Ligands that target fibroblast-activating proteins

Abstract

This disclosure relates to ligands targeting fibroblast-activating proteins, and more particularly to ligands targeting fibroblast-activating proteins represented by formula (I) and their radiolabeling, wherein the definitions of each substituent are as set forth in the specification, and the ligands can be used to image diseases or disorders related to fibroblast-activating proteins or to treat diseases or disorders related to fibroblast-activating proteins. JPEG2026515806000101.jpg1982

Description

[Technical Field]

[0001] This disclosure relates to ligands targeting fibroblast-activating proteins, their radiolabeling, and pharmaceutical applications. [Background technology]

[0002] Fibroblast-activating protein (FAP) is a membrane-bound gelatinase that can promote tumor growth and progression and is overexpressed in cancer-associated fibroblasts. Due to its low expression in normal organs, FAP represents an ideal target for the development of small molecule drug conjugates (SMDCs) and small molecule radioactive conjugates (SMRCs).

[0003] Research on fibroblast-activating protein (FAP) inhibitors includes WO2019154886A, WO2019154859A, WO2019118932A, WO2019083990A, WO2013107820A, WO2018111989A, WO2023 / 057457A, and others. However, the development of effective FAP conjugates with excellent targeting properties, as well as targeted small molecule drug conjugates and small molecule radioactive conjugates based thereon, remains a challenge. It is particularly desirable that small molecule radioactive conjugates exhibit favorable in vivo distribution to tumors and organs, high activity labeling, and / or good compound stability. [Overview of the project]

[0004] This disclosure relates to ligands for fibroblast-activating proteins (FAPs) for actively delivering radioactive payloads to disease sites.

[0005] This disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, [ka] Here, R 1 and R 1’ is independently selected from hydrogen, a cyano group, a carboxyl group, a sulfonic acid group, a phosphoric acid group or B(OH)2, R 2 is independently selected from a hydroxy group, a halogen, C 1-6 alkyl group, halo C 1-6 alkyl group, -NR’R’’, -O-C 1-6 alkyl group or -S-C 1-6 alkyl group, R 3 and R 3 ’ are independently selected from hydrogen, a hydroxy group, a halogen or C 1-6 alkyl group, R 4 is selected from a hydroxy group, a halogen, C 1-6 alkyl group, halo C 1-6 alkyl group, -NR’R’’, -O-C 1-6 alkyl group or -S-C 1-6 alkyl group, Ring A is selected from a 3- to 12-membered cycloalkylene group or a 3- to 12-membered heterocycloalkylene group, R 5 is selected from a halogen, a hydroxy group, C 1-6 alkyl group, halo C 1-6 alkyl group, -NR’R’’ or -O-C 1-6 alkyl group, L1 is selected from a bond, -NH-, -CH2-NH- or -CH₂CH₂-NH-, x is selected from 0, 1, 2 or 3, R’ and R’’ are independently selected from hydrogen, C 1-6 alkyl group or halo C 1-6 alkyl group, y is selected from 1 or 2, z is selected from 0, 1, 2 or 3, u is selected from 0, 1 or 2, and B is selected from any optical or radioactive labeling functional group suitable for optical imaging, positron emission tomography imaging, single photon emission computed tomography imaging or radiation therapy.

[0006] In an optional embodiment, B comprises a chelating agent and a radioactive element.

[0007] In an optional embodiment, ring A is selected from 4- to 7-membered cycloalkylene groups, such as cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene groups.

[0008] In an optional embodiment, ring A is a cyclohexylene group.

[0009] In an optional embodiment, the R 1 and R 1 Each of these is independently selected from either a hydrogen or a cyano group.

[0010] In an optional embodiment, the R 2 Each of these independently comprises a hydroxyl group, a halogen, or C 1-6 Selected from alkyl groups, x is selected from 2 or 3.

[0011] In an optional embodiment, the R 2 Each of these is independently selected from fluorine or chlorine, and x is selected from 2 or 3.

[0012] In an optional embodiment, the R 3 and R 3 ' are, independently, hydrogen, halogen, or C 1-6 Selected from alkyl groups.

[0013] In an optional embodiment, the R 3 and R 3 ' is hydrogen in all cases.

[0014] In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to this disclosure is the compound represented by formula (II-1) or a pharmaceutically acceptable salt thereof. [ka] Here, X1 and X2 are independently selected from CH or N. s and t are each independently selected from 0, 1, or 2, and R 4 , R 5 L1, B, z, and u are defined in equation (I).

[0015] In an optional embodiment, X1 is CH and X2 is N.

[0016] In an optional embodiment, X1 is N and X2 is CH.

[0017] In an optional embodiment, X1 is CH and X2 is CH.

[0018] In an optional embodiment, s and t are each independently selected from 0 or 1.

[0019] In an optional embodiment, both s and t are 1.

[0020] In an optional embodiment, L1 is selected from bonded or -NH-.

[0021] In an optional embodiment, L1 is selected from CH2-NH- or -CH2CH2-NH-.

[0022] In an optional embodiment, L1 is CH2-NH-.

[0023] In an optional embodiment, L1 is -CH2CH2-NH-.

[0024] In an optional embodiment, X1 is CH, X2 is CH, s and t are both 1, and L1 is selected from CH2-NH- or -CH2CH2-NH-.

[0025] In an optional embodiment, X1 is CH, X2 is CH, s and t are both 1, and L1 is -CH2-NH-.

[0026] In an optional embodiment, the R 4 is a hydroxyl group, halogen or C 1-6 The alkyl group is selected from alkyl groups, and the z is selected from 0, 1, 2, or 3.

[0027] In an optional embodiment, the R 4 z is selected from fluorine, chlorine, a methyl group, or an ethyl group, and z is selected from 0 or 1.

[0028] In an optional embodiment, the R 5 is a hydroxyl group, halogen or C 1-6 Selected from alkyl groups, the above u is selected from 0, 1, or 2.

[0029] In an optional embodiment, the R 5 is selected from fluorine, chlorine, a methyl group, or an ethyl group, and the value of u is selected from 0 or 1.

[0030] In an optional embodiment, the R 4 and R 5 Each of these is independently selected from fluorine, chlorine, a methyl group, or an ethyl group, and each of z and u is independently selected from 0 or 1.

[0031] In an optional embodiment, the compound shown in formula (I) or a pharmaceutically acceptable salt thereof is the compound shown in formula (II-2) or a pharmaceutically acceptable salt thereof. [ka] Here, X3 and X4 are independently selected from CH, N, or O. s and t are each independently selected from 0, 1, or 2. w and v are independently selected from 0, 1, or 2, and R 4 , R 5 L1, B, z, and u are defined in equation (I).

[0032] In an optional embodiment, X3 is CH and X4 is O.

[0033] In an optional embodiment, X3 is CH and X4 is N.

[0034] In an optional embodiment, X3 is N and X4 is CH.

[0035] In an optional embodiment, s and t are each independently selected from 0 or 1, and w and v are each independently selected from 0 or 1.

[0036] In an optional embodiment, s and t are both 1, and w and v are both 1.

[0037] In an optional embodiment, L1 is a coupling.

[0038] In an optional embodiment, L1 is NH-.

[0039] In an optional embodiment, L1 is selected from CH2-NH- or -CH2CH2-NH-.

[0040] In an optional embodiment, L1 is CH2-NH-.

[0041] In an optional embodiment, L1 is -CH2CH2-NH-.

[0042] In an optional embodiment, X3 is CH, X4 is O, s and t are both 1, w and v are both 1, and L1 is a bond.

[0043] In an optional embodiment, the R 4 is a hydroxyl group, halogen or C 1-6 The alkyl group is selected from alkyl groups, and the z is selected from 0, 1, 2, or 3.

[0044] In an optional embodiment, the R 4 z is selected from fluorine, chlorine, a methyl group, or an ethyl group, and z is selected from 0 or 1.

[0045] In an optional embodiment, the R 5 is a hydroxyl group, halogen or C 1-6 Selected from alkyl groups, the above u is selected from 0, 1, or 2.

[0046] In an optional embodiment, the R 5 is selected from fluorine, chlorine, a methyl group, or an ethyl group, and the value of u is selected from 0 or 1.

[0047] In an optional embodiment, the R 4 and R 5 Each of these is independently selected from fluorine, chlorine, a methyl group, or an ethyl group, and each of z and u is independently selected from 0 or 1.

[0048] In an optional embodiment, the chelating agent in B is [ka] Selected from.

[0049] In an optional embodiment, the chelating agent in B is [ka] That is the case.

[0050] In an optional embodiment, the chelating agent in B is [ka] That is the case.

[0051] In an optional embodiment, the radioactive element in B is, 223 Ra, 89 Sr, 94m Tc, 99m Tc, 186 Re, 188 Re, 203 Pb, 212 Pb, 67 Ga, 68 Ga, 47 Sc, 111 In, 97 Ru, 62 Cu, 64 Cu, 86 Y, 88 Y, 90 Y, 121 Sn, 161 Tb, 153 Sm, 166 Ho, 105 Rh, 177 Lu, 123 I, 124 I, 125 I, 18 F, 211 At, 225 Ac, 89 Sr, 117m Sn or 169 Selected from Er.

[0052] In an optional embodiment, the radioactive element in B is, 64 It is Cu.

[0053] In an optional embodiment, the radioactive element in B is, 68 It is Ga.

[0054] In an optional embodiment, the radioactive element in B is, 18 It is F.

[0055] In an optional embodiment, the radioactive element in B is 43 Sc, 44 Sc, 51 Mn, 52 Mn, 152 Tb, 155 Tb, 201 TI, 76 Br, 77 Br, 89 Zr, 47 Sc, 67 Cu, 149 Tb, 213 Bi, 226 Th, 227 Th or 131 selected from I.

[0056] In an optional embodiment, the present disclosure

Chemical formula

[0057] In an optional embodiment, the present disclosure

Chemical formula

[0058] In an optional embodiment, the present disclosure

Chemical formula

Chemical formula

[0059] In an optional embodiment, the present disclosure

Chemical formula

[0060] In optional embodiments, this disclosure is: [ka] This provides a compound or a pharmaceutically acceptable salt thereof, the structural formula of which is: [ka] That's fine.

[0061] In optional embodiments, this disclosure is: [ka] This provides a compound or a pharmaceutically acceptable salt thereof, the structural formula of which is: [ka] That's fine.

[0062] In optional embodiments, this disclosure is: [ka] This provides a compound or a pharmaceutically acceptable salt thereof, the structural formula of which is: [ka] That's fine.

[0063] In optional embodiments, this disclosure is: [ka] This provides a compound or a pharmaceutically acceptable salt thereof, the structural formula of which is: [ka] That's fine.

[0064] In optional embodiments, this disclosure is: [ka] The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0065] In optional embodiments, this disclosure is: [ka] The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0066] In optional embodiments, this disclosure is: [ka] The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0067] In optional embodiments, this disclosure is: [ka] The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0068] This disclosure further provides pharmaceutical compositions comprising the aforementioned compounds or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents, and excipients.

[0069] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0070] In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01 to 99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic variant. In some embodiments, the pharmaceutical composition contains 0.1 to 99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic variant. In some embodiments, the pharmaceutical composition contains 0.5 to 99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic variant. In some embodiments, the pharmaceutical composition contains 1 to 99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic variant. In some embodiments, the pharmaceutical composition contains 2 to 98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic variant.

[0071] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% of pharmaceutically acceptable excipients.

[0072] Another aspect of the present disclosure discloses a method for producing the aforementioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions, comprising the step of complexing the compounds represented by formula (I), formula (II-1), formula (II-2), or pharmaceutically acceptable salts thereof with a radioactive element.

[0073] This disclosure further discloses a method for imaging diseases or disorders related to fibroblast-activating proteins, which comprises: 1) administering to a patient the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition; and 2) acquiring an image.

[0074] This disclosure further discloses a method for inhibiting fibroblast-activating proteins, which comprises administering to a patient the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

[0075] This disclosure further discloses a method for diagnosing or treating a disease or disorder related to fibroblast-activating proteins, which includes administering to a patient the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

[0076] In an optional embodiment, a method for imaging a disease or disorder related to fibroblast-activating protein, a method for suppressing a disease or disorder related to fibroblast-activating protein, or a method for treating a disease or disorder related to fibroblast-activating protein, according to the Disclosure, involves administering to a patient an effective amount of a compound shown in formula (I), formula (II-1), formula (II-2) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0077] This disclosure further discloses uses of the aforementioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions, in the manufacture of drugs for imaging or treating diseases or disorders related to fibroblast-activating proteins.

[0078] This disclosure further relates to compounds represented by formula (I), formula (II-1), formula (II-2), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing thereof, which are used as drugs.

[0079] This disclosure further relates to compounds represented by formula (I), formula (II-1), formula (II-2), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, for imaging diseases or disorders related to fibroblast-activating proteins.

[0080] This disclosure further relates to compounds represented by formula (I), formula (II-1), formula (II-2), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, for the purpose of inhibiting fibroblast-activating proteins.

[0081] This disclosure further relates to compounds represented by formula (I), formula (II-1), formula (II-2), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, for the diagnosis or treatment of diseases or disorders related to fibroblast-activating proteins.

[0082] In this disclosure, the disease or disorder related to fibroblast-activating proteins is selected from proliferative disorders, chronic inflammation, fibrosis (liver, kidney, lung), tissue remodeling, scarring, tissue infection, or inflammatory lesions.

[0083] This disclosure further discloses the uses of the aforementioned compounds or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the manufacture of drugs for the prevention, diagnosis, or treatment of proliferative disorders, chronic inflammation, fibrosis (liver, kidney, lung), tissue remodeling, scarring, tissue infection, or inflammatory lesions.

[0084] The proliferative diseases in this disclosure are selected from the group consisting of breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, lung adenocarcinoma, kidney cancer, liver cancer, lung cancer, esophageal cancer, hepatobiliary tract cancer, gastric cancer, nasopharyngeal cancer, head and neck cancer, bladder cancer, glioblastoma, peritoneal metastasis cancer, melanoma, fibrosarcoma, bone and connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma and adenocarcinoma, and benign tumors.

[0085] The chronic inflammation in this disclosure is selected from rheumatoid arthritis, osteoarthritis, Crohn's disease, and atherosclerotic plaque.

[0086] The tissue remodeling described herein is performed after myocardial infarction. The scar disease described herein is selected from scar formation, scar tumor, or keloid.

[0087] The following is a method for producing compound 7, [ka] Compound 2 is subjected to acidic conditions (e.g., acetic acid / sodium acetate buffer), 18 F - The method also includes the step of reacting AlCl3 under high temperature conditions (e.g., 75-100°C). [ka]

[0088] The following is a method for producing compound 5, [ka] Compound 2 is subjected to acidic conditions (e.g., acetic acid / sodium acetate buffer), 68 The process includes the step of reacting GaCl3 under high temperature conditions (e.g., 75-100°C).

[0089] The method for producing the compound 9 shown below, [ka] Compound 2 is subjected to acidic conditions (e.g., acetic acid / sodium acetate buffer), 64 The process includes the step of reacting CuCl2 with high temperature conditions (e.g., 75-100°C).

[0090] A method for producing compound 2, comprising the step of removing the tert-butyl protecting group from compound 2-a under acidic conditions (e.g., trifluoroformic acid). [ka]

[0091] In an optional embodiment, the method for producing compounds 5, 7, and 9 described above includes the step of removing the tert-butyl protecting group from compound 2-a under acidic conditions (e.g., trifluoroformic acid) to obtain compound 2. [ka]

[0092] In an optional embodiment, the method for producing compounds 5, 7, and 9 or compound 2 includes the step of reacting compound 1-b with NOTA-di-tert-butyl ester (NOTA-bis(t-Bu ester)) under the catalytic action of a polypeptide condensation reagent (for example, an onium salt type condensation reagent, specifically HATU may be selected) to obtain compound 2-a. [ka]

[0093] In an optional embodiment, the method for producing compounds 5, 7, and 9 or compound 2 includes the step of removing the tert-butoxycarbonyl protecting group from compound 1-c under acidic (e.g., hydrochloric acid) or basic conditions to obtain compound 1-b. [ka]

[0094] In an optional embodiment, the method for producing compounds 5, 7, and 9 or compound 2 includes the step of reacting compounds 1-f and 1-d under the action of a condensing agent (e.g., a tricyclic anhydride of 1-propylphosphonic acid) to obtain compound 1-c. [ka]

[0095] In an optional embodiment, the method for producing compounds 5, 7, and 9 or compound 2 includes the step of removing a methyl protecting group from compound 1-g under basic conditions (e.g., lithium hydroxide) to obtain compound 1-f. [ka]

[0096] A method for producing compound 8 shown below, [ka] Compound 1 is subjected to acidic conditions (e.g., acetic acid / sodium acetate buffer), 64 The process includes the step of reacting CuCl2 with high temperature conditions (e.g., 75-100°C). [ka]

[0097] A method for producing compound 1, comprising the step of removing the tert-butyl protecting group from compound 1-a under acidic conditions (e.g., trifluoroformic acid). [ka]

[0098] In an optional embodiment, the method for producing compound 8 or compound 1 described above includes the step of reacting compound 1-b with compound DOTA-tri-tert-butyl ester (DOTA-tris(t-Bu ester)) under the catalytic action of a polypeptide condensation reagent (for example, an onium salt type condensation reagent, specifically HATU may be selected) to obtain compound 1-a. [ka]

[0099] In an optional embodiment, the method for producing compound 8 or compound 1 described above includes the step of removing the tert-butoxycarbonyl protecting group from compound 1-c under acidic (e.g., hydrochloric acid) or basic conditions to obtain compound 1-b. [ka]

[0100] In an optional embodiment, the method for producing compound 8 or compound 1 includes the step of reacting compounds 1-f and 1-d under the action of a condensing agent (e.g., tricyclic anhydride of 1-propylphosphonic acid) to obtain compound 1-c. [ka]

[0101] In an optional embodiment, the method for producing compound 8 or compound 1 described above includes the step of removing a methyl protecting group from compound 1-g under basic conditions (e.g., lithium hydroxide) to obtain compound 1-f. [ka]

[0102] This disclosure will be furthered, [ka] The following compounds are provided.

[0103] In the compound shown in formula (I) in this disclosure [ka] The way to represent long combinations is, [ka] This demonstrates that it can be linked to any site of the quinoline ring except for positions 1 and 4.

[0104] In this disclosure, the method of indicating the linkage between the chelating agent and the radioactive element in the compound structure labeled with a radioactive element is not limited to one form. For example, compound 7: [ka] The structural formula is, [ka] It can also be expressed as follows: Here, [ka] Both of these involve a chelating agent and Al 18This indicates that a coordination bond has been formed between F and F.

[0105] The pharmaceutically acceptable salts of the compounds described herein may be selected from inorganic salts or organic salts.

[0106] The compounds of this disclosure may have specific geometric or stereoisomeric forms. In this disclosure, all such compounds include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as mixtures concentrated from enantiomers or diastereomers, all of which are assumed to be within the scope of this disclosure. Substituents such as alkyl groups may contain other chiral carbon atoms. All of these isomers and mixtures thereof are within the scope of this disclosure. The chiral carbon-containing compounds of this disclosure can be separated in optically active pure forms or in racemic forms. The optically active pure forms can be separated from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0107] Optically active (R)- and (S)-isomers and D- and L-isomers can be produced by chiral synthesis, chiral reagents, or other prior art. When it is intended to obtain an enantiomer of a compound in this disclosure, it can be produced by asymmetric synthesis or by the inductive action of a chiral auxiliary agent, where the resulting diastereomer mixture is separated and the auxiliary groups are cleaved to provide the pure, desired enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of the diastereomer is formed with a suitable optically active acid or base, and the diastereomer is resolved by a conventional method known in the art, and the resulting pure enantiomer is recovered. The separation of enantiomers and diastereomers is generally completed by chromatography, which employs a chiral stationary phase and optionally combines with a chemical induction method (e.g., producing a carbamate salt from an amine).

[0108] In the chemical structure of the compounds described in this disclosure, [ka] This indicates that the stereochemistry is not specified, meaning that if chiral isomers exist in the chemical structure, a bond is formed. [ka] teeth, [ka] It may be, or [ka] The two stereoconfigurations may be included simultaneously. In the chemical structure of the compound described herein, the bond [ka] The spatial arrangement is not specified, i.e., bonded. [ka] The three-dimensional configuration may be E-type or Z-type, or it may include both E and Z configurations simultaneously.

[0109] The compounds and intermediates of this disclosure may also exist in different tautomerized forms, and all such forms are included within the scope of this disclosure. The term “tautomer” or “tautomerized form” refers to structural isomers of different energies that are interconvertible across a low-energy barrier. For example, proton tautomers (also called proton-transfer tautomers) include tautomerization by proton transfer, e.g., keto-enol and imine-enamine, lactam-lactim isomerization. An example of lactam-lactim equilibrium is shown between A and B below. [ka]

[0110] All compounds in this disclosure may be classified as either type A or type B. All tautomer forms are within the scope of the present invention. The naming of the compounds does not exclude any tautomers.

[0111] This disclosure is the same as those described herein, but further includes several compounds of this disclosure in which one or more atoms are substituted with atoms whose atomic weight or mass number differs from those commonly found in nature, and which are labeled with isotopes. Examples of isotopes that can be bound to the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, respectively 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Examples include Cl.

[0112] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood to be deuterium having an abundance at least 1000 times greater than the natural abundance of deuterium (0.015%) (i.e., at least 10% deuterium incorporation). In the example compounds, deuterium having an abundance greater than the natural abundance of deuterium may be deuterium having an abundance of at least 1000 times, deuterium having an abundance of at least 2000 times, deuterium having an abundance of at least 3000 times, deuterium having an abundance of at least 4000 times, deuterium having an abundance of at least 5000 times, deuterium having an abundance of at least 6000 times, or deuterium having an abundance higher than that. The disclosure further includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom bonded to a carbon atom can be independently substituted with a deuterium atom. Those skilled in the art can synthesize compounds of formula (I) in deuterated forms by referring to relevant literature. When producing compounds of formula (I) in deuterated form, commercially available deuterated starting materials may be used, or they may be synthesized using conventional techniques with deuterated reagents, which include, but are not limited to, borane deuterated, borane-tetrahydrofuran trihydrogenated solution, lithium aluminum deuterated, iodoethane deuterated, and iodomethane deuterated.

[0113] "Optionally" or "optionally" means that the event or environment described later may occur, but is not required, and the description includes cases where the event or environment occurs or does not occur. For example, "C optionally substituted with a halogen or cyano group." 1-6 The term "alkyl group" means that a halogen or cyano group may be present, but is not necessarily required, and this description includes cases where the alkyl group is substituted with a halogen or cyano group, and cases where the alkyl group is not substituted with a halogen or cyano group.

[0114] Interpretation of terms: "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically and pharmaceutically acceptable salts or prodrugs with other chemical components, as well as other components, such as physiologically and pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to a living organism, to facilitate the absorption of the active ingredient, and thereby to exert biological activity.

[0115] "Pharmacologically acceptable excipients" include, but are not limited to, any excipients, carriers, fluidizers, sweeteners, diluents, preservatives, dyes / colorants, fragrances, surfactants, humectants, dispersants, suspension aids, stabilizers, isotonic agents, solvents, or emulsifiers approved by the U.S. Food and Drug Administration (FDA) for use in humans or livestock.

[0116] The “effective dose” or “effective therapeutic dose” as described in this disclosure includes the amount sufficient to improve or prevent the symptoms or signs of a medical condition. The effective dose also means the amount sufficient to enable or facilitate a diagnosis. The effective dose for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the patient’s overall health, the method, route and dose of administration, and the severity of side effects. The effective dose may be the maximum dose or administration protocol that avoids significant side effects or toxic effects.

[0117] "Alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms. It is an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, and their various branched isomers.

[0118] An "alkenyl group" refers to an unsaturated aliphatic linear or branched hydrocarbon group containing one or more carbon-carbon double bonds. Exemplary alkenyl groups include C2-C8, C2-C7, C2-C6, C2-C4, and C3-C 12and C3-C6 alkenyl groups. This includes, but is not limited to, vinyl groups (i.e., vinyl group (vinyl)), 1-propenyl group, 2-propenyl group (i.e., allyl group), 2-methyl-1-propenyl group, 1-butenyl group, 2-butenyl group (i.e., crotonyl group), etc.

[0119] An "alkenyl group" refers to an unsaturated aliphatic linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds. Exemplary alkenyl groups include C2-C8, C2-C7, C2-C6, C2-C4, and C3-C 12 and C3-C6 alkynyl groups. This includes, but is not limited to, ethynyl groups, propa-1-alkynyl groups, butane-1-alkynyl groups, penta-1-alkynyl groups, penta-4-alkynyl groups, and penta-1,4-dialkynyl groups. Alkenyl groups used in any context herein may be optionally substituted in the same manner as alkyl groups.

[0120] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the ring of a cycloalkyl group contains 3 to 12 carbon atoms, preferably 4 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl groups, while polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, parallel rings, and crosslinked rings.

[0121] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, where one or more ring atoms are nitrogen, oxygen, or S(O). mA heteroatom selected from (where m is an integer from 0 to 2), but without the ring portion of -OO-, -OS-, or -SS-, and the other ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, where 1 to 4 are heteroatoms, and more preferably 3 to 7 ring atoms. Non-limiting examples of "heterocycloalkyl groups" are: [ka] This includes, among others.

[0122] The heterocycloalkyl ring can be condensed with an aryl group or a heteroaryl group ring, where the ring linked to the basic skeleton is a heterocycloalkyl group, and non-limiting examples include: [ka] This includes, among others.

[0123] The heterocycloalkyl group may be optionally substituted or unsubstituted.

[0124] The term "alkoxy group" refers to an -O-(alkyl group), where the definition of an alkyl group is as described above. Non-exclusive examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy groups.

[0125] The term "alkylthio group" refers to -S-(alkyl), where the definition of alkyl is as described above. Non-exclusive examples of alkoxy groups include methylthio, ethylthio, propylthio, and butylthio groups.

[0126] A "monovalent group" refers to a compound from which one monovalent atom or group is formally removed. A "subunit" refers to a compound from which two monovalent or one divalent atom or group of atoms is formally removed.

[0127] The term "alkylene group" refers to the remaining portion after removing two hydrogen atoms from an alkane molecule, and includes linear and branched subunits of 1 to 20 carbon atoms. Alkylene groups containing 1 to 6 carbon atoms include, in non-limiting examples, methylene (-CH2-) and ethylene (e.g., -CH2CH2- or -CH(CH3)-).

[0128] Similarly, "alkylene oxy group," "alkenylene group," "alkenylene oxy group," "cycloalkylene group," and "heterocycloalkylene group" are synonymous with "alkylene group."

[0129] The term "aryl group" refers to a 6-14 membered all-carbon monocyclic or condensed polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6-12 membered, such as a phenyl group and a naphthyl group. The aryl group ring can be condensed to a heteroaryl group, a heterocycloalkyl group, or a cycloalkyl group ring, where the ring linked to the basic skeleton is an aryl group ring, and non-limiting examples include: [ka] Includes.

[0130] The aryl group may be substituted or unsubstituted. If substituted, the substituent is preferably one or more of the following groups, which are independently halogen, hydroxyl, oxo, nitro, cyano, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyloxy group, C 2-6 Alkynyloxy group, 3-6 membered cycloalkoxy group, 3-6 membered heterocycloalkoxy group, C 3-8 Selected from a cycloalkenyloxy group, a 5-6 membered aryl group, or a heteroaryl group, the C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyloxy group, C 2-6An alkynyloxy group, a 3- to 6-membered cycloalkoxy group, a 3- to 6-membered heterocycloalkoxy group, a 3- to 8-membered cycloalkenyloxy group, a 5- to 6-membered aryl group or a heteroaryl group is optionally substituted with one or more selected from halogen, a hydroxy group, a cyano group, an amino group, a C 1-6 alkyl group or a C 1-6 alkoxy group.

[0131] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12 members, more preferably 5 or 6 members. For example, non-limiting examples thereof are an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a pyrrolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, an oxadiazolyl, a pyrazinyl group, a triazolyl group, an indazolyl group, a benzimidazolyl group, [Chemical formula] and the like.

[0132] The ring of the heteroaryl group can be fused to the ring of an aryl group, a heterocycloalkyl group or a cycloalkyl group, where the ring linked to the basic skeleton is the ring of the heteroaryl group, and non-limiting examples thereof are [Chemical formula] including.

[0133] The heteroaryl group may optionally be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently halogen, a hydroxy group, a cyano group, an amino group, a C 1-6 alkyl group or a C 1-6 alkoxy group.

[0134] The term "spiro ring" refers to a compound in which two rings share one atom. Non-limiting examples of spirocycloalkyl groups are [Chemical formula] including.

[0135] The term "fused ring" refers to a compound formed by the fusion of two or more rings sharing two adjacent atoms. Non-limiting examples of fused cycloalkyl groups are [Chemical formula] including.

[0136] The term "bridged ring" refers to a structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. Depending on the number of constituent rings, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include the following. [Chemical formula] <00个00925> The term "heterocycle" refers to a ring containing atoms other than carbon atoms in addition to carbon atoms, which includes heterocycloalkyl groups and heteroaromatic rings.

[0138] The term "hydroxy group" refers to the -OH group. <0个000931> The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0140] The term "cyano group" refers to -CN.

[0141] The term "amino group" refers to -NH2.

[0142] Note: There seems to be an error in the original text where "0个000931" and "00个00925" are likely incorrect notations. I translated them as they are but they might need to be corrected in the original source.The term "nitro group" refers to -NO2.

[0143] The term "oxo" refers to the =O substituent.

[0144] "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced by the corresponding number of substituents. When the substituent is a ketone or oxo (i.e., =O), two (2) hydrogens on the atom are replaced.

[0145] DOTA-tri-tert-butyl ester: [Chemical formula] NOTA-di-tert-butyl ester: [Chemical formula] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate. T3P: 1-propylphosphonic acid tricyclic anhydride. [Modes for Carrying Out the Invention]

[0146] Hereinafter, the present disclosure will be further described together with examples, but these examples do not limit the scope of the present disclosure.

[0147] For experimental methods where specific conditions are not specified in the examples of the present disclosure, they are generally carried out according to conventional conditions or the conditions proposed by the raw material or commodity manufacturer. Reagents for which specific sources are not specified are common reagents purchased on the market.

[0148] The chromatographic conditions for HPLC / MS analysis in the present disclosure are as follows: 10 μl of each sample was automatically dispensed. Mobile phase: A: 0.1% formic acid aqueous solution, B: 0.1% formic acid acetonitrile solution. Flow rate: 1.5 ml / min. Gradient: B was increased from 10% to 95% over 0-6 mins, increased from 95% to 100% over 6-8 mins, decreased from 100% to 10% over 8-8.10 mins, and maintained at 10% over 8.10-11.0 mins.

[0149] Equipment model number: Thermo Fisher Ultimate 3000 ISQEM.

[0150] Chromatography column: Eclipse Plus C18, 3.5nm, 4.6×100mm.

[0151] UV detection wavelength: 254 nM.

[0152] The purity data of the compound was obtained by manual integration, and the molecular weight [M+1] + I collected them.

[0153] The chromatography conditions for liquid phase preparation in this disclosure are as follows: Mobile phase: A: 0.1% trifluoroacetic acid aqueous solution, B: 0.1% trifluoroacetic acid acetonitrile solution. Flow rate: 16 ml / min. Gradient: B was increased from 25% to 35% from 0 to 25.0 min, B was increased from 35% to 70% from 25.0 to 25.1 min, and B was maintained at 70% from 25.1 to 33.0 min.

[0154] Equipment model number: Agilent AGILENT 1260II.

[0155] Chromatography column: HPLCONE, 5.0 μm, 30 × 250 mm.

[0156] UV detection wavelength: 254 nM. After collecting the target compound, it was freeze-dried.

[0157] Example 1. Preparation of 6-(trans-4-(((2-(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-yl)acetyl)amino)methyl)cyclohexane-1-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (1) [ka] Step 1. Preparation of 6-aminoquinoline-4-carboxylate methyl hydrochloride (1-h) Under ice bath conditions, 12.5 g of acetyl chloride was slowly added dropwise to 100 ml of methanol, stirred at room temperature for 0.5 hours, 5.0 g of 6-aminoquinoline-4-carboxylic acid was added, and the mixture was heated under reflux for 12 hours. The solvent was evaporated to dryness, the mixture was slurryed with isopropyl ether, filtered, and compound 1-h (6.23 g, yield: 98.2%) was obtained. MS m / z(ESI):203.03[M+1] + .

[0158] Step 2. Preparation of 6-(trans-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-yl)carboxamidequinoline-4-carboxylate methyl ester (1-g) Under ice bath conditions, 500 mg of compound 1-h, 636 mg of trans-4-(tert-butoxycarbonylaminomethyl)cyclohexanecarboxylic acid, 2832 mg of ethyl acetate solution of tricyclic propylphosphonic acid anhydride (T3P, 50% by mass), and 959 mg of N,N-diisopropylethylamine were added to 30 ml of tetrahydrofuran. The reaction was carried out at 35°C for 8 hours. The reaction mixture was poured into 0.5 N hydrochloric acid, extracted with ethyl acetate, washed the organic phase with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain compound 1-g (887 mg, yield: 95.9%). MS m / z(ESI):442.32[M+1] + .

[0159] Step 3. Preparation of 6-(trans-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-yl)carboxamidequinoline-4-carboxylic acid (1-f) 600 mg of compound 1-g was added to 20 ml of a tetrahydrofuran / water 1:1 mixed solvent, and 171 mg of lithium hydroxide monohydrate was added. The mixture was reacted at room temperature for 3 hours, and the tetrahydrofuran in the solvent was evaporated to dryness. The pH was adjusted to 3-4 with 0.5 N hydrochloric acid, and a large amount of solid precipitated. The mixture was filtered to obtain compound 1-f (543 mg, yield: 93.6%). MS m / z (ESI): 428.11 [M+1] +

[0160] Step 4. Preparation of (S)-1-(2-((tert-butoxycarbonyl)amino)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile(1-e) Under ice bath conditions, 5.0 g of (S)-4,4-difluoropyrrolidine-2-carbonitride hydrochloride, 5.0 g of Boc-glycine, 31.5 g of ethyl acetate solution of tricyclic propylphosphonic acid anhydride (T3P, 50% by mass), and 10.68 g of N,N-diisopropylethylamine were added to 100 ml of tetrahydrofuran and reacted at 35°C for 5 hours. The reaction mixture was poured into 0.5 N hydrochloric acid, extracted with ethyl acetate, washed the organic phase with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain compound 1-e (7.8 g, yield: 90.4%). MS m / z (ESI): 290.08 [M+1] + .

[0161] Step 5. Preparation of (S)-1-aminoacetyl-4,4-difluoropyrrolidine-2-carbonitrile (1-d) 7.8 g of compound 1-e was dissolved in 100 ml of 3.0 mol / L ethyl hydrochloride solution, stirred at room temperature for 5 hours, and the solvent was evaporated to dryness to obtain compound 1-d (6.07 g, yield: 98.7%). MS m / z (ESI): 190.13 [M+1] + .

[0162] Step 6. Preparation of 6-(trans-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (1-c) Under ice bath conditions, 500 mg of compound 1-f, 221 mg of compound 1-d, 1340 mg of ethyl acetate solution of 1-propylphosphonic acid tricyclic anhydride (T3P) (T3P, 50% mass concentration), and 453 mg of N,N-diisopropylethylamine were added to 20 ml of tetrahydrofuran and reacted at 35°C for 5 hours. The reaction mixture was poured into 0.5 N hydrochloric acid, extracted with ethyl acetate, washed the organic phase with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain compound 1-c (572 mg, yield: 81.7%). MS m / z(ESI): 599.10[M+1] + .

[0163] Step 7. Preparation of 6-(trans-4-(aminomethyl)cyclohexane-1-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (1-b) Compound 1-c (572 mg) was dissolved in 30 ml of 3.0 mol / L ethyl hydrochloride solution, stirred at room temperature for 5 hours, and the solvent was evaporated to dryness to obtain compound 1-b (461 mg, yield: 96.7%). MS m / z(ESI):499.13[M+1] + .

[0164] Step 8. Preparation of 6-(trans-4-(((2-(4,7,10-tritert-butoxycarbonylmethyl-1,4,7,10-tetraazacyclododecane-1-yl)acetyl)amino)methyl)cyclohexane-1-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (1-a) Compound 1-b (300 mg), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate tri-tert-butyl ester (DOTA-tris(t-Bu ester)), HATU (412 mg), and N,N-diisopropylethylamine (233 mg) were dissolved in tetrahydrofuran and reacted at 35°C for 5 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the compound was purified by elution with a dichloromethane / methanol = methanol (0%~20%) eluent system by silica gel column chromatography to obtain compound 1-a (464 mg, yield: 73.2%). MS m / z(ESI):1053.46[M+1] + .

[0165] Step 9. Preparation of 6-(trans-4-(((2-(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-yl)acetyl)amino)methyl)cyclohexane-1-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (1) 464 mg of compound 1-a was dissolved in 20 ml of dichloromethane, 20 ml of trifluoroacetic acid was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated to dryness, and the mixture was separated by preparative liquid phase, purified, and freeze-dried to obtain target compound 1 (166 mg, yield: 42.5%). MS m / z(ESI):885.36[M+1] + .

[0166] Example 2. Preparation of 6-(trans-4-(((2-(4,7-dicarboxymethyl-1,4,7-triazaheterocyclononanan-1-yl)acetyl)amino)methyl)cyclohexane-1-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (2) [ka] Compound 2 was prepared by following the same method as for Compound 1.

[0167] Step 1. Preparation of 6-(trans-4-(((2-(4,7-dittert-butoxycarbonylmethyl-1,4,7-triazaheterocyclononanan-1-yl)acetyl)amino)methyl)cyclohexane-1-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (2-a) Compound 1-b 300 mg, 1,4,7,-triazaheterocyclononane-1,4,7-triacetate di-tert-butyl ester (NOTA-bis(t-Bu ester)) 300 mg, HATU 412 mg, and N,N-diisopropylethylamine 233 mg were dissolved in tetrahydrofuran and reacted at 35°C for 5 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the compound was purified by elution with a dichloromethane / methanol = methanol (0%~20%) eluent system by silica gel column chromatography to obtain compound 2-a (368 mg, yield: 68.2%). MS m / z(ESI):896.33[M+1] + .

[0168] Step 2. Preparation of 6-(trans-4-(((2-(4,7-dicarboxymethyl-1,4,7-triazaheterocyclononanan-1-yl)acetyl)amino)methyl)cyclohexane-1-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (2) 368 mg of compound 2-a was dissolved in 20 ml of dichloromethane, 20 ml of trifluoroacetic acid was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated to dryness, and the mixture was separated and purified by preparative liquid phase. The mixture was then freeze-dried to obtain target compound 2 (125 mg, yield: 38.7%). 1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),9.10(t,1H),8.90(d,1H),8.57(s,1H),8.25(t,1H),8.03(m,2H),7.59(d,1H),5.15(dd,1H),4.11 -4.34(m,4H),3.78(d,2H),3.62(s,4H),2.81-3.01(m,16H),2.34-2.40(m,1H),1.80-1.92(m,4H),1.40-1.48(m,3H),0.93-1.02(m,2H). MS m / z(ESI):784.10[M+1] + .

[0169] Example 3. Preparation of 6-((6r,9r)-N-(2-(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-yl)acetyl)-1-oxa-4-azaspiro[5.5]undecane-9-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (3) [ka] Compounds 1-h and 1-d were prepared according to the method for compound 1.

[0170] Step 1. Preparation of 6-((6r,9r)-N-tert-butoxycarbonyl-1-oxa-4-azaspiro[5.5]undecane-9-yl)carboxamidequinoline-4-carboxylate methyl ester (3-g) Under ice bath conditions, 500 mg of compound 1-h, 528 mg of (6r,9r)-N-Boc-1-oxa-4-azaspiro[5.5]undecane-9-carboxylic acid, 2832 mg of ethyl acetate solution (T3P, 50% by mass) of 1-propylphosphonic acid tricyclic anhydride, and 959 mg of N,N-diisopropylethylamine were added to 30 ml of tetrahydrofuran. The reaction was carried out at 35°C for 8 hours. The reaction mixture was poured into 0.5 N hydrochloric acid, extracted with ethyl acetate, washed the organic phase with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain compound 3-g (815 mg, yield: 93.2%). MS m / z (ESI): 484.35 [M+1] + .

[0171] Step 2. Preparation of 6-((6r,9r)-N-tert-butoxycarbonyl-1-oxa-4-azaspiro[5.5]undecane-9-yl)carboxamidequinoline-4-carboxylic acid (3-f) 815 mg of compound 3-g was added to 20 ml of a tetrahydrofuran / water 1:1 mixed solvent, and 214 mg of lithium hydroxide monohydrate was added. The mixture was reacted at room temperature for 3 hours, and the tetrahydrofuran in the solvent was evaporated to dryness. The pH was adjusted to 3-4 with 0.5 N hydrochloric acid, and a large amount of solid precipitated. The mixture was filtered to obtain compound 3-f (543 mg, yield: 95.7%). MS m / z (ESI): 470.31 [M+1] + .

[0172] Step 3. Preparation of 6-((6r,9r)-N-tert-butoxycarbonyl-1-oxa-4-azaspiro[5.5]undecane-9-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (3-c) Under ice bath conditions, 500 mg of compound 3-f, 240 mg of compound 1-d, 1340 mg of ethyl acetate solution of tricyclic propylphosphonic acid anhydride (T3P, 50% by mass), and 453 mg of N,N-diisopropylethylamine were added to 20 ml of tetrahydrofuran and reacted at 35°C for 5 hours. The reaction mixture was poured into 0.5 N hydrochloric acid, extracted with ethyl acetate, washed the organic phase with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain compound 3-c (521 mg, yield: 76.3%). MS m / z (ESI): 641.29 [M+1] + .

[0173] Step 4. Preparation of 6-((6r,9r)-1-oxa-4-azaspiro[5.5]undecane-9-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (3-b) Compound 3-c (521 mg) was dissolved in 30 ml of 3.0 mol / L ethyl hydrochloride solution, stirred at room temperature for 5 hours, and the solvent was evaporated to dryness to obtain compound 3-b (619 mg, yield: 94.8%). MS m / z(ESI):541.24[M+1] + .

[0174] Step 5. Preparation of 6-((6r,9r)-N-(2-(4,7,10-tritert-butoxycarbonylmethyl-1,4,7,10-tetraazacyclododecane-1-yl)acetyl)-1-oxa-4-azaspiro[5.5]undecane-9-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (3-a) Compound 3-b (300 mg), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate tri-tert-butyl ester (DOTA-tris(t-Bu ester)), HATU (356 mg), and N,N-diisopropylethylamine (202 mg) were dissolved in 20 ml of tetrahydrofuran and reacted at 35°C for 5 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the compound was purified by elution with a dichloromethane / methanol = methanol (0%~20%) eluent system by silica gel column chromatography to obtain compound 3-a (395 mg, yield: 69.4%). MS m / z(ESI):1095.58[M+1] + .

[0175] Step 6. Preparation of 6-((6r,9r)-N-(2-(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-yl)acetyl)-1-oxa-4-azaspiro[5.5]undecane-9-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (3) 395 mg of compound 3-a was dissolved in 20 ml of dichloromethane, 20 ml of trifluoroacetic acid was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated to dryness, and the mixture was separated and purified by preparative liquid phase. The mixture was then freeze-dried to obtain target compound 3 (89 mg, yield: 26.6%). MS m / z(ESI):927.34[M+1] + .

[0176] Example 4. Preparation of 6-((6r,9r)-N-(2-(4,7-dicarboxymethyl-1,4,7-triazaheterocyclononanan-1-yl)acetyl)-1-oxa-4-azaspiro[5.5]undecane-9-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (4) [ka] Compound 4 was obtained by following the same method as for compound 3.

[0177] Step 1. Preparation of 6-((6r,9r)-4-(N-(2-(4,7-ditert-butoxycarbonylmethyl-1,4,7-triazaheterocyclononanan-1-yl)acetyl)-1-oxa-4-azaspiro[5.5]undecane-9-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (4-a) Compound 3-b (300 mg), 1,4,7,-triazaheterocyclononane-1,4,7-triacetate di-tert-butyl ester (NOTA-bis(t-Bu ester)) (259 mg), HATU (1.8 equivalents) (356 mg), and N,N-diisopropylethylamine (202 mg) were dissolved in 20 ml of tetrahydrofuran and reacted at 35°C for 5 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The compound was purified by elution with a dichloromethane / methanol = methanol (0%~20%) eluent system by silica gel column chromatography to obtain compound 4-a (386 mg, yield: 79.1%). MS m / z (ESI): 938.42 [M+1] + .

[0178] Step 2. Preparation of 6-((6r,9r)-4-(N-(2-(4,7-dicarboxymethyl-1,4,7-triazaheterocyclononanan-1-yl)acetyl)-1-oxa-4-azaspiro[5.5]undecane-9-yl)carboxamide-4-((S)-2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoylquinoline (4) 386 mg of compound 4-a was dissolved in 20 ml of dichloromethane, 20 ml of trifluoroacetic acid was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated to dryness, and the mixture was separated and purified by preparative liquid phase. The mixture was then freeze-dried to obtain target compound 4 (179 mg, yield: 52.7%). 1H NMR(400MHz,DMSO-d6)δ10.29(d,1H),9.07(s,1H),8.87(d,1H),8.52(d,1H),8.03(d,2H),7.56(d ,1H),5.15(t,1H),4.19-4.45(m,7H),3.58-4.19(m,24H),1.94(m,2H),1.67(m,4H),1.27(m,2H). MS m / z (ESI): 826.33 [M+1] + .

[0179] Example 5. Preparation of Compound 5 [ka] Add 0.1 ml of sodium acetate buffer to the reaction flask, then 68 0.9 mL of GaCl3 solution (0.1 N hydrochloric acid solution) and 5 μL of an aqueous solution of 6 nmol of compound 2 were added. The pH of the reaction mixture was maintained at 3.0 to 5.0, and the mixture was heated at 95°C for 10 to 15 minutes.

[0180] The labeled reaction solution was diluted with 2 mL of physiological saline. According to ITLC detection, the impurity content was less than 10%, and it was used directly in animal imaging experiments.

[0181] Example 6. Preparation of Compound 6 [ka] Add 0.1 ml of sodium acetate buffer to the reaction flask, then 68 0.9 mL of GaCl3 solution (0.1 N hydrochloric acid solution) and 5 μL of an aqueous solution of 6 nmol of compound 4 were added. The reaction mixture was heated at 95°C for 10 to 15 minutes while maintaining the pH of the reaction mixture between 3.0 and 5.0.

[0182] The labeled reaction solution was diluted with 2 mL of physiological saline. According to ITLC detection, the impurity content was less than 10%, and it was used directly in animal imaging experiments.

[0183] Example 7. Preparation of Compound 7 [ka] 7 Add 1 μl of 10 mM Compound 2 aqueous solution to 50-100 μl of 0.5 M acetic acid / sodium acetate buffer at pH 4.0-4.4, then add 2 mM AlCl3 aqueous solution in a molar ratio of 2:1, and 1850 MBq of QMA-purified solution. 18 F - 50 μl of ions were added, and the reaction was carried out at 100°C for 10-15 minutes. The solution was purified using an HLB solid-phase extraction column (HLB cartridge), rinsed with ethanol / water (1:1), and diluted with physiological saline until the ethanol content was less than 10%. Radio-HPLC detection revealed a radiochemical purity exceeding 90%, and the solution was used directly for animal imaging experiments.

[0184] Example 8. Preparation of Compound 8 [ka] Dissolve 5 μl of 10 mM aqueous solution of compound 1 in 100 μl of acetic acid / sodium acetate buffer solution with a pH of 3.5-6.5, and then dissolve 1850 MBq of it in 0.1 M hydrochloric acid. 64 50 μl of CuCl2 solution was added, and the reaction was carried out at 80°C for 15 minutes. The solution was purified using a C18 column and diluted with physiological saline until the ethanol content was less than 10%. Radiochemical purity was detected using radioactive HPLC, and the radiochemical purity was found to be 95.26%.

[0185] Example 9. Preparation of Compound 9 [ka] Dissolve 5 μl of 10 mM aqueous solution of compound 2 in 100 μl of acetic acid / sodium acetate buffer solution with a pH of 3.5-6.5, and then dissolve 1850 MBq of it in 0.1 M hydrochloric acid. 64 50 μl of CuCl2 solution was added, and the reaction was carried out at 80°C for 15 minutes. The solution was purified using a C18 column and diluted with physiological saline until the ethanol content was less than 10%. Radiochemical purity was detected using radioactive HPLC, and the radiochemical purity was found to be 95.82%. Biological evaluation

[0186] The following sections will further explain and interpret this disclosure in conjunction with test examples, but these test examples are not intended to limit the scope of this disclosure.

[0187] Test Example 1: Enzyme Activity Test of FAPα 1.1 Experimental materials and equipment [Table 1]

[0188] 1.2 Experimental Steps A 0.5 mM stock solution was prepared by diluting the substrate (Z-Gly-Pro-AMC) with DMSO, and before each experiment, the 0.5 mM stock solution was diluted to 50 μM with PBS to prepare for use. The FAPα protein was diluted to 0.5 ng / μl with PBS to prepare for use. The test compound and positive control were diluted to a concentration of 100 nM or 200 nM with PBS and used to measure the single-point inhibition rate. For compounds whose single-point inhibition rate was equivalent to that of the positive control compound, IC was then performed. 50 The values ​​were measured, and the test compound and positive control were diluted using PBS to a maximum concentration of 10 μM and a minimum concentration of 0 nM. A 5-fold gradient dilution was performed using a total of 8 gradients to prepare for use. Test method: 85 μl of FAPα diluent and 10 μl of compound diluent were placed in a microplate and mixed uniformly. The mixture was incubated at 37°C for 10 minutes, and 5 μL of 50 μM substrate was added and mixed uniformly. The mixture was incubated at 37°C for 10 minutes. The values ​​were read using a microplate reader, with the excitation light at 380 nm and the synchrotron radiation at 465 nm.

[0189] 1.3 Experimental Results [Table 2] Using the same method, IC of compound 2 against the FAPα enzyme 50 The value was 0.71 times that of the positive drug FAPI-04, and was equivalent to that of the positive drug, indicating that FAP-42's IC for the FAPα enzyme was equivalent.50 The value was detected as being 2.27 times higher than that of the positive drug FAPI-04.

[0190] Note: The structure of FAPI-04 is as follows: Cited document: CN111699181A, P.60 [ka] The structure of the FAP-42 is as shown below, CN111699181A, P.61 [ka]

[0191] Test example 2. 68 Ga, 18 PET imaging experiment of F-labeled compounds 2.1 Experimental Materials cell: Cell information: U-87MG cells (Wuhan Pnuozai Life Science and Technology Co., Ltd., catalog number: CL-0238, lot number: YBMIL8BQH0), culture conditions: U-87MG cell special medium (MEM + 10% FBS + 1% P / S), passage number: 6 to 9 generations, Laboratory animals: Germline: BALB / c nude mouse, age: 4-5 weeks, weight: 15-22g reagent: PBS (Soraibao, P1020) Matrigel (ABW, 0827045) Trypsin-EDTA (Gibco, 25200-072) U-87 MG-specific culture medium (Punosai, CM-0238) Instruments: Small animal PET / CT (ediso, nanoScan PET / CT 4heads) Activity meter (Capintec, activity meter) Electronic balance (Changzhou Shuangjie, DT100)

[0192] 2.2. Experimental Steps Model Building A sufficient quantity of U-87 MG cells was prepared and inoculated into the right forelimb of B-NDG mice at a slightly posterior position, with an inoculation volume of 100 μL, containing 50% Matrigel and 4 × 10⁶ cells. 6 It contains individual cells. Operation Steps The workbench was wiped with 75% medical alcohol, and a sterile disposable tablecloth was laid down. A 0.5 mL insulin syringe, alcohol swabs, cotton swabs, and a marking pen were prepared in the injection room. These were placed in the mouse fixator, and the mouse tails were disinfected with alcohol swabs. 0.2–0.5 mL of the prepared test was intravenously administered to the tail of each mouse, and the time of each injection, needle tubular activity, and empty needle tubular activity were recorded. Tumor-bearing mice were anesthetized with isoflurane, then placed face down on a PET bed and fixed in place. PET static imaging was performed for 10 minutes at 0.5 h, 1 h, 2 h, and 4 h after administration, and a whole-body CT scan was performed before each static scan to obtain images of the whole-body distribution of the labeled compound in tumor-bearing mice. PET imaging images were obtained at different time points after administration for each experimental animal. Major organs were selected and drawn, specifically including tumors, muscles, skeleton, lungs, brain, liver, and kidneys. We observed the radioactive enrichment and clearance of labeled compounds in tumors and non-target tissues of tumor-bearing mice.

[0193] 3. Experimental Results [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] Conclusion: Compound 5 showed higher uptake in tumors than FAPI-04, lower uptake in non-target organs (tissues) than FAPI-04, and a superior tumor / non-target organ (tissue) ratio compared to FAPI-04. Compound 7 showed higher uptake in tumors than FAPI-04 and a superior tumor / non-target organ (tissue) ratio compared to FAPI-04.

[0194] Comparative Example 1. 18 PET imaging test of F-FAPI-42 Using the same experimental method as in Example 2, labeling 18 The radioactive enrichment ratio of F-FAPI-42 compound in tumor-bearing mice and in non-target tissues was observed. [Table 4] Experimental conclusion: In the U-87 mouse model, compound 7 was 18 Compared to F-FAPI-42, compound 7 had lower uptake into non-target organs such as the gallbladder and intestine, indicating that compound 7 has higher safety. Furthermore, compound 7 had a higher tumor / gallbladder ratio and tumor / intestine uptake ratio, meaning that compound 7 has superior targeting properties, allowing it to better distinguish between tumor lesions and normal tissue organs.

Claims

1. A compound shown in formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 R １ and R １ ' is independently of hydrogen, cyano group, carboxyl group, sulfonic acid group, phosphate group or B(OH) ２ Selected from, R ２ These are, independently, a hydroxyl group, a halogen, and C. １－６ Alkyl, halo C １－６ Alkyl alkyl, -NR'R'', -O-C １－６ Alkyl alkyl group or -S-C １－６ Selected from alkyl groups, R ３ and R ３ ’ are each independently selected from hydrogen, a hydroxy group, a halogen or a C １－６ alkyl group, R ４ is a hydroxyl group, halogen, C １－６ Alkyl, halo C １－６ Alkyl alkyl, -NR'R'', -O-C １－６ Alkyl alkyl group or -S-C １－６ Selected from alkyl groups, Ring A is selected from a 3- to 12-membered cycloalkylene group or a 3- to 12-membered heterocycloalkylene group. R ５ is a halogen, hydroxyl group, C １－６ Alkyl, halo C １－６ Alkyl alkyl group, -NR'R'' or -O-C １－６ Selected from alkyl groups, L １ The bond is -NH-, -CH ２ -NH- or -CH ２ CH ２ Selected from -NH-, x is selected from 0, 1, 2, or 3. R' and R'' are, independently, hydrogen and C. １－６ Alkyl or halo C １－６ Selected from alkyl groups, y is selected from 1 or 2. z is selected from 0, 1, 2, or 3. u is selected from 0, 1 or 2, and B is selected from any optical or radiolabeling functional group suitable for optical imaging, positron emission tomography imaging, single-photon emission computed tomography imaging, or radiotherapy, and preferably B is a compound or a pharmaceutically acceptable salt thereof comprising a chelating agent and a radioactive element.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a 4- to 7-membered cycloalkylene group, preferably a cyclohexylene group.

3. R １ and R １’ Each of these is independently selected from a hydrogen or a cyano group, and is the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

4. R ２ Each of these independently comprises a hydroxyl group, a halogen, or C １－６ Selected from alkyl groups, x is selected from 2 or 3, preferably R ２ Each is independently selected from fluorine or chlorine, and is a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. R ３ and R ３ ' are, independently, hydrogen, halogen, or C １－６ Selected from alkyl groups, preferably R ３ and R ３ ' is a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein all of the compounds are hydrogen.

6. The compound shown in formula (II-1) or a pharmaceutically acceptable salt thereof, 【Chemistry 2】 Here, X １ and X ２ Each is independently selected from CH or N. s and t are each independently selected from 0, 1, or 2, and R ４ , R ５ , L １ A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 and 3 to 5, wherein B, z, and u are as defined in claim 1.

7. i) X １ CH is X ２ is N, or, ii) X １ is N, X ２ is CH, or, iii) X １ CH is X ２ is CH, Preferably, X １ CH is X ２ The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein is CH.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 6 or 7, wherein s and t are each independently selected from 0 or 1, and preferably both s and t are 1.

9. L １ - is CH ２ A compound according to any one of claims 6 to 8, or a pharmaceutically acceptable salt thereof, wherein the compound is -NH-.

10. X １ CH is X ２ is CH, and s and t are both 1, L １ CH ２ -NH- or -CH ２ CH ２ Selected from -NH-, preferably -CH ２ A compound according to any one of claims 6 to 9, or a pharmaceutically acceptable salt thereof, wherein the compound is -NH-.

11. The compound shown in formula (II-2) or a pharmaceutically acceptable salt thereof, 【Transformation 3】 Here, X ３ and X ４ Each is independently selected from CH, N, or O. s and t are independently selected from 0, 1, or 2. w and v are each independently selected from 0, 1, or 2, and R ４ , R ５ , L １ A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 and 3 to 5, wherein B, z, and u are as defined in claim 1.

12. X ３ CH is X ４ is O, or, X ３ CH is X ４ is N, or X ３ is N, X ４ is CH, Preferably, X ３ CH is X ４ The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein is O.

13. s and t are each independently selected from 0 or 1, and w and v are each independently selected from 0 or 1. Preferably, the compound according to claim 11 or 12 or a pharmaceutically acceptable salt thereof, wherein s and t are both 1, and w and v are both 1.

14. L １ The compound according to any one of claims 11 to 13, or a pharmaceutically acceptable salt thereof, wherein is a bond.

15. X ３ CH is X ４ is O, s and t are both 1, w and v are both 1, L １ The compound according to any one of claims 11 to 14 or a pharmaceutically acceptable salt thereof, wherein the compound is a bond.

16. R ４ is a hydroxyl group, halogen or C １－６ Selected from alkyl groups, z is selected from 0, 1, 2, or 3. Preferably, R ４ The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein z is selected from fluorine, chlorine, a methyl group, or ethyl, and z is selected from 0 or 1.

17. R ５ is a hydroxyl group, halogen or C １－６ Selected from alkyl groups, u is selected from 0, 1, or 2. Preferably, R ５ The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein is selected from fluorine, chlorine, a methyl group or an ethyl group, and u is selected from 0 or 1.

18. The chelating agent in B above is 【Chemistry 4】 Selected from, preferably, 【Transformation 5】 The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

19. Said B contains a radioactive element, and the radioactive element is ２２３ Ra, ８９ Sr, ９４ｍ Tc, ９９ｍ Tc, １８６ Re, １８８ Re, ２０３ Pb, ２１２ Pb, ６７ Ga, ６８ Ga, ４７ Sc, １１１ In, ９７ Ru, ６２ Cu, ６４ Cu, ８６ Y, ８８ Y, ９０ Y, １２１ Sn, １６１ Tb, １５３ Sm, １６６ Ho, １０５ Rh, １７７ Lu, １２３ I, １２４ I, １２５ I, １８ F, ２１１ At, ２２５ Ac, ８９ Sr, １１７ｍ Sn or １６９ selected from Er, preferably １８ F or ６８ Ga, Or the radioactive element is, ４３ Sc, ４４ Sc, ５１ Mn, ５２ Mn, １５２ Tb, １５５ Tb, ２０１ TI, ７６ Br, ７７ Br, ８９ Zr, ４７ Sc, ６７ Cd, １４９ Tb, ２１３ Bi, ２２６ Th, ２２７ Th or １３１ A compound according to any one of claims 1 to 18, selected from I, or a pharmaceutically acceptable salt thereof. 【Request Item 20】 【Chemistry 6】 Selected from, preferably, 【Transformation 7】 And in particular, it is, 【Transformation 8】 A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, selected from among.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

22. A method for producing the compound or a pharmaceutically acceptable salt thereof described in claim 20, or the pharmaceutical composition described in claim 21, comprising the step of complexing the compound or a pharmaceutically acceptable salt thereof with a radioactive element.

23. Uses of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, in the manufacture of a drug for imaging a disease or disorder related to fibroblast-activating protein, or for treating a disease or disorder related to fibroblast-activating protein.

24. The disease or disorder related to fibroblast-activating protein is selected from proliferative disorders, chronic inflammation, fibrosis (liver, kidney, lung), tissue remodeling, scarring disease, tissue infection, or inflammatory lesions; the proliferative disorder is selected from the group consisting of breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, lung adenocarcinoma, kidney cancer, liver cancer, lung cancer, esophageal cancer, hepatobiliary tract cancer, gastric cancer, nasopharyngeal cancer, head and neck cancer, bladder cancer, glioblastoma, peritoneal metastasis, melanoma, fibrosarcoma, bone and connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma and adenocarcinoma, and benign tumors; the chronic inflammation is selected from rheumatoid arthritis, osteoarthritis, Crohn's disease, or atherosclerotic plaque; the tissue remodeling occurs after myocardial infarction; and the scarring disease is selected from scar formation, scar tumor, or keloid.

25. Uses of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, in the manufacture of a drug for the prevention, diagnosis, or treatment of proliferative disorders, chronic inflammation, fibrosis (liver, kidney, lung), tissue remodeling, scarring, tissue infection, or inflammatory lesions, wherein the proliferative disorders are breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, lung adenocarcinoma, kidney cancer, liver cancer, lung cancer, esophageal cancer, hepatobiliary cancer. The use is selected from the group consisting of cancer, gastric cancer, nasopharyngeal cancer, head and neck cancer, bladder cancer, glioblastoma, peritoneal metastatic cancer, melanoma, fibrosarcoma, bone and connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma and adenocarcinoma, and benign tumors; the chronic inflammation is selected from rheumatoid arthritis, osteoarthritis, Crohn's disease, or atherosclerotic plaque; the tissue remodeling is performed after myocardial infarction; and the scar disease is selected from scar formation, scar tumor, or keloid.

26. The method for producing compound 7 shown below, 【Chemistry 9】 Compound 2 under acidic conditions, １８ F － and AlCl ３ This includes a step that causes a reaction, 【Chemistry 10】 A method for producing compound 7.

27. A method for producing compound 2, comprising the step of removing a tert-butyl protecting group from compound 2-a under acidic conditions, 【Chemistry 11】 A method for producing compound 2.

28. A method for producing compound 7 according to claim 26, comprising the step of producing compound 2 according to claim 27.

29. The process includes the step of reacting compound 1-b with NOTA-di-tert-butyl ester under the catalytic action of a polypeptide condensation reagent to obtain compound 2-a. 【Chemistry 12】 A method for producing compound 7 according to claim 26 or 28, or a method for producing compound 2 according to claim 27.

30. The process includes the step of removing the tert-butoxycarbonyl protecting group from compound 1-c under acidic or basic conditions to obtain compound 1-b. 【Chemistry 13】 A method for producing compound 7 according to any one of claims 26 and 28-29, or a method for producing compound 2 according to any one of claims 27 and 29.

31. The step includes reacting compounds 1-f and 1-d under the action of a condensing agent to obtain compound 1-c. 【Chemistry 14】 A method for producing compound 7 according to any one of claims 26 and 28-30, or a method for producing compound 2 according to any one of claims 27 and 29-30.

32. The process includes the step of removing a methyl protecting group from compound 1-g under basic conditions. 【Chemistry 15】 A method for producing compound 7 according to any one of claims 26 and 28-31, or a method for producing compound 2 according to any one of claims 27 and 29-31. 【Request Item 33】 【Chemistry 16】 The compound shown.

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