditions and processes can be applied to the preparation of these compounds.

[0189] Preparations of thin layer chromatography (Pre-TLC) were performed on 20 x 20 cm plates (1 mm thick silica gel). Silica gel chromatography was performed using a Biotage flash chromatography system.

[0190] In the LCMS (liquid chromatography-mass spectrometry) test, the liquid chromatography uses Agilent LC1260 model; for the liquid chromatography, the mobile phase is acetonitrile and water and 0.01% formic acid, and the SBC1850 millimeter x 4.6 millimeter x 2.7 micrometer capillary column is used; the mass spectrometry (MS) is determined by electrospray ion mass spectrometry (ESI).

[0191] Specific embodiment 1:

[0192] Preparation of (S)-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl) tert-butyl carbamate (A0-2):

[0193] (S)-4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (500 mg, 2.96 mmol), (tert-butoxycarbonyl)glycine (570 mg, 3.25 mmol), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.35 g, 3.56 mmol), N,N-diisopropyl ethylamine (1.14 g, 8.88 mmol) were dissolved in dichloromethane (10 ml). Stirring at room temperature for 2 hours, TLC shows that the raw material disappears. Pour the reaction solution into water, add dichloromethane (20 ml) to extract, separate the liquid, wash the organic phase with water (20 ml) and then with saturated brine (20 ml), dry the dichloromethane layer with anhydrous sodium sulfate, rotary evaporation, and purify the residue by column chromatography (n-hexane: ethyl acetate) = (10:1) to obtain 680 mg of white solid. MS (ESI) m / z [M+H] + = 290.3;

[0194] Preparation of (S)-4,4-difluoro-1-glycylpyrrolidine-2-carbonitrile (A0):

[0195] (S)-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl) tert-butyl carbamate (600 mg, 2.07 mmol) was dissolved in dichloromethane (10 ml), and trifluoroacetic acid (3 ml) was added. Stirring at room temperature for 5 hours, TLC shows that the raw material disappears. Pour the reaction solution into water, add dichloromethane (10 ml) to extract, separate the liquid, wash the organic phase with dilute ammonia water until it is neutral, dry the dichloromethane layer with anhydrous sodium sulfate, rotary evaporation, and obtain 353 mg of light yellow oil, which is directly used in the next step reaction. MS (ESI) m / z [M+H] + = 190.2;

[0196] Preparation of 6-bromoquinoline-4-carboxylic acid methyl ester (1-1):

[0197] 6-bromoquinoline-4-carboxylic acid (5 g, 19.8 mmol) was dissolved in thionyl chloride (20 ml) and heated to reflux for 2 hours. The reaction was then concentrated and methanol (30 ml) was added and heated to reflux for 5 hours. TLC indicated that the starting material was consumed. The reaction was concentrated and the residue was purified by column chromatography (hexane: ethyl acetate = 5: 1) to give 3.6 g of a brown solid. MS (ESI) m / z [M+H] + = 265.2, 267.1;

[0198] Preparation of methyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinoline-4- carboxylate (1-2):

[0199] Methyl 6-bromoquinoline-4-carboxylate (3 g, 11.3 mmol), tert-butyl piperazine-1- carboxylate (2.5 g, 13.5 mmol), tris(dibenzylideneacetone)dipalladium (1 g, 1.13 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (877 mg, 2.23 mmol), potassium carbonate (4.7 g, 33.9 mmol) were dissolved in 1,4-dioxane (20 ml) and heated to 100 °C for 8 hours under nitrogen. TLC indicated that the starting material was consumed. The reaction was diluted with ethyl acetate (30 ml) and filtered through celite. The filtrate was concentrated and the residue was purified by column chromatography (hexane: ethyl acetate = 1: 1) to give 3.2 g of a yellow solid. MS (ESI) m / z [M+H] + = 372.2;

[0200] Preparation of 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinoline-4-carboxylic acid (1-3):

[0201] Methyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinoline-4-carboxylate (2.5 g, 6.7 mmol) was dissolved in tetrahydrofuran (20 ml) and a solution of lithium hydroxide monohydrate (1.4 g, 33.5 mmol) in water (5 ml) was added. The reaction was stirred at room temperature overnight. TLC indicated that the starting material was consumed. The reaction was adjusted to pH 6 with 1 M hydrochloric acid and extracted with ethyl acetate three times. The ethyl acetate was dried over anhydrous sodium sulfate and concentrated to give 1.9 g of a yellow solid which was used directly in the next reaction. MS (ESI) m / z [M+H] + = 358.2;

[0202] Preparation of (S)-tert-butyl 4-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)piperazine-1-carboxylate (1-4):

[0203] 6-(4-(tert-butoxycarbonyl)piperazin-l-yl)quinoline-4-carboxylic acid (300 mg, 0.84 mmol), (S)-4,4-difluoro-l-glycinylpyrrolidine-2-carbonitrile (190 mg, 1 mmol), 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (479 mg, 1.26 mmol), N,N-diisopropylethylamine (216 mg, 1.68 mmol) were dissolved in dichloromethane (10 ml). Stirring at room temperature for 2 hours, TLC showed that the starting material disappeared, dichloromethane (20 ml) was added, washed with water and then saturated brine, the dichloromethane layer was dried over anhydrous sodium sulfate, rotary evaporation, the residue was purified by Pre-TLC (n-hexane: ethyl acetate) = (2: 1), 383 mg of yellow solid was obtained. MS (ESI) m / z [M+H] = 529.6; + = 529.6;

[0204] Preparation of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-l-yl)-2-oxoethyl)-6-(piperazin-l- yl)quinoline-4-carboxamide (1-5):

[0205] (S)-tert-butyl 4-(4-((2-(2-cyano-4,4-difluoropyrrolidin-l-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)piperazine-l-carboxylate (360 mg, 0.68 mmol) was dissolved in ethyl acetate (10 ml), 3M hydrogen chloride ethyl acetate solution (5 ml) was added, stirring at room temperature for 2 hours, TLC showed that the starting material disappeared, the reaction solution was directly rotary evaporated, 330 mg of yellow solid was obtained, which was directly used in the next step reaction.

[0206] Preparation of (S)-tert-butyl (2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-l-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)piperazin-l-yl)ethyl)carbamate (1-6):

[0207] (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-l-yl)-2-oxoethyl)-6-(piperazin-l-yl)quinoline-4- carboxamide (320 mg, 0.68 mmol), tert-butyl (2-bromoethyl)carbamate (457 mg, 2.04 mmol), potassium carbonate (469 mg, 3.4 mmol) were placed in acetonitrile (10 ml), reacted at 80°C overnight, TLC showed that the starting material disappeared, the reaction solution was filtered and rotary evaporated, the residue was purified by Pre-TLC (dichloromethane:methanol = 30: 1), 310 mg of yellow solid was obtained. MS (ESI) m / z [M+H] = 572.4; + = 572.4;

[0208] Preparation of (S)-6-(4-(2-aminoethyl)piperazin-l-yl)-N-(2-(2-cyano-4,4- difluoropyrrolidin-l-yl)-2-oxoethyl)quinoline-4-carboxamide (1-7):

[0209] (S)-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-l-yl)-2-oxoethyl)carbamoyl)quinolin- 6-yl)piperazin-l-yl)ethyl)carbamic acid tert-butyl ester (280 mg, 0.49 mmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added, stirred at room temperature for 6 hours, LCMS showed the starting material disappeared, main peak was product, the reaction solution was rotary evaporated, purified by preparative chromatography (mobile phase 0.1% TFA water / acetonitrile), after freeze-drying, 165 mg of yellow solid was obtained. MS (ESI) m / z [M+H] + = 472.3;

[0210] Preparation of (S)-2,2'-(7-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-l-yl)-2-oxoethyl) carbamoyl)quinolin-6-yl)piperazin-l-yl)ethyl)amino)-2-oxoethyl)-l,4,7-triazole-l,4- diyl)diacetic acid (1):

[0211] (S)-6-(4-(2-aminoethyl)piperazin-l-yl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-l-yl)-2- oxoethyl)quinoline-4-carboxamide (60 mg, 0.13 mmol) was dissolved in dimethyl sulfoxide (2 ml), 2,2'-(7-(2-(2,5-dioxopyrrolidin-l-yl)oxy)-2-oxoethyl)-l,4,7-triazole-l,4- diyl)diacetic acid (60 mg, 0.15 mmol), triethylamine (40 mg, 0.39 mmol) were added, stirred at room temperature overnight, LCMS showed the starting material disappeared, main peak was product, the reaction solution was purified by preparative chromatography (mobile phase 0.1% TFA water / acetonitrile), after freeze-drying, 16 mg of yellow solid was obtained. MS (ESI) m / z [M+H] + = 757.4. The relevant analysis spectrum is shown in Figure 1.

[0212] Specific Example 2:

[0213] Preparation of (R)-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)carbamic acid tert-butyl ester (A2-2):

[0214] (R)-thiazolidine-4-carbonitrile hydrochloride (500 mg, 3.32 mmol), (tert- butoxycarbonyl)glycine (700 mg, 3.98 mmol), 2-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (1.5 g, 3.98 mmol), N,N-diisopropyl- ethylamine (1.28 g, 9.96 mmol) were dissolved in dichloromethane (10 ml). Stirring at room temperature for 2 hours, TLC showed that the starting material disappeared. The reaction was poured into water, dichloromethane (20 ml) was added to extract, the organic phase was washed with water (20 ml) and then with saturated brine (20 ml), the dichloromethane layer was dried over anhydrous sodium sulfate, rotary evaporation, the residue was purified by column chromatography (n-hexane: ethyl acetate) = (10: 1), 633 mg of white solid was obtained. MS (ESI) m / z [M+H] = 272.2; + = 272.2;

[0215] Preparation of (R)-3-glycinylthiazolidine-4-carbonitrile (A2):

[0216] (R)-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)carbamic acid tert-butyl ester (610 mg, 2.25 mmol) was dissolved in dichloromethane (10 ml), trifluoroacetic acid (3 ml) was added, stirring at room temperature for 5 hours, TLC showed that the starting material disappeared. The reaction was poured into water, dichloromethane (10 ml) was added to extract, the organic phase was washed with dilute ammonia water until neutral, the dichloromethane layer was dried over anhydrous sodium sulfate, rotary evaporation, 332 mg of light yellow oil was obtained, which was directly used in the next step. MS (ESI) m / z [M+H] = 172.1; + = 172.1;

[0217] Preparation of (R)-4-(4-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)piperazine-1-carboxylic acid tert-butyl ester (2-1):

[0218] 6-(4-(tert-butoxycarbonyl)piperazin-l-yl)quinoline-4-carboxylic acid (1-3) (300 mg, 0.84 mmol), (R)-3-glycinylthiazolidine-4-carbonitrile (172 mg, 1 mmol), 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (479 mg, 1.26 mmol), N,N-diisopropyl-ethylamine (216 mg, 1.68 mmol) were dissolved in dichloromethane (10 ml). Stirring at room temperature for 2 hours, TLC showed that the starting material disappeared, dichloromethane (20 ml) was added to wash with water and then with saturated brine, the dichloromethane layer was dried over anhydrous sodium sulfate, rotary evaporation, the residue was purified by Pre-TLC (n-hexane: ethyl acetate) = (2: 1), 340 mg of yellow solid was obtained. MS (ESI) m / z [M+H] = 572.2;+ = 511.3;

[0219] Preparation of (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(piperazin-l- yl)quinoline-4-carboxamide (2-2):

[0220] (R)-4-(4-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)piperazine- 1 -carboxylic acid tert-butyl ester (320 mg, 0.63 mmol) was dissolved in ethyl acetate (10 ml), 3M hydrogen chloride ethyl acetate solution (5 ml) was added, stirred at room temperature for 2 hours, TLC showed the starting material was consumed, the reaction was directly spin dried to get 296 mg of yellow solid, which was used directly for the next step;

[0221] Preparation of (R)-(2-(4-(4-cyanothiazolidin-3-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)piperazin-l-yl)ethyl)carbamic acid tert-butyl ester (2-3):

[0222] (R)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)-6-(piperazin-l-yl)quinoline-4- carboxamide (280 mg, 0.63 mmol), (2-bromoethyl)carbamic acid tert-butyl ester (423 mg, 1.89 mmol), potassium carbonate (435 mg, 3.15 mmol) were dissolved in acetonitrile (10 ml), reacted at 80 °C overnight, TLC showed the starting material was consumed, the reaction was filtered and spin dried, the residue was purified by Pre-TLC (dichloromethane: methanol = 30: 1) to get 263 mg of yellow solid. MS (ESI) m / z [M+H] + = 554.3;

[0223] Preparation of (R)-6-(4-(2-aminoethyl)piperazin-l-yl)-N-(2-(4-cyanothiazolidin-3-yl)- 2-oxoethyl)quinoline-4-carboxamide (2-4):

[0224] (R)-(2-(4-(4-cyanothiazolidin-3-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)piperazin-l- yl)ethyl)carbamic acid tert-butyl ester (240 mg, 0.43 mmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added, stirred at room temperature for 8 hours, LCMS showed the starting material was consumed, the main peak was the product, the reaction was spin dried and purified by preparative chromatography (mobile phase 0.1% TFA water / acetonitrile), after lyophilization, 133 mg of yellow solid was obtained. MS (ESI) m / z [M+H] + = 454.3;

[0225] (R)-2,2'-(7-(2-(4-(4-(2-(-4-cyanothiazolidin-3-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)piperazin-1-yl)ethyl)amino)-2-oxoethyl)-1,4,7-triazole-1,4-diyl)diacetic acid (2):

[0226] (R)-6-(4-(2-aminoethyl)piperazin-1-yl)-N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)quinoline-4-carboxamide (60 mg, 0.13 mmol) was dissolved in dimethyl sulfoxide (2 ml), 2,2'-(7-(2-(2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7-triazole-1,4-diyl)diacetic acid (60 mg, 0.15 mmol), triethylamine (40 mg, 0.39 mmol) were added, stirred at room temperature overnight, LCMS showed the disappearance of the starting material, the main peak was the product, the reaction solution was purified by preparative chromatography (mobile phase 0.1% TFA water / acetonitrile), and 19 mg of yellow solid was obtained after freeze-drying. MS (ESI) m / z [M+H] + = 739.3; the correlation analysis spectrum is shown in Figure 2.

[0227] Specific embodiment 3:

[0228] 18 Preparation of F-Al-compound 1:

[0229] 50 μL of 1 M sodium acetate buffer (pH = 4) and 10 μL of 10 mM aluminum chloride solution (dissolved in 1 M sodium acetate buffer (pH = 4)) were added to the reaction bottle; the proton cyclotron was bombarded to obtain 18 F radionuclide, enriched by QMA column, eluted with 0.5 mL of sodium chloride injection, compound 1 was dissolved in sterilized water for injection to prepare a precursor solution of 1 mg / mL, and 100 μL was added to the reaction bottle; 600 μL of acetonitrile was added to the reaction bottle, which was sealed and heated to 100°C, reacted for 10 min, cooled to room temperature, diluted with 10 mL of sterilized water for injection, passed through a tC18 column, washed twice with 10 mL of sterilized water for injection, and then blown dry. The tC18 column was washed with 1 mL of ethanol, and diluted with 10 mL of sodium chloride injection to obtain 18 F-Al-compound 1. Its radiochemical purity was determined by Radio-HPLC. The correlation analysis spectrum is shown in Figure 3. The specific reaction route is as follows:

[0230] Specific embodiment 4:

[0231] 18 Preparation of F-Al-compound 2:

[0232] Into the reaction bottle, 50 μL of 1M pH=4 sodium acetate buffer, 10 μL of 10 mM aluminum chloride solution (1M pH=4 sodium acetate buffer dissolved) were added; proton cyclotron bombardment was carried out to obtain 18 F isotope, enriched by QMA column, eluted into the reaction bottle with 0.5 mL of sodium chloride injection, compound 2 was dissolved with sterile water for injection to prepare a precursor solution of 1 mg / mL, 100 μL of which was added into the reaction bottle; 600 μL of acetonitrile was added into the reaction bottle, the reaction bottle was sealed, heated to 100°C, reacted for 10 min, cooled to room temperature, diluted with 10 mL of sterile water for injection, passed through a tC18 column, washed twice with 10 mL of sterile water for injection, and dried the tC18 column, eluted the tC18 column with 1 mL of ethanol, and diluted with 10 mL of sodium chloride injection to obtain 18 F-Al-compound 2. Its radiochemical purity was determined by Radio-HPLC. The relevant analysis spectrum is shown in FIG. 4. The specific reaction route is as follows:

[0233] PET imaging study:

[0234] SPF level Balb / c nude mice, female, 6 weeks old, the animal model is HT1080 human fibrosarcoma cells, which are provided by Beijing Vital River Laboratory Animal Technology Co., Ltd., and are used for imaging experiments when the solid tumor mass grows to a suitable volume.

[0235] 100 μCi / 0.2 mL of 18 F-Al-compound 1, 18 F-Al-compound 2, 18 F-Al-FAPI-74 were injected through the tail vein respectively, and 1h dynamic imaging experiment was carried out immediately after injection, and the imaging results are shown in FIG. 5, FIG. 6 and FIG. 7. The results show that the FAP-positive HT1080 tumor has a higher uptake of the three labeled compounds.

[0236] Further quantitative results show that the tumor uptake 18 The ID % / g value of F-Al-compound 1 is 27.33±10.27, the tumor uptake 18 The ID % / g value of F-Al-compound 2 is 17.28±5.27, the tumor uptake 18 The ID % / g value of F-Al-FAPI-74 is 23.44±9.00.

[0237] Liver uptake 18 The ID % / g value of F-Al-compound 1 is 7.80±5.15, the liver uptake 18 The ID % / g value of F-Al-compound 2 is 7.38±3.22, the liver uptake 18 The ID % / g value of F-Al-FAPI-74 is 8.13±5.96.

[0238] kidney uptake 18 The ID % / g value of F-Al-Compound 1 was 22.70 ± 20.14, kidney uptake 18 The ID % / g value of F-Al-Compound 2 was 33.13 ± 14.00, kidney uptake 18 The ID % / g value of F-Al-FAPI-74 was 67.78 ± 23.42.

[0239] muscle uptake 18 The ID % / g value of F-Al-Compound 1 was 2.79 ± 0.80, muscle uptake 18 The ID % / g value of F-Al-Compound 2 was 2.90 ± 0.94, muscle uptake 18 The ID % / g value of F-Al-FAPI-74 was 3.42 ± 0.78.

[0240] bone uptake 18 The ID % / g value of F-Al-Compound 1 was 4.11 ± 0.81, bone uptake 18 The ID % / g value of F-Al-Compound 2 was 3.09 ± 1.04, bone uptake 18 The ID % / g value of F-Al-FAPI-74 was 6.30 ± 1.18.

[0241] It can be seen from the experiment that, using the fibrosarcoma tumor-bearing mouse model with high expression of FAP for imaging, the compounds of the present application all showed targeted uptake values on the tumor, and showed lower liver uptake and kidney uptake than FAPI-74.

[0242] The above is based on the ideal embodiment of the present application, through the above description, relevant personnel can make various changes and modifications without deviating from the technical idea of the present application. The technical scope of the present application is not limited to the contents of the specification, and the technical scope must be determined according to the scope of claims.

Claims

1. A compound targeting FAP, characterized in that, comprises: a compound of Formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof; wherein X 1 is CR X1a R X1b ; X 2 CR X2a R X2b S, O or -S(=O)2; X 3 is CR X3a R X3b ; R X1a , R X1b , R X2a , R X2b , R X3a , R X3b , R X4 are each independently H, halogen, alkyl, alkenyl, alkynyl, -OR, cycloalkyl or heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl optionally substituted with 1, 2 or 3 R x ; or R X1a with R X1b together to form a cycloalkyl, heterocyclyl or alkylidene group, the cycloalkyl, heterocyclyl or alkylidene group being optionally substituted by 1, 2 or 3 R x groups; or R X2a and R X2b are connected together to form a cycloalkyl, heterocyclyl or alkylidene group, the cycloalkyl, heterocyclyl or alkylidene group being optionally substituted by 1, 2 or 3 R x groups; or R X3a with R X3b together to form a cycloalkyl, heterocyclyl or alkylidene group, the cycloalkyl, heterocyclyl or alkylidene group being optionally substituted by 1, 2 or 3 R x groups; or R X1a with R X2a together to form a cycloalkyl or heterocyclyl group, which cycloalkyl or heterocyclyl group is optionally substituted with 1, 2 or 3 R x groups; or R X1a with R X3a together to form a cycloalkyl or heterocyclyl group, which cycloalkyl or heterocyclyl group is optionally substituted with 1, 2 or 3 R x groups; or R X1a with R X4 together to form a cycloalkyl or heterocyclyl group, which cycloalkyl or heterocyclyl group is optionally substituted with 1, 2 or 3 R x groups; or R X2a with R X3a together to form a cycloalkyl or heterocyclyl group, which cycloalkyl or heterocyclyl group is optionally substituted with 1, 2 or 3 R x groups; or R X2a with R X4 together to form a cycloalkyl or heterocyclyl group, which cycloalkyl or heterocyclyl group is optionally substituted with 1, 2 or 3 R x groups; or R X3a and R X4 are linked together to form a cycloalkyl or heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 R x groups; ring A is a heterocyclic group; R A , R B are each independently halogen, alkyl, alkenyl, alkynyl, -OR, cycloalkyl or heterocyclyl, said alkyl, alkenyl, alkynyl, -OR, cycloalkyl or heterocyclyl being optionally substituted with 1, 2 or 3 OH, CN, halogen or alkyl; n, m are independently 0, 1, 2, 3 or 4; R 1 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or one R A is connected together to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by 1, 2 or 3 R 1 substituents; and wherein each R 1a is independently selected from halo, cyano, nitro, hydroxy, mercapto, oxo, carboxy, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, heter L 1 , L 2 , L 3 , L 4 are each independently a single bond, O, S, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with 1, 2, or 3 R L . Z is a radioactive moiety, a chelator, a fluorescent dye or a contrast agent; R is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl being optionally substituted by 1, 2 or 3 alkyl, OH, halogen, cycloalkyl, heterocyclic group, aryl or heteroaryl; R 1a , R x , and R L are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with 1, 2, or 3 alkyl, OH, halo, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p is independently 1, 2 or 3; said "alkylidene" is a carbon, hydrogen, oxygen, nitrogen and heteroatom to link two carbon atoms of the molecular skeleton with two single bonds.

2. The targeted FAP compound according to claim 1, characterized in that: wherein, The compound of formula (I) has a structure as shown in formula (I-1) or formula (I-2):

3. The compound of any one of claims 1 or 2, wherein: wherein, ring A is a 3-12 membered heterocyclic group, Optionally, ring A is Optional, R A Independent of halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -OR, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -OR, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally surrounded by 1, 2 or 3 OH, CN, halogen or C groups. 1-6 Alkyl substitution; Optionally, R A independently halogen, methyl, ethyl, fluoromethyl, or hydroxymethyl; optionally, n is 0, 1, 2 or 3; optionally, n is 0 or 1; Optionally, For # end represents a bond to L 1 connected.

4. A compound targeted to FAP according to any one of claims 1-3, wherein R X1a , R X1b , R X2a , R X2b , R X3a , R X3b , R X4 are each independently H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl optionally substituted with 1, 2 or 3 R x ; R is independently H, C x independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 1, 2 or 3 C 1-6 alkyl, OH, halo, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; Optionally, R X1a and R X1b are each independently selected from H, halogen or C 1-6 alkyl; Optionally, X 1 is CH2; Optionally, X 2 is CR X2a R X2b S, O, S(=O) or S(=O)2; Optionally, X 2 is CR X2a R X2b or S; Optionally, X 2 is S; Optionally, X 2 is CR X2a R X2b and R X2a and R X2b are each independently selected from H, halogen or C 1-6 alkyl; Optionally, X 2 is CF2; Optionally, R X3a and R X3b are each independently selected from H, halogen or C 1-6 alkyl; Optionally, X 3 is CH2or C(CH3)2; Optionally, R X4 is H, halogen or C 1-6 alkyl; Optionally, R X4 is H; R X1a R X1b together with the carbon to which they are attached, form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl or C 2-6 alkyl, cycloalkyl, heterocyclyl or alkylidene is optionally substituted with 1, 2 or 3 R x substituents; R X2a R X2b together with the carbon to which they are attached, form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl or C 2-6 alkyl, cycloalkyl, heterocyclyl or alkylidene is optionally substituted with 1, 2 or 3 R x substituents; R X3a R X3b together with the carbon to which they are attached, form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl or C 2-6 alkyl, cycloalkyl, heterocyclyl or alkylidene is optionally substituted with 1, 2 or 3 R x substituents; Optional, R X1a With R X2a Connected together, forming C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, optionally surrounded by 1, 2 or 3 R groups. x replace; Optional, R X1a With R X3a Connected together, forming C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, optionally surrounded by 1, 2 or 3 R groups. x replace; R X1a and R X4 are linked together to form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 R x substituents; Optionally, R X2a are linked together to form a C X3a ring; and R 3-6 cycloalkyl or 3-6 membered heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2, or 3 R x substituents; Optional, R X2a With R X4 Connected together, forming C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, optionally surrounded by 1, 2 or 3 R groups. x replace; Optionally, R X3a with R X4 together, forming C 3-6 cycloalkyl or 3-6 membered heterocyclyl, which cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 R x substituents; Optionally, For Optionally, For 5. A compound targeting FAP according to any one of claims 1 to 4, characterized in that: wherein, R 1 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; optionally, one of R A is connected together to form a C 1 ring; and R 3-6 is a 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally substituted with 1, 2 or 3 R 1a substituents; R is independently H, C 1a R is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl or heteroaryl being optionally substituted with 1, 2 or 3 C 1-6 alkyl, OH, halo, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, aryl or 5-6 membered heteroaryl; optionally, m is 0 or 1.

6. A compound targeted to FAP according to any one of claims 1-5, characterized in that: wherein, Z is a radioactive moiety; optionally, Z is a fluorescent dye, said fluorescent dye being a xanthine, acridine, oxazine, cyanine, styryl dye, coumarin, porphyrin, metal ligand-complex, fluorescent protein, nanocrystal, perylene, boron dipyrromethene or phthalocyanine, as well as conjugates and combinations of these classes of dyes; optionally, Z is a chelator, the chelator being 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), triethylenetetramine (TETA), iminodiacetic acid, diethylenetriamine-N,N,N',N',N"-pentaacetic acid (DTPA), bis-(carboxymethylimidazole)glycine or 6-hydrazinopyridine-3-carboxylic acid (HYNIC); optionally, Z is a contrast agent comprising a paramagnetic agent; Optionally, the radioactive moiety comprises 18 F, 51 Cr, 67 Ga, 68 Ga, 111 In, 99m Tc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 88 Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101 Rh, 119 Sb, 128 Ba, 123 I, 124 I, 131 I, 197 Hg, 211 At, 151 Eu, 153 Eu, 169 Eu, 201 Tl, 203 Pb, 212 Pb, 64 Cu, 67 Cu, 188 Re, 186 Re, 198 Au, 225 Ac, 227 Th and 199 Ag; Optionally, Z is selected from one of the following structures:

7. A compound targeting FAP according to any one of claims 1 to 6, characterized in that, wherein, L 1 , L 2 , L 3 , L 4 are each independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with 1, 2, or 3 R L ; L 1 , L 2 , L 3 , L 4 are each independently a single bond, O, S, C(R La )(R Lb ), N(R Lc ), C(=O), S(=O), S(=O)2, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, which cycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 R L , R La , R Lb , and R Lc are each independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl, which alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1, 2, or 3 C 1-6 alkyl, OH, halogen, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl; optionally, L 1 , L 2 , L 3 , L 4 are each independently a single bond, O, S, CH2, CH2CH2, NH, CH=CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl or piperidinyl, said CH2, CH2CH2, NH, CH=CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl or piperidinyl being optionally substituted with 1, 2 or 3 methyl, ethyl, halogen or OH; Optionally, For Optionally, For 8. The compound of claim 1, wherein: a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is one of the compounds in Table 1.

9. A method of preparing a compound targeted to FAP according to any one of claims 1-8, characterized in that, comprises the following steps: S1: B-1 is synthesized to B-2 by reacting with thionyl chloride and methanol; S2: B-2 is synthesized to B-3 by Buchwald coupling reaction; S3: B-3 is synthesized to B-4 by hydrolysis under alkaline conditions; S4: B-4 is synthesized to B-6 by condensation reaction and deprotection under acidic conditions, respectively; S5: B-6 is finally obtained to the final product B by two-step substitution reaction or condensation reaction.

10. A pharmaceutical composition according to claims 1-8, characterized in that: wherein, the pharmaceutical composition comprises at least one compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

11. The compound of any one of claims 1 to 10 or the pharmaceutical composition of claim 9, wherein: for use in the manufacture of a medicament for the diagnosis or treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in an animal or human subject, wherein the disease characterized by overexpression of FAP is selected from the group consisting of cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and scarring. for use in the manufacture of a medicament for the diagnosis or treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in an animal or human subject, wherein the disease characterized by overexpression of FAP is selected from the group consisting of cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and scarring.

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