Ligands targeting fibroblast activating proteins

Abstract

The present disclosure relates to a ligand targeting a fibroblast activating protein, in particular to a ligand targeting a fibroblast activating protein represented by formula (I) and a radiomarker thereof, where each substituent is defined in the specification, the ligand can be used for imaging diseases or conditions associated with a fibroblast activating protein, or for treating fibroblast activating protein related diseases or conditions.

Description

Ligands targeting fibroblast activation protein Technical Field

[0001] The present disclosure relates to a ligand targeting fibroblast activation protein and a radioactive label thereof, and medical uses. Background Art

[0002] Fibroblast activation protein (FAP) is a membrane-bound gelatinase that promotes 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 targeted small molecule drug conjugates (SMDCs) and small molecule radioconjugates (SMRCs).

[0003] Research on fibroblast activation protein (FAP) inhibitors includes WO2019154886A, WO2019154859A, WO2019118932A, WO2019083990A, WO2013107820A, WO2018111989A, WO2023 / 057457A, etc. However, the development of effective FAP binders with excellent targeting properties and targeted small molecule drug conjugates and small molecule radioconjugates based thereon remains a challenging task. It is particularly desirable that the small molecule radioconjugates exhibit favorable tumor-to-organ biodistribution, high activity labeling, and / or good compound stability.

[0004] Summary of the Invention

[0005] The present disclosure relates to ligands of fibroblast activation protein (FAP) for active delivery of radioactive payloads to disease sites.

[0006] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0007] Among them, R 1 and R 1 ' are each independently selected from hydrogen, cyano, carboxyl, sulfonic acid, phosphoric acid or B(OH)2;

[0008] R 2 Each independently selected from hydroxyl, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR'R", -OC 1-6 Alkyl or -SC 1-6 alkyl;

[0009] R 3 and R 3 ' are each independently selected from hydrogen, hydroxy, halogen or C 1-6 alkyl;

[0010] R 4 Selected from hydroxyl, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR'R", -OC 1-6 Alkyl or -SC 1-6 alkyl;

[0011] Ring A is selected from 3- to 12-membered cycloalkylene or 3- to 12-membered heterocycloalkylene;

[0012] R 5 Selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR'R" or -OC 1-6 alkyl;

[0013] L1 is selected from a linker, -NH-, -CH2-NH- or -CH2CH2-NH-;

[0014] x is selected from 0, 1, 2 or 3;

[0015] R' and R" are each independently selected from hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0016] y is selected from 1 or 2;

[0017] z is selected from 0, 1, 2 or 3;

[0018] u is selected from 0, 1 or 2; and

[0019] 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.

[0020] In an alternative embodiment, said B consists of a chelating agent and a radioactive element.

[0021] In an optional embodiment, the ring A is selected from 4- to 7-membered cycloalkylene groups, such as cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene.

[0022] In an optional embodiment, the ring A is cyclohexylene.

[0023] In an optional embodiment, the R 1 and R 1 ' are each independently selected from hydrogen or cyano.

[0024] In an optional embodiment, the R 2 Each independently selected from hydroxy, halogen or C 1-6 Alkyl, wherein x is selected from 2 or 3.

[0025] In an optional embodiment, the R 2 are each independently selected from fluorine or chlorine, and x is selected from 2 or 3.

[0026] In an optional embodiment, the R 3 and R 3 ' are each independently selected from hydrogen, halogen or C 1-6 alkyl.

[0027] In an optional embodiment, the R 3 and R 3 ' are all hydrogen.

[0028] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof,

[0029] wherein X1 and X2 are each independently selected from CH or N,

[0030] s and t are each independently selected from 0, 1 or 2, and

[0031] R 4 、R 5 , L1, B, z and u are as defined in formula (I).

[0032] In an optional embodiment, X1 is CH, and X2 is N.

[0033] In an optional embodiment, X1 is N, and X2 is CH.

[0034] In an optional embodiment, X1 is CH, and X2 is CH.

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

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

[0037] In an optional embodiment, said L1 is selected from a linker or -NH-.

[0038] In an optional embodiment, said L1 is selected from CH2-NH- or -CH2CH2-NH-.

[0039] In an optional embodiment, said L1 is CH2-NH-.

[0040] In an optional embodiment, said L1 is -CH2CH2-NH-.

[0041] 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-.

[0042] In an optional embodiment, X1 is CH, X2 is CH; s and t are both 1; and L1 is -CH2-NH-.

[0043] In an optional embodiment, the R 4 Selected from hydroxy, halogen or C 1-6 Alkyl, wherein z is selected from 0, 1, 2 or 3.

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

[0045] In an optional embodiment, the R 5 Selected from hydroxy, halogen or C 1-6 Alkyl, wherein u is selected from 0, 1 or 2.

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

[0047] In an optional embodiment, the R 4 and R 5 are each independently selected from fluorine, chlorine, methyl or ethyl, and said z and u are each independently selected from 0 or 1.

[0048] In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by formula (II-2) or a pharmaceutically acceptable salt thereof,

[0049] wherein X3 and X4 are each independently selected from CH, N or O;

[0050] s and t are each independently selected from 0, 1 or 2;

[0051] w and v are each independently selected from 0, 1 or 2; and

[0052] R 4 、R 5 , L1, B, z and u are as defined in formula (I).

[0053] In an optional embodiment, X3 is CH, and X4 is O.

[0054] In an optional embodiment, X3 is CH, and X4 is N.

[0055] In an optional embodiment, X3 is N, and X4 is CH.

[0056] In an optional embodiment, said s and t are each independently selected from 0 or 1, and said w and v are each independently selected from 0 or 1.

[0057] In an optional embodiment, said s and t are both 1, and said w and v are both 1.

[0058] In an optional embodiment, L1 is a connecting bond.

[0059] In an optional embodiment, said L1 is NH-.

[0060] In an optional embodiment, said L1 is selected from CH2-NH- or -CH2CH2-NH-.

[0061] In an optional embodiment, said L1 is CH2-NH-.

[0062] In an optional embodiment, said L1 is -CH2CH2-NH-.

[0063] 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 connecting bond.

[0064] In an optional embodiment, the R 4 Selected from hydroxy, halogen or C 1-6 Alkyl, wherein z is selected from 0, 1, 2 or 3.

[0065] In an optional embodiment, the R 4 is selected from fluorine, chlorine, methyl or ethyl, and z is selected from 0 or 1.

[0066] In an optional embodiment, the R 5 Selected from hydroxy, halogen or C 1-6 Alkyl, wherein u is selected from 0, 1 or 2.

[0067] In an optional embodiment, the R 5 is selected from fluorine, chlorine, methyl or ethyl, and u is selected from 0 or 1.

[0068] In an optional embodiment, the R 4 and R 5 are each independently selected from fluorine, chlorine, methyl or ethyl, and said z and u are each independently selected from 0 or 1.

[0069] In an optional embodiment, the chelating agent in B is selected from:

[0070] In an optional embodiment, the chelating agent in B is

[0071] In an optional embodiment, the chelating agent in B is

[0072] In an optional embodiment, the radioactive element in B is selected from 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 Such as 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 Er.

[0073] In an optional embodiment, the radioactive element in B is 64 Cu.

[0074] In an optional embodiment, the radioactive element in B is 68 Ga.

[0075] In an optional embodiment, the radioactive element in B is 18 F.

[0076] In an optional embodiment, the radioactive element in B is selected from: 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 I.

[0077] In an optional embodiment, the present disclosure provides the following compound or a pharmaceutically acceptable salt thereof,

[0078] In an optional embodiment, the present disclosure provides the following compound or a pharmaceutically acceptable salt thereof,

[0079] In an optional embodiment, the present disclosure provides the following compound or a pharmaceutically acceptable salt thereof,

[0080] The structural formula can also be

[0081] In an optional embodiment, the present disclosure provides the following compound or a pharmaceutically acceptable salt thereof,

[0082] The structural formula can also be

[0083] In an optional embodiment, the present disclosure provides the following compound or a pharmaceutically acceptable salt thereof,

[0084] The structural formula can also be

[0085] In an optional embodiment, the present disclosure provides the following compound or a pharmaceutically acceptable salt thereof,

[0086] The structural formula can also be

[0087] In an optional embodiment, the present disclosure provides the following compound or a pharmaceutically acceptable salt thereof,

[0088] The structural formula can also be

[0089] In an optional embodiment, the present disclosure provides the following compound or a pharmaceutically acceptable salt thereof,

[0090] The structural formula can also be

[0091] In an optional embodiment, the present disclosure provides the following compound or a pharmaceutically acceptable salt thereof,

[0092] In an optional embodiment, the present disclosure provides the following compound or a pharmaceutically acceptable salt thereof,

[0093] In an optional embodiment, the present disclosure provides the following compound or a pharmaceutically acceptable salt thereof,

[0094] In an optional embodiment, the present disclosure provides the following compound or a pharmaceutically acceptable salt thereof,

[0095] The present disclosure further provides a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents, and excipients.

[0096] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0097] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0098] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0099] On the other hand, the present disclosure discloses a method for preparing the aforementioned compound or its pharmaceutically acceptable salt, or drug combination, comprising the step of complexing the compound represented by formula (I), formula (II-1), or formula (II-2) or its pharmaceutically acceptable salt with a radioactive element.

[0100] The present disclosure further discloses a method for imaging a disease or condition associated with fibroblast activation protein, comprising the steps of: 1) administering the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition to a patient; 2) acquiring an image.

[0101] The present disclosure further discloses a method for inhibiting fibroblast activation protein, which comprises administering the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition to a patient.

[0102] The present disclosure further discloses a method for diagnosing or treating a disease or disorder associated with fibroblast activation protein, comprising administering the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition to a patient.

[0103] In an optional embodiment, in the method of imaging a disease or condition associated with fibroblast activation protein, the method of inhibiting fibroblast activation protein, or the method of treating a disease or condition associated with fibroblast activation protein provided by the present disclosure, an effective amount of a compound represented by formula (I), formula (II-1), or formula (II-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, is administered to the patient.

[0104] The present disclosure further discloses use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the preparation of a medicament for imaging a disease or condition associated with fibroblast activation protein, or for treating a disease or condition associated with fibroblast activation protein.

[0105] The present disclosure further relates to compounds represented by formula (I), formula (II-1), and formula (II-2), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, which are used as drugs.

[0106] The present disclosure further relates to compounds represented by formula (I), formula (II-1), and formula (II-2), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, for use in imaging diseases or conditions associated with fibroblast activation protein.

[0107] The present disclosure further relates to compounds represented by formula (I), formula (II-1), and formula (II-2), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, for use in inhibiting fibroblast activation protein.

[0108] The present disclosure further relates to compounds represented by formula (I), formula (II-1), and formula (II-2), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, which are used for diagnosing or treating diseases or conditions associated with fibroblast activation protein.

[0109] The diseases or disorders associated with fibroblast activation protein described in the present disclosure are selected from the group consisting of proliferative diseases, chronic inflammation, fibrosis (liver, kidney, lung), tissue remodeling, scarring, tissue infection, or inflammatory lesions.

[0110] The present disclosure further discloses the use of the aforementioned compound or its pharmaceutically acceptable salt or pharmaceutical composition in the preparation of a medicament for preventing, diagnosing, or treating proliferative diseases, chronic inflammation, fibrosis (liver, kidney, lung), tissue remodeling, scar disease, tissue infection, or inflammatory lesions.

[0111] The proliferative disease described in the present disclosure 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 carcinoma, melanoma, fibrosarcoma, bone and connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma and adenocarcinoma, and benign tumors.

[0112] The chronic inflammation in the present disclosure is selected from rheumatoid arthritis, osteoarthritis, Crohn's disease, and atherosclerotic plaque.

[0113] The tissue remodeling in the present disclosure is performed after myocardial infarction. The scar disease in the present disclosure is selected from scar formation, scar tumor or scar.

[0114] A preparation method of compound 7 shown below,

[0115] Including compound 2 under acidic conditions (such as acetic acid / sodium acetate buffer) and 18 F - and AlCl3 at a high temperature (e.g. 75-100° C.)

[0116] A preparation method of compound 5 shown below,

[0117] Including compound 2 under acidic conditions (such as acetic acid / sodium acetate buffer) and 68 The step of reacting GaCl3 at high temperature (e.g. 75-100°C).

[0118] A preparation method of compound 9 shown below,

[0119] Including compound 2 under acidic conditions (such as acetic acid / sodium acetate buffer) and 64 The step of reacting CuCl2 at high temperature (e.g. 75-100°C).

[0120] A method for preparing compound 2, comprising the step of removing the tert-butyl protecting group of compound 2-a under acidic conditions (such as trifluoroformic acid),

[0121] In an optional embodiment, the preparation method of the aforementioned compounds 5, 7 and 9 comprises the step of removing the tert-butyl protecting group of compound 2-a under acidic conditions (eg, trifluoroformic acid) to obtain compound 2,

[0122] In an optional embodiment, the preparation method of the aforementioned compounds 5, 7 and 9 or compound 2 comprises 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 (eg, an onium salt-type condensation agent, specifically HATU, etc.) to obtain compound 2-a.

[0123] In an optional embodiment, the preparation method of the aforementioned compounds 5, 7 and 9 or compound 2 comprises the step of removing the tert-butyloxycarbonyl protecting group of compound 1-c under acidic (eg, hydrochloric acid, etc.) or alkaline conditions to obtain compound 1-b.

[0124] In an optional embodiment, the preparation method of the aforementioned compounds 5, 7 and 9 or compound 2 comprises the step of reacting compounds 1-f and 1-d in the presence of a condensing agent (e.g., 1-propylphosphotricyclic anhydride) to obtain compound 1-c.

[0125] In an optional embodiment, the preparation method of the aforementioned compounds 5, 7 and 9 or compound 2 comprises the step of demethylating the protecting group of compound 1-g under alkaline conditions (eg, lithium hydroxide) to obtain compound 1-f:

[0126] A preparation method of compound 8 shown below,

[0127] Including compound 1 under acidic conditions (such as acetic acid / sodium acetate buffer) and 64 The step of reacting CuCl2 at a high temperature (e.g. 75-100°C)

[0128] A method for preparing compound 1, comprising the step of removing the tert-butyl protecting group of compound 1-a under acidic conditions (such as trifluoroformic acid),

[0129] In an optional embodiment, the preparation method of the aforementioned compound 8 or compound 1 comprises the step of reacting compound 1-b with a compound DOTA-tris(t-Bu ester) under the catalytic action of a polypeptide condensation reagent (e.g., an onium salt-type condensation agent, specifically HATU, etc.) to obtain compound 1-a.

[0130] In an optional embodiment, the preparation method of the aforementioned compound 8 or compound 1 comprises the step of removing the tert-butyloxycarbonyl protecting group of compound 1-c under acidic (eg, hydrochloric acid, etc.) or alkaline conditions to obtain compound 1-b.

[0131] In an optional embodiment, the preparation method of the aforementioned compound 8 or compound 1 comprises the step of reacting compounds 1-f and 1-d in the presence of a condensing agent (e.g., 1-propylphosphotricyclic anhydride) to obtain compound 1-c.

[0132] In an optional embodiment, the preparation method of the aforementioned compound 8 or compound 1 comprises the step of demethylating the protecting group of compound 1-g under alkaline conditions (eg, lithium hydroxide) to obtain compound 1-f:

[0133] The present disclosure further provides the following compounds:

[0134] In the compound represented by formula (I) of the present disclosure

[0135] The long key representation, indicating It can be connected to any position of the quinoline ring except the 1-position and the 4-position.

[0136] In the present disclosure, the way in which the chelating agent and the radioactive element are connected in the structure of the radioactive element labeled compound is not limited to one. Taking compound 7 as an example,

[0137] The structural formula can also be expressed as:

[0138] in All represent chelating agents and Al 18 F forms a coordination bond.

[0139] The pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts.

[0140] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0141] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0142] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations. In the chemical structure of the compound disclosed in the present invention, the bond No configuration is specified, i.e. the bond The configuration can be E-type or Z-type, or include both E and Z configurations.

[0143] Compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. The lactam-lactim equilibrium example is between A and B as shown below.

[0144] All compounds in this disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of the present invention. The naming of the compounds does not exclude any tautomers.

[0145] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 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 Cl et al.

[0146] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0147] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0148] Explanation of terms:

[0149] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0150] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration (FDA) for use by humans or domestic animals.

[0151] As used herein, an "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0152] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups having 1 to 20 carbon atoms. Alkyl groups having 1 to 6 carbon atoms include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched chain isomers.

[0153] "Alkenyl" refers to an unsaturated aliphatic straight or branched chain hydrocarbon group containing one or more carbon-carbon double bonds. Exemplary alkenyl groups include C2-C8, C2-C7, C2-C6, C2-C4, C3-C 12 and C3-C6 alkenyl, including, but not limited to, ethenyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotyl), and the like.

[0154] "Alkynyl" refers to an unsaturated aliphatic straight or branched chain hydrocarbon group containing one or more carbon-carbon triple bonds. Exemplary alkenyl groups include C2-C8, C2-C7, C2-C6, C2-C4, C3-C 12 and C3-C6 alkynyl. Including but not limited to ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl and pent-1,4-diynyl. Alkenyl used in any context herein is optionally substituted in the same manner as alkyl.

[0155] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 12 carbon atoms, preferably 4 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0156] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 7 ring atoms. Non-limiting examples of "heterocycloalkyl" include:

[0157] wait.

[0158] The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples of which include:

[0159] wait.

[0160] Heterocycloalkyl groups may be optionally substituted or unsubstituted.

[0161] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy.

[0162] The term "alkylthio" refers to -S-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include methylthio, ethylthio, propylthio, and butylthio.

[0163] A "monovalent group" is a compound formed by formally eliminating a monovalent atom or group. A "subunit" is a compound formed by formally eliminating two monovalent or one divalent atom or group.

[0164] The term "alkylene" refers to the portion remaining after removing two hydrogen atoms from an alkane molecule, including straight and branched subgroups of 1 to 20 carbon atoms. Non-limiting examples of alkylene groups containing 1 to 6 carbon atoms include methylene (-CH2-), ethylene (e.g., -CH2CH2- or -CH(CH3)-).

[0165] Similarly, the definitions of "alkyleneoxy", "alkenylene", "alkenyleneoxy", "cycloalkylene" and "heterocycloalkylene" are the same as "alkylene".

[0166] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0167] Aryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 3 to 8 membered cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl are optionally substituted by one or more selected from halogen, hydroxy, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy substitution.

[0168] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, wait.

[0169] The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0170] Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy.

[0171] The term "spirocyclic" refers to a compound in which two rings share one atom. Non-limiting examples of spiroalkyl groups include:

[0172] The term "cycloalkyl" refers to a compound in which two or more rings are joined by sharing two adjacent atoms. Non-limiting examples of cycloalkyl groups include:

[0173] 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, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0174] The term "heterocycle" refers to a ring having atoms other than carbon atoms, and includes heterocycloalkyl and heteroaryl rings.

[0175] The term "hydroxy" refers to an -OH group.

[0176] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0177] The term "cyano" refers to -CN.

[0178] The term "amino" refers to -NH2.

[0179] The term "nitro" refers to -NO2.

[0180] The term "oxo" refers to a =0 substituent.

[0181] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently replaced by a corresponding number of substituents. When the substituent is keto or oxo (i.e., =O), then two (2) hydrogen atoms on the atom are replaced.

[0182] DOTA-tri-tert-butyl ester:

[0183] NOTA-di-tert-butyl ester:

[0184] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0185] T3P: 1-propylphosphonic tricyclic anhydride. DETAILED DESCRIPTION

[0186] The present disclosure is further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure.

[0187] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0188] The HPLC / MS analysis chromatographic conditions in the present disclosure are as follows:

[0189] 10 μl of each sample was automatically injected. Mobile phase: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile. Flow rate: 1.5 ml / min. Gradient: B increased from 10% to 95% over 0-6 min, from 95% to 100% over 6-8 min, from 100% to 10% over 8-8.10 min, and maintained at 10% B over 8.10-11.0 min.

[0190] Equipment model: Thermo Fisher ULTIMATE3000 ISQEM.

[0191] Chromatographic column: Eclipse Plus C18, 3.5 nm, 4.6 × 100 mm.

[0192] UV detection wavelength: 254nM.

[0193] Compound purity data were obtained by manual integration and molecular weight [M+1] was collected. + .

[0194] The chromatographic conditions for the preparative liquid phase in this disclosure are as follows:

[0195] Mobile phase: A: 0.1% trifluoroacetic acid in water, B: 0.1% trifluoroacetic acid in acetonitrile. Flow rate: 16 ml / min. Gradient: B increased from 25% to 35% over 0-25.0 min, from 35% to 70% over 25.0-25.1 min, and maintained at 70% B over 25.1-33.0 min.

[0196] Equipment model: Agilent AGILENT1260Ⅱ.

[0197] Chromatographic column: HPLCONE, 5.0 μm, 30 × 250 mm.

[0198] UV detection wavelength: 254 nM. The target compound was collected and lyophilized.

[0199] Example 1. Preparation of 6-(trans-4-(((2-(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl)amino)methyl)cyclohexane-1-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (1)

[0200] Step 1. Preparation of methyl 6-aminoquinoline-4-carboxylate hydrochloride (1-h)

[0201] In an ice bath, 12.5 g of acetyl chloride was slowly added dropwise to 100 ml of methanol. The mixture was stirred at room temperature for 0.5 h. 5.0 g of 6-aminoquinoline-4-carboxylic acid was added and the mixture was heated under reflux for 12 h. The solvent was evaporated to dryness, the mixture was slurried with isopropyl ether, and filtered to obtain compound 1-h (6.23 g, yield: 98.2%).

[0202] MS m / z(ESI):203.03[M+1] + .

[0203] Step 2. Preparation of methyl 6-(trans-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexan-1-yl)formamidoquinoline-4-carboxylate (1-g)

[0204] Compound 1-h (500 mg, 636 mg of trans-4-(tert-butyloxycarbonylaminomethyl)cyclohexanecarboxylic acid, 2832 mg of propylphosphonic tricyclic anhydride ethyl acetate solution (T3P, 50% mass concentration), and 959 mg of N,N-diisopropylethylamine) were added to 30 ml of tetrahydrofuran under ice-cooling conditions. The mixture was allowed to react at 35°C for 8 hours. The reaction solution was poured into 0.5N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain compound 1-g (887 mg, yield: 95.9%).

[0205] MS m / z(ESI):442.32[M+1] + .

[0206] Step 3. Preparation of 6-(trans-4-(((tert-Butoxycarbonyl)amino)methyl)cyclohexan-1-yl)formamidoquinoline-4-carboxylic acid (1-f)

[0207] Compound 1-g (600 mg) was added to 20 ml of a 1:1 tetrahydrofuran / water mixed solvent, followed by 171 mg of lithium hydroxide monohydrate. The mixture was reacted at room temperature for 3 hours. The tetrahydrofuran in the solvent was evaporated, and the pH was adjusted to 3-4 with 0.5N hydrochloric acid. A large amount of solid precipitated, which was filtered to obtain compound 1-f (543 mg, yield: 93.6%).

[0208] MS m / z(ESI):428.11[M+1] +

[0209] Step 4. Preparation of (S)-1-(2-((tert-Butyloxycarbonyl)amino)acetyl)-4,4-difluoropyrrolidine-2-carbonitrile (1-e)

[0210] Under ice conditions, 5.0 g of (S)-4,4-difluoropyrrolidine-2-carbonitrile hydrochloride, 5.0 g of Boc-glycine, 31.5 g of propylphosphonic tricyclic anhydride in ethyl acetate (T3P, 50% mass concentration), 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 solution was poured into 0.5 N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain compound 1-e (7.8 g, 90.4% yield).

[0211] MS m / z(ESI):290.08[M+1] + .

[0212] Step 5. Preparation of (S)-1-aminoacetyl-4,4-difluoropyrrolidine-2-carbonitrile (1-d)

[0213] 7.8 g of compound 1-e was dissolved in 100 ml of 3.0 mol / L hydrochloric acid and ethyl acetate solution, stirred at room temperature for 5 hours, and the solvent was evaporated to obtain compound 1-d (6.07 g, yield: 98.7%).

[0214] MS m / z(ESI):190.13[M+1] + .

[0215] Step 6. Preparation of 6-(trans-4-(((tert-Butoxycarbonyl)amino)methyl)cyclohexan-1-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (1-c)

[0216] Under ice conditions, 500 mg of compound 1-f, 221 mg of 1-d, 1340 mg of 1-propylphosphoric acid tricyclic anhydride (T3P) in ethyl acetate (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 solution was poured into 0.5N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain compound 1-c (572 mg, 81.7% yield).

[0217] MS m / z(ESI):599.10[M+1] + .

[0218] Step 7. Preparation of 6-(trans-4-(aminomethyl)cyclohexan-1-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (1-b)

[0219] 572 mg of compound 1-c was dissolved in 30 ml of 3.0 mol / L hydrochloric acid and ethyl acetate solution, stirred at room temperature for 5 hours, and the solvent was evaporated to obtain compound 1-b (461 mg, yield: 96.7%).

[0220] MS m / z(ESI):499.13[M+1] + .

[0221] Step 8. Preparation of 6-(trans-4-(((2-(4,7,10-tri-tert-butoxycarbonylmethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl)amino)methyl)cyclohexan-1-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (1-a)

[0222] Compound 1-b (300 mg), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl ester (DOTA-tris(t-Bu ester)) (413 mg), HATU (412 mg), and N,N-diisopropylethylamine (233 mg) were dissolved in tetrahydrofuran and reacted at 35°C for 5 hours. The reaction solution 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 and purified by silica gel column chromatography using a dichloromethane / methanol (0% to 20%) eluent to afford compound 1-a (464 mg, 73.2% yield).

[0223] MS m / z(ESI):1053.46[M+1] + .

[0224] Step 9. Preparation of 6-(trans-4-(((2-(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl)amino)methyl)cyclohexane-1-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (1)

[0225] 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 at room temperature overnight. The solvent was evaporated to dryness, and the mixture was purified by preparative liquid separation and lyophilized to obtain the target compound 1 (166 mg, yield: 42.5%).

[0226] MS m / z(ESI):885.36[M+1] + .

[0227] Example 2. Preparation of 6-(trans-4-(((2-(4,7-dicarboxymethyl-1,4,7-triazacyclopentane-1-yl)acetyl)amino)methyl)cyclohexane-1-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (2)

[0228] Compound 2 was prepared by the same method as compound 1.

[0229] Step 1. Preparation of 6-(trans-4-(((2-(4,7-di-tert-butoxycarbonylmethyl-1,4,7-triazacyclopentane-1-yl)acetyl)amino)methyl)cyclohexane-1-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (2-a)

[0230] Compound 1-b (300 mg), di-tert-butyl 1,4,7-triazacyclononane-1,4,7-triacetate (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 solution 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 and purified by silica gel column chromatography using an eluent system of dichloromethane / methanol = methanol (0% to 20%) to obtain compound 2-a (368 mg, yield: 68.2%).

[0231] MS m / z(ESI):896.33[M+1] + .

[0232] Step 2. Preparation of 6-(trans-4-(((2-(4,7-dicarboxymethyl-1,4,7-triazacyclopentane-1-yl)acetyl)amino)methyl)cyclohexane-1-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (2)

[0233] 368 mg of compound 2-a was dissolved in 20 ml of dichloromethane, and 20 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature overnight, and the solvent was evaporated to dryness. The mixture was purified by preparative liquid separation and lyophilized to obtain the target compound 2 (125 mg, yield: 38.7%).

[0234] 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).

[0235] MS m / z(ESI):784.10[M+1] + .

[0236] Example 3. Preparation of 6-((6r,9r)-N-(2-(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1-oxa-4-azaspiro[5.5]undec-9-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (3)

[0237] Compounds 1-h and 1-d were prepared by referring to the method of compound 1.

[0238] Step 1. Preparation of methyl 6-((6r,9r)-N-tert-butyloxycarbonyl-1-oxa-4-azaspiro[5.5]undec-9-yl)formamidoquinoline-4-carboxylate (3-g)

[0239] Under ice 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 1-propylphosphonic tricyclic anhydride in ethyl acetate (T3P, 50% mass concentration), and 959 mg of N,N-diisopropylethylamine were added to 30 mL of tetrahydrofuran. The reaction was allowed to proceed at 35°C for 8 hours. The reaction solution was poured into 0.5N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain compound 3-g (815 mg, 93.2% yield).

[0240] MS m / z(ESI):484.35[M+1] + .

[0241] Step 2. Preparation of 6-((6r,9r)-N-tert-butyloxycarbonyl-1-oxa-4-azaspiro[5.5]undec-9-yl)formamidoquinoline-4-carboxylic acid (3-f)

[0242] Compound 3-g (815 mg) was added to 20 ml of a 1:1 tetrahydrofuran / water mixed solvent. 214 mg of lithium hydroxide monohydrate was added and the mixture was reacted at room temperature for 3 hours. The tetrahydrofuran in the solvent was evaporated and the pH was adjusted to 3-4 with 0.5 N hydrochloric acid. A large amount of solid precipitated and was filtered to obtain compound 3-f (543 mg, yield: 95.7%). MS m / z (ESI): 470.31 [M+1] + .

[0243] Step 3. Preparation of 6-((6r,9r)-N-tert-butyloxycarbonyl-1-oxa-4-azaspiro[5.5]undec-9-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (3-c)

[0244] Under ice-cooling conditions, 500 mg of compound 3-f, 240 mg of 1-d, 1340 mg of propylphosphonic tricyclic anhydride in ethyl acetate (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 solution was poured into 0.5N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated to give compound 3-c (521 mg, yield: 76.3%). MS m / z (ESI): 641.29 [M+1]. + .

[0245] Step 4. Preparation of 6-((6r,9r)-1-oxa-4-azaspiro[5.5]undec-9-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (3-b)

[0246] 521 mg of compound 3-c was dissolved in 30 ml of 3.0 mol / L hydrochloric acid and ethyl acetate solution, stirred at room temperature for 5 hours, and the solvent was evaporated to obtain compound 3-b (619 mg, yield: 94.8%).

[0247] MS m / z(ESI):541.24[M+1] + .

[0248] Step 5. Preparation of 6-((6r,9r)-N-(2-(4,7,10-tri-tert-butoxycarbonylmethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1-oxa-4-azaspiro[5.5]undec-9-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (3-a)

[0249] Compound 3-b (300 mg), tri-tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA-tris(t-Bu ester)) (357 mg), 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 solution 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 and purified by silica gel column chromatography using a dichloromethane / methanol (0% to 20%) eluent to obtain compound 3-a (395 mg, 69.4% yield).

[0250] MS m / z(ESI):1095.58[M+1] + .

[0251] Step 6. Preparation of 6-((6r,9r)-N-(2-(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1-oxa-4-azaspiro[5.5]undec-9-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (3)

[0252] 395 mg of compound 3-a was dissolved in 20 ml of dichloromethane, and 20 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature overnight, and the solvent was evaporated to dryness. The mixture was purified by preparative liquid separation and freeze-dried to obtain the target compound 3 (89 mg, yield: 26.6%).

[0253] MS m / z(ESI):927.34[M+1] + .

[0254] Example 4. Preparation of 6-((6r,9r)-N-(2-(4,7-dicarboxymethyl-1,4,7-triazacyclopentane-1-yl)acetyl)-1-oxa-4-azaspiro[5.5]undec-9-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (4)

[0255] Compound 4 was prepared by the same method as compound 3.

[0256] Step 1. Preparation of 6-((6r,9r)-4-(N-(2-(4,7-di-tert-butoxycarbonylmethyl-1,4,7-triazacyclopentane-1-yl)acetyl)-1-oxa-4-azaspiro[5.5]undec-9-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (4-a)

[0257] Compound 3-b (300 mg), 1,4,7-triazacyclononane-1,4,7-triacetic acid 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 solution 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 and purified by silica gel column chromatography using an eluent system of dichloromethane / methanol = methanol (0% to 20%) to obtain compound 4-a (386 mg, yield: 79.1). MS m / z (ESI): 938.42 [M+1]. + .

[0258] Step 2. Preparation of 6-((6r,9r)-4-(N-(2-(4,7-dicarboxymethyl-1,4,7-triazacyclopentane-1-yl)acetyl)-1-oxa-4-azaspiro[5.5]undec-9-yl)formamido-4-((S)-2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoylquinoline (4)

[0259] 386 mg of compound 4-a was dissolved in 20 ml of dichloromethane, and 20 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature overnight, and the solvent was evaporated to dryness. The mixture was purified by preparative liquid separation and freeze-dried to obtain the target compound 4 (179 mg, yield: 52.7%).

[0260] 1 H 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).

[0261] MS m / z(ESI):826.33[M+1]+ .

[0262] Example 5. Preparation of Compound 5

[0263] Add 0.1 ml of sodium acetate buffer to the reaction flask, and then add 0.9 mL 68 GaCl3 solution (0.1N hydrochloric acid solution) and 5 μL aqueous solution of 6 nmol of compound 2. The reaction solution was kept at pH 3.0-5.0 and heated at 95°C for 10-15 minutes.

[0264] The labeled reaction solution was diluted with 2 mL of normal saline. The impurity content was less than 10% as determined by ITLC and was used directly in animal imaging experiments.

[0265] Example 6. Preparation of Compound 6

[0266] Add 0.1 ml of sodium acetate buffer to the reaction flask, and then add 0.9 ml 68 GaCl3 solution (0.1N hydrochloric acid solution) and 5 μL aqueous solution of 6 nmol of compound 4. The pH of the reaction solution was maintained at 3.0-5.0 and heated at 95°C for 10-15 minutes.

[0267] The labeled reaction solution was diluted with 2 mL of normal saline. The impurity content was less than 10% as determined by ITLC and was used directly in animal imaging experiments.

[0268] Example 7. Preparation of Compound 7

[0269] 1 μl of 10 mM compound 2 aqueous solution was added to 50-100 μl of 0.5 M acetic acid / sodium acetate buffer at pH 4.0-4.4, followed by 2 mM AlCl3 aqueous solution at a molar ratio of 2:1, and 1850 MBq of QMA-purified 18 F - 50 μl of ion was reacted at 100°C for 10-15 minutes. Purification was performed using an HLB solid-phase extraction cartridge, eluting with ethanol / water (1:1), and diluting with saline to less than 10% ethanol. Radiochemical purity was greater than 90% as determined by radio-HPLC and was used directly in animal imaging experiments.

[0270] Example 8. Preparation of Compound 8

[0271] 5 μl of 10 mM compound 1 aqueous solution was dissolved in 100 μl of pH 3.5-6.5 acetic acid / sodium acetate buffer solution, and then 1850 MBq of 0.1 M hydrochloric acid was added. 64 50 μl of CuCl2 solution was reacted at 80°C for 15 min, purified using a C18 column, and diluted with saline to a concentration of less than 10% ethanol. Radiochemical purity was determined by radio-HPLC, with a radiochemical purity of 95.26%.

[0272] Example 9. Preparation of Compound 9

[0273] 5 μl of 10 mM compound 2 aqueous solution was dissolved in 100 μl of pH 3.5-6.5 acetic acid / sodium acetate buffer solution, and then 1850 MBq of 0.1 M hydrochloric acid was added. 64 50 μl of CuCl2 solution was reacted at 80°C for 15 min, purified using a C18 column, and diluted with physiological saline to a concentration of less than 10% ethanol. Radiochemical purity was determined by radio-HPLC, with a radiochemical purity of 95.82%.

[0274] Biological evaluation

[0275] The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure.

[0276] Test Example 1: FAPα enzyme activity test

[0277] 1.1 Experimental materials and instruments

[0278] Table 1. Source information of experimental materials and instruments

[0279] 1.2 Experimental steps

[0280] Dilute the substrate (Z-Gly-Pro-AMC) to a 0.5 mM stock solution with DMSO. Dilute the 0.5 mM stock solution to 50 μM with PBS before each experiment. Dilute FAPα protein to 0.5 ng / μl with PBS. Dilute the test compound and positive control to a concentration of 100 nM or 200 nM with PBS for single-point inhibition determination. For single-point inhibition rates comparable to those of the positive compound, further IC 50To determine the value, dilute the test compound and positive control with PBS to a maximum concentration of 10 μM and a minimum concentration of 0 nM. Perform a 5-fold serial dilution, for a total of eight steps. Testing method: Add 85 μl of FAPα dilution and 10 μl of compound dilution to the microplate, mix thoroughly, incubate at 37°C for 10 minutes, add 5 μL of 50 μM substrate, mix thoroughly, and incubate at 37°C for 10 minutes. Read on a microplate reader with excitation at 380 nm and emission at 465 nm.

[0281] 1.3 Experimental Results

[0282] Table 2.1 Inhibition rate (100 nM) and IC of the disclosed compounds on FAPα enzyme 50

[0283] The IC of compound 2 against FAPα was determined using the same method. 50 The value is 0.71 times that of the positive drug FAPI-04, which is equivalent to the positive drug; the IC of FAP-42 for FAPα enzyme 50 The value is 2.27 times that of the positive drug FAPI-04.

[0284] Note: The structure of FAPI-04 is as follows:

[0285] Reference: CN111699181A, P.60

[0286] The structure of FAP-42 is shown below: CN111699181A, p.61

[0287] Test Example 2. 68 Ga, 18 PET imaging testing of F-labeled compounds

[0288] 2.1 Experimental Materials

[0289] cell:

[0290] Cell information: U-87MG cells (Wuhan Pronocell Life Science Co., Ltd., Catalog No. CL-0238, Lot No. YBMIL8BQH0); Culture conditions: U-87MG cell-specific medium (MEM + 10% FBS + 1% P / S); Passage number: 6-9;

[0291] Experimental animals:

[0292] Strain: BALB / c nude mice; Age: 4-5 weeks; Weight: 15-22 g;

[0293] Reagents:

[0294] PBS (Solaibao, P1020)

[0295] Matrigel (ABW, 0827045)

[0296] Trypsin-EDTA (Gibco, 25200-072)

[0297] U-87MG special culture medium (Punosai, CM-0238)

[0298] instrument:

[0299] Small animal PET / CT (ediso, nanoScan PET / CT 4 heads)

[0300] Activity meter (Capintec, activity meter)

[0301] Electronic balance (Changzhou Shuangjie, DT100)

[0302] 2.2 Experimental steps

[0303] Model building

[0304] Prepare sufficient amount of U-87MG cells and inoculate them into the posterior position of the right forelimb of B-NDG mice. The inoculation volume is 100 μL containing 50% Matrigel and 4×10 6 cells.

[0305] Steps

[0306] Wipe the work surface with 75% medical alcohol and lay a disposable sterile tablecloth. Prepare a 0.5mL insulin syringe, alcohol pad, cotton swab, and marker in the injection room. Place the mouse in a mouse holder and disinfect the mouse's tail with an alcohol pad. Administer 0.2-0.5mL of the prepared test sample via the tail vein of each mouse. Record the time of each injection, the activity of the syringe, and the activity of the empty needle. Anesthetize the tumor-bearing mouse with isoflurane and place it in a prone position on a small animal PET station and secure it. Perform static PET images for 10 minutes at 0.5, 1, 2, and 4 hours after administration. Perform a whole-body CT scan before each static scan to obtain images of the labeled compound's distribution throughout the tumor-bearing mouse. Obtain PET images of each experimental animal at different time points after administration. Select and outline major organs, including the tumor, muscle, bone, lungs, brain, liver, and kidneys. Observe the radioactivity accumulation and clearance of the labeled compound in the tumor and non-target tissues of the tumor-bearing mouse.

[0307] 3. Experimental Results

[0308] Table 3.1 Uptake of the compounds disclosed herein in tumor (tissue)

[0309] Table 3.2 Uptake of the compounds disclosed herein in tumor (tissue)

[0310] Table 3.3 Uptake of the compounds disclosed herein in tumor (tissue)

[0311] Table 3.4 Ratio of the compounds disclosed herein in tumor tissue to non-target organs (tissues)

[0312] Table 3.5 Ratio of the compounds disclosed herein in tumor tissue to non-target organs (tissues)

[0313] Conclusion: Compound 5 exhibits higher tumor uptake than FAPI-04, but lower uptake in non-target organs (tissues), and a superior tumor / non-target organ (tissue) ratio compared to FAPI-04. Compound 7 exhibits higher tumor uptake than FAPI-04, and a superior tumor / non-target organ (tissue) ratio compared to FAPI-04.

[0314] Comparative Example 1. 18 PET imaging test of F-FAPI-42

[0315] The same experimental method as in Example 2 was used to observe the markings 18 The radioactivity concentration ratio of F-FAPI-42 compound in tumor and non-target tissues in tumor-bearing mice.

[0316] Table 4.1 18 F-FAPI-42 ratio of tumor tissue to non-target organs (tissues)

[0317] Experimental conclusion: In the U-87 mouse model, compound 7 18 F-FAPI-42 has lower non-target organ uptake in the gallbladder and intestine, indicating a higher safety profile for compound 7. Furthermore, compound 7 has higher tumor / gallbladder and tumor / intestinal uptake ratios, indicating that compound 7 can better distinguish tumor lesions from normal tissues and organs, demonstrating excellent targeting properties.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, R 1 and R 1 'Each independently selected from hydrogen, cyano, carboxyl, sulfonic acid, phosphoric acid or B (OH) 2; R 2 Each independently selected from hydroxyl, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR'R", -OC 1-6 Alkyl or -SC 1-6 alkyl; R 3 and R 3 ' are each independently selected from hydrogen, hydroxyl, halogen or C 1-6 alkyl; R 4 Selected from hydroxyl, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR'R", -OC 1-6 Alkyl or -SC 1-6 alkyl; Ring A is selected from 3- to 12-membered cycloalkylene or 3- to 12-membered heterocycloalkylene; R 5 Selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR'R" or -OC 1-6 alkyl; L1 is selected from a linking bond, -NH-, -CH2-NH- or -CH2CH2-NH-; x is selected from 0, 1, 2 or 3; R' and R" are each independently selected from hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl; 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 radiolabeled functional group suitable for optical imaging, positron emission tomography imaging, single photon emission computed tomography imaging or radiotherapy; preferably, B consists of a chelator 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. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1’ are each independently selected from hydrogen or cyano.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 2 Each independently selected from hydroxyl, halogen or C 1-6 Alkyl, x is selected from 2 or 3, preferably, R 2 are each independently selected from fluorine or chlorine.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 3 ' are each independently selected from hydrogen, halogen or C 1-6 Alkyl; preferably, R 3 and R 3 ' are all hydrogen.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 and 3 to 5, which is a compound represented by formula (II-1) or a pharmaceutically acceptable salt thereof, in, X1 and X2 are each 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 as defined in claim 1.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein i) X1 is CH, X2 is N; or ii) X1 is N, X2 is CH; or iii) X1 is CH, X2 is CH; Preferably, X1 is CH and X2 is CH.

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

9. The compound according to any one of claims 6 to 8 or a pharmaceutically acceptable salt thereof, wherein L1- is CH2-NH-.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 6 to 9, wherein X1 is CH, X2 is CH; s and t are both 1; L1 is selected from CH2-NH- or -CH2CH2-NH-, preferably -CH2-NH-.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 and 3 to 5, which is a compound represented by formula (II-2) or a pharmaceutically acceptable salt thereof, in, X3 and X4 are each independently selected from CH, N or O; s and t are each independently selected from 0, 1 or 2; w and v are each independently selected from 0, 1 or 2; and R 4 , R 5 , L1, B, z and u are as defined in claim 1.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein X3 is CH, X4 is O; or X3 is CH, X4 is N, or X3 is N, X4 is CH; Preferably, X3 is CH and X4 is O.

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

14. The compound according to any one of claims 11 to 13 or a pharmaceutically acceptable salt thereof, wherein L1 is a connecting key.

15. The compound according to any one of claims 11 to 14 or a pharmaceutically acceptable salt thereof, wherein X3 is CH, X4 is O; s and t are both 1, w and v are both 1; L1 is a connecting bond.

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

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

18. The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein The chelating agent in B is selected from: Best 19. The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein The B comprises a radioactive element, and the radioactive element is selected from 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 Such as 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 2. Optimum 18 F or 68 Ga; Or the radioactive element is selected from: 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 I.

20. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, selected from Best In particular, it is selected from 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, excipients.

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

23. Use 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 preparation of a medicament for imaging a disease or condition associated with fibroblast activation protein, or for treating a disease or condition associated with fibroblast activation protein.

24. The use according to claim 23, wherein The disease or condition associated with fibroblast activation protein is selected from a proliferative disease, chronic inflammation, fibrosis (liver, kidney, lung), tissue remodeling, scar disease, tissue infection or inflammatory lesions. The proliferative disease 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 plaques; the tissue remodeling occurs after myocardial infarction; the scar disease is selected from scar formation, scar tumor or scar scar.

25. Use 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 preparation of a medicament for preventing, diagnosing, or treating proliferative diseases, chronic inflammation, fibrosis (liver, kidney, lung), tissue remodeling, scar disease, tissue infection, or inflammatory lesions, wherein: The proliferative disease 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 plaques; the tissue remodeling occurs after myocardial infarction; the scar disease is selected from scar formation, scar tumor or scar scar.

26. A method for preparing compound 7 as shown below, Including compound 2 under acidic conditions with 18 F - The steps of the reaction with AlCl3, 27. A method for preparing compound 2, comprising the step of removing the tert-butyl protecting group of compound 2-a under acidic conditions, 28. The method for preparing compound 7 according to claim 26, comprising the step of preparing compound 2 according to claim 27.

29. The method for preparing compound 7 according to claim 26 or 28, or the method for preparing compound 2 according to claim 27, comprising the step of reacting compound 1-b with NOTA-di-tert-butyl ester under the catalysis of a polypeptide condensation reagent to obtain compound 2-a, 30. The method for preparing compound 7 according to any one of claims 26 and 28 to 29, or the method for preparing compound 2 according to any one of claims 27 and 29, comprising the step of removing the tert-butyloxycarbonyl protecting group of compound 1-c under acidic or alkaline conditions to obtain compound 1-b, 31. The method for preparing compound 7 according to any one of claims 26 and 28 to 30, or the method for preparing compound 2 according to any one of claims 27 and 29 to 30, comprising the step of reacting compounds 1-f and 1-d in the presence of a condensing agent to obtain compound 1-c, 32. The method for preparing compound 7 according to any one of claims 26 and 28 to 31, or the method for preparing compound 2 according to any one of claims 27 and 29 to 31, comprising the step of demethylating the protecting group of compound 1-g under alkaline conditions:

33. The compound shown below:

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