Compounds targeting folate receptors and uses thereof

Abstract

This application discloses a compound targeting the folic acid receptor and its uses. The compound is a structure represented by formula (I) or an isotopic variant thereof, a hydrate, an ester or solvate, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt. The compound of this application links a folic acid molecule fragment to a chelating group R via a linking group L, which can improve the compound's targeting and uptake in tumor tissues and reduce uptake in non-target tissues. It can be used as a PET imaging agent for tumor diagnosis, as a drug for tumor treatment, and as a therapeutic radiopharmaceutical. (I)

Description

Technical Field

[0001] This application belongs to the field of biomedical technology, specifically relating to compounds that target folate receptors and their uses, and more specifically to folate receptor-targeting compounds, metal complexes, pharmaceutical compositions and their uses. Background Technology

[0002] Folic acid receptors (FR-α) are a family of glycoproteins including FR-α, FR-β, FR-γ, and FR-δ. FR-α is expressed on the luminal surface of polarized epithelial cells in normal adult tissues, including proximal renal tubules, type I and type II alveolar cells in the lungs, choroid plexus, ovaries, fallopian tubes, uterus, epididymis, submandibular salivary glands and bronchial glands, trophoblasts in the placenta, and the basolateral membrane of retinal pigment epithelial cells. FR-α is overexpressed in various epithelial carcinomas, such as ovarian cancer, non-small cell lung cancer, breast cancer, and mesothelioma. It participates in DNA synthesis, repair, and methylation in tumor cells by transporting folic acid, and also participates in various cancer-related signaling pathways (JAK-STAT3, ER1 / 2, etc.), supporting the growth, proliferation, and survival of cancer cells. Studies have confirmed that ovarian cancer patients with high FR-α expression have shorter survival times compared to those with low expression, and increased FR-α expression during chemotherapy significantly shortens overall survival and progression-free survival. Because of the well-known inter- and intra-patient variability in the expression level of folate receptors in metastatic cancer patients, a method that can quantify the systemic folate receptor expression level will greatly benefit the clinical research and future practical application of folate receptor-targeted drugs (radioactive or non-radioactive).

[0003] Therefore, there is an urgent need to find a new type of folic acid receptor-targeted PET imaging agent and therapeutic agent. Summary of the Invention

[0004] This application aims to at least partially address one of the technical problems existing in the prior art. To this end, this application provides a compound that targets the folic acid receptor.

[0005] In the first aspect of this application, a compound is proposed, as follows: In one aspect, this application proposes a compound that is a structure of formula (I) or an isotopic variant thereof, a hydrate, an ester or solvate, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof: (I); in: Z is selected from a chelating group; L is selected from ; R1 and R2 are each independently empty, H, and -C. 1~3 Alkyl or -C1~3 Halogenated alkyl groups; It can be a single bond or a double bond; R3 is -C 1~3 Alkylene (6-12 membered aromatic group) or -C 1~3 alkylene-(5-12-membered heteroaryl); R4, R5, R6, and R7 are each independently -C 1~6 Alkylene; n is 0 or 1.

[0006] On the other hand, this application provides a compound that is the structure shown in formula (II) or an isotopic variant thereof, hydrate, ester or solvate, tautomer, stereoisomer, or pharmaceutically acceptable salt: (II); in, R1 and R2 are each independently empty, H, and -C. 1~3 Alkyl or -C 1~3 Halogenated alkyl groups; It can be a single bond or a double bond; R3 is -C 1~3 alkylene-(6-12-membered aromatic group); R4 is -C 1~6 Alkylene; n is 0 or 1; Z is selected from chelating groups.

[0007] In another aspect, this application provides a compound that is a structure or isotopic variant thereof, a hydrate, an ester or solvate, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt: , , , , , , , ,or .

[0008] In a second aspect of this application, a complex is proposed. According to an embodiment of this application, the complex comprises the compound described in the first aspect, and M complexed with the compound; the M is selected from radionuclides or non-radioactive elements.

[0009] In a third aspect of this application, a pharmaceutical composition is provided. According to embodiments of this application, the pharmaceutical composition comprises the compound described in the first aspect or the complex described in the second aspect.

[0010] In a fourth aspect of this application, the use of the compound described in the first aspect, the complex described in the second aspect, or the pharmaceutical composition described in the third aspect in the preparation of a medicament for the diagnosis and / or treatment of folic acid receptor overexpression diseases is provided.

[0011] In a fifth aspect of this application, a method for diagnosing and / or treating folic acid receptor overexpression disorders is provided. According to embodiments of this application, the method comprises administering to a subject a pharmaceutically acceptable dose of the compound described in the first aspect, the complex described in the second aspect, or the pharmaceutical composition described in the third aspect.

[0012] Beneficial effects: 1. The compounds in this application are mainly cleared by the kidneys, have high targeting, low uptake in non-target tissues, good targeting distribution ability and acceptable pharmacokinetic characteristics.

[0013] 2. The compounds in this application can effectively enter target cells and have good cellular uptake capacity.

[0014] 3. The compound of this application reaches the tumor site in about 0.5 hours and does not show a significant decrease in activity after about 4 hours. In terms of imaging performance, the compound of this application can form a clear tumor image in about 0.5 hours after administration, and the radioactive signal of the tumor area is clearly distinguished from the surrounding background tissue throughout the imaging process.

[0015] 4. The compounds in this application have anti-tumor activity and can significantly control tumor growth.

[0016] 5. The compounds in this application can maintain high tumor targeting while increasing tumor uptake, and can be used to develop therapeutic radiopharmaceuticals.

[0017] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description

[0018] The above and / or additional aspects and advantages of this application will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1 This is a diagram showing the cellular uptake results of each compound in Experiment 1 of this application in KB cells; Figure 2 Dosing in Trial 2 of this application 68 Figure 1 shows the uptake results of Ga-compound 1 in different tissues of SKOV-3 model mice. Figure 3Different time points after drug administration in Example 2 of this application 68 PET / CT imaging results of Ga-compound 1 on KB model mice; Figure 4 Different time points after drug administration in Experiment 2 of this application 68 Figure 1 shows the uptake results of Ga-compound 1 in different tissues of KB model mice; Figure 5 Different time points after drug administration in Experiment 2 of this application 18 PET / CT imaging results of F-compound 5 on KB model mice; Figure 6 Different time points after drug administration in Experiment 2 of this application 18 Figure 1: Uptake of F-compound 5 in different tissues of KB model mice; Figure 7 For the 4 hours and 48 hours after administration in Trial 3 of this application 177 Distribution of Lu-compound 1 in KB model ex vivo tissues; Figure 8 Dosing in Trial 4 of this application 177 A graph showing the tumor volume changes in a model mouse of Lu-compound 1. Detailed Implementation

[0019] The embodiments of this application are described in detail below. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0020] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this application, unless otherwise stated, "multiple" means two or more.

[0021] It should be noted that the structural and chemical formula descriptions in the embodiments or implementations of this application are intended to cover all alternatives, modifications, and equivalent technical solutions, all of which are within the scope of this application as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice this application. This application is by no means limited to the methods and materials described herein. In the event that one or more of the cited documents, patents, and similar materials differ from or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0022] It should be further appreciated that some features of this application, for clarity, have been described in multiple independent embodiments or implementations, but may also be provided in combination in a single embodiment or implementation. Conversely, various features of this application, for the sake of brevity, have been described in a single embodiment or implementation, but may also be provided individually or in any suitable sub-combination.

[0023] Unless otherwise stated, the technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains, and unless otherwise stated, all patent publications cited in the entirety of this application are incorporated herein by reference.

[0024] This application will apply the following definitions unless otherwise indicated. For the purposes of this application, chemical elements are defined according to the periodic table, CAS version, and Chemical Handbook, 75, 1994. Furthermore, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007; therefore, all contents of this application incorporate the references.

[0025] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this application but do not exclude other contents.

[0026] In this document, the compounds of this application also include isotopically labeled compounds of this application that are identical to those compounds described herein except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those of naturally common atomic masses or mass numbers. Exemplary isotopes that may also be introduced into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 16 O、 17 O、 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0027] Compounds of this application containing other isotopes of the aforementioned isotopes and / or other atoms, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of this application. Isotope-labeled compounds of this application, such as radioactive isotopes, are also included. 3 H and 14 The incorporation of tritium into the compounds of this application can be used for drug and / or substrate tissue distribution analysis. Due to its ease of preparation and detection, tritium-substituted compounds... 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred. In addition, heavier isotopes, such as deuterium, are used. 2 H substitution can offer therapeutic advantages stemming from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. Therefore, it may be preferred in some cases.

[0028] In this document, the term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is treated.

[0029] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of this application that are suitable for contact with patient tissues within the bounds of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of this application.

[0030] Pharmaceutically acceptable base addition salts are those formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0031] The base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form a salt. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and then separating the free acid. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents; however, for the purposes of this application, the salts are equivalent to their respective free acids.

[0032] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethanesulfonate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. It also covers amino acid salts, such as arginine salts, gluconates, galacturons, etc. (see, for example, Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0033] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0034] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0035] In this article, "C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl, C 1-3 Alkyl and C 1-2 Alkyl groups are preferred. C 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2). In some embodiments, straight-chain alkyl groups are preferred.

[0036] In this article, "C 1-6 "Alkylene" refers to the removal of C 1-6 The alkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene, C 1-3 Alkylene, C 1-2Alkylenes and methylene groups are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc. In some embodiments, straight-chain alkylene groups are preferred.

[0037] In this article, "halogenated" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0038] Therefore, "C" 1-6 "Halogenated alkyl" refers to the above "C 1-6 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl groups are particularly preferred, and C4 groups are more preferred. 1-3 Halogenated alkyl, more preferably C 1-2 The haloalkyl group, more preferably halomethyl, is used. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CH2CF3, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The haloalkyl group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] In this article, "C 8-12 "Aromatic group" and "8-12 membered aromatic group" both refer to monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring systems (e.g., groups having 6, 10, or 14 shared π electrons arranged in a ring) having 8-12 ring carbon atoms and zero heteroatoms. In some embodiments, C 10-12Aryl groups are preferred. In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C14”). 14 "Aryl"; for example, anthracene and phenanthrene (e.g., 1-anthrayl, 2-anthrayl, 1-phenanthrene, and 2-phenanthrene). Aryl groups also include ring systems in which the aforementioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0040] As used herein, the term “treatment” refers to reversing, alleviating, inhibiting, or preventing the progression of an obstacle or condition to which the term applies, or one or more symptoms of such an obstacle or condition. The noun “treatment” as used herein also refers to the action of the verb “to treat,” as defined above.

[0041] The "group description in this application" "" is used to describe the position of the substituent group.

[0042] In this application, the chemical structure of the compound contains the bond " "" indicates that the configuration is not specified. If chiral isomerism exists in the chemical structure, the bond " "can be " "", ", or both contain " "and" "Two configurations. Although all the above structural formulas are drawn in some isomer form for simplicity, this article may include all isomers, such as: tautomers, rotational isomers, geometric isomers, diastereomers, racemates and enantiomers."

[0043] In the chemical structure of the ligands or compounds described in this article, the bond " "" indicates that the configuration is not specified. If cis-trans isomerism exists in the chemical structure, the bond " The configuration of “” can be E type, Z type, or both E and Z types.

[0044] In this document, the term "pharmaceuticalally acceptable excipient" includes any solvent, salt, pharmaceutical stabilizer, or combination thereof, all of which are known to those skilled in the art (as described in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in cases where any conventional excipient is incompatible with the active ingredient, it covers its use in therapeutic or pharmaceutical compositions.

[0045] In this document, the term "subject" as used to administer the drug includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0046] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds in this application can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0047] Unless otherwise stated, the term "therapeuticly effective amount" of a compound as used herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0048] Unless otherwise stated, the “preventively effective amount” of a compound as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term “preventively effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0049] In this document, the term "administration" refers to the introduction of a predetermined amount of a substance into a patient in a suitable manner. The compounds or pharmaceutical compositions of this application may be administered via any common route, as long as it can reach the intended tissue. Various routes of administration are foreseeable, including peritoneal, intravenous, intramuscular, subcutaneous, etc., but this application is not limited to these exemplified routes of administration. Preferably, the compositions of this application are administered via intravenous or subcutaneous injection.

[0050] In this document, the term "treatment" refers to the administration of a drug or compound to an individual to achieve a desired pharmacological and / or physiological effect. This effect may be preventative in terms of complete or partial prevention of a disease or its symptoms, and / or therapeutic in terms of partial or complete cure of a disease and / or adverse effects caused by the disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) prevention of disease or the onset of a condition in an individual who is susceptible but has not yet been diagnosed with the disease; (b) inhibition of disease, such as blocking disease progression; or (c) relief of disease, such as reducing symptoms associated with the disease. As used herein, "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, relieve, improve, reduce, or inhibit the individual's disease, including but not limited to administration of a drug containing a compound described herein to an individual in need.

[0051] In this article, the terms “disease,” “disorder,” and “symptom” are used interchangeably.

[0052] In this document, the terms "cancer" or "tumor" can refer to any unregulated cell growth. Examples include, but are not limited to, non-small cell lung cancer, papillary thyroid carcinoma, glioblastoma multiforme, colon cancer, rectal cancer, lung cancer, head and neck cancer, kidney cancer, bladder cancer, breast cancer, ovarian cancer, liver cancer, bile duct cancer or sarcoma, acute myeloid leukemia, large cell neuroendocrine carcinoma, neuroblastoma, prostate cancer, neuroblastoma, pancreatic cancer, melanoma, head and neck squamous cell carcinoma, cervical cancer, skin cancer, glioma, esophageal cancer, oral squamous cell carcinoma, or gastric cancer, etc.

[0053] The term "combination" and related terms refer to the simultaneous or sequential administration of the compound of this application and other therapeutic agents. For example, the compound of this application may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form.

[0054] This application discloses a folic acid receptor-targeting compound, a metal complex, a pharmaceutical composition, and their uses, which will be described in detail below.

[0055] compound In the first aspect of this application, a compound is proposed, as follows: In one aspect, this application proposes a compound that is a structure of formula (I) or an isotopic variant thereof, a hydrate, an ester or solvate, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof: (I); in: Z is selected from a chelating group; L is selected from ; R1 and R2 are each independently empty, H, and -C. 1~3 Alkyl or -C 1~3 Halogenated alkyl groups; It can be a single bond or a double bond; R3 is -C 1~3 alkylene-(6-12 aryl) or -C 1~3 alkylene-(5-12-membered heteroaryl); R4, R5, R6, and R7 are each independently -C 1~6 Alkylene; n is 0 or 1.

[0056] According to embodiments of this application, the above-mentioned compound may further include at least one of the following technical features: According to an embodiment of this application, N is connected to R1. When it is a double bond, R1 is empty, and it is connected to N via R2. When it is a double bond, R2 is empty.

[0057] According to an embodiment of this application, N is connected to R1. N connected to R2 All are double bonds, with R1 and R2 being empty.

[0058] According to an embodiment of this application, N is connected to R1. N connected to R2 All are single bonds, R1 is H, -C 1~3 Alkyl or -C 1~3 For alkyl halogens, R2 is always H.

[0059] According to an embodiment of this application, R3 is -C 1~3 alkylene-(8-12 aryl) or -C 1~3 Alkylene-(8-12-membered heteroaryl).

[0060] According to an embodiment of this application, R3 is a methylene-10-membered aromatic group.

[0061] According to an embodiment of this application, R3 is -methylene-naphthyl.

[0062] According to an embodiment of this application, R4 is -C 3~6 Alkylene.

[0063] According to an embodiment of this application, R5 is -C 1~3 Alkylene.

[0064] According to an embodiment of this application, R6 is -C 3~6 Alkylene.

[0065] According to an embodiment of this application, R7 is -C 1~3 Alkylene.

[0066] According to an embodiment of this application, n is 0.

[0067] According to an embodiment of this application, L is selected from... or .

[0068] According to an embodiment of this application, L is selected from... or .

[0069] According to the embodiments of this application, Structure selected from , , , or .

[0070] According to embodiments of this application, the chelating group is derived from a chelating agent; The chelating agent is selected from 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid (DOTA). N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC) 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA), 1,4,7-Triazacyclononanephosphonic acid (TRAP) 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO) Diethyltriaminepentaacetic acid (DTPA) trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA) 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A) p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isocyanothiobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isocyanothiobenzyl)-4-methyl-DTPA (1M3B), 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA), [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA), 6-Hydroxypyridine-3-carboxylic acid (HYNIC) 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA), or 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA).

[0071] According to embodiments of this application, Z is selected from... DOTA NOTA、 NODAGA、 DOTAGA, HBED-CC, p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA and p-SCN-Bn-DOTA.

[0072] According to embodiments of this application, Z is selected from... DOTA, or NOTA.

[0073] On the other hand, this application provides a compound that is the structure shown in formula (II) or an isotopic variant thereof, hydrate, ester or solvate, tautomer, stereoisomer, or pharmaceutically acceptable salt: (II); in, R1 and R2 are each independently empty, H, and -C. 1~3 Alkyl or -C 1~3 Halogenated alkyl groups; It can be a single bond or a double bond; R3 is -C 1~3 alkylene-(6-12-membered aromatic group); R4 is -C 1~6 Alkylene; n is 0 or 1; Z is selected from chelating groups.

[0074] According to embodiments of this application, the above-mentioned compound may further include at least one of the following technical features: According to an embodiment of this application, n is 1, and R3 is a -methylene-10-membered aromatic group.

[0075] According to an embodiment of this application, n is 1, and R3 is -methylene-naphthyl.

[0076] According to an embodiment of this application, n is 0.

[0077] According to an embodiment of this application, N is connected to R1. When it is a double bond, R1 is empty, and it is connected to N via R2. When it is a double bond, R2 is empty.

[0078] According to an embodiment of this application, N is connected to R1. N connected to R2 All are double bonds, with R1 and R2 being empty.

[0079] According to an embodiment of this application, N is connected to R1. N connected to R2 All are single bonds, R1 is H, -C 1~3 Alkyl or -C 1~3 For alkyl halogens, R2 is always H.

[0080] According to embodiments of this application, the chelating group is derived from a chelating agent; The chelating agent is selected from 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid (DOTA). N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC) 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA), 1,4,7-Triazacyclononanephosphonic acid (TRAP) 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO) Diethyltriaminepentaacetic acid (DTPA) trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA) 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A) p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isocyanothiobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isocyanothiobenzyl)-4-methyl-DTPA (1M3B), 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA), [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA), 6-Hydroxypyridine-3-carboxylic acid (HYNIC) 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA), or 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA).

[0081] According to embodiments of this application, Z is selected from... DOTA NOTA、 NODAGA、 DOTAGA, HBED-CC, p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA and p-SCN-Bn-DOTA.

[0082] According to embodiments of this application, Z is selected from... DOTA, or NOTA.

[0083] According to the embodiments of this application, Structure selected from , , , or .

[0084] In another aspect, this application provides a compound that is a structure or isotopic variant thereof, a hydrate, an ester or solvate, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt: , , , , , , , ,or .

[0085] Complex In a second aspect of this application, a complex is proposed. According to an embodiment of this application, the complex comprises the compound described in the first aspect, and M complexed with the compound; the M is selected from radionuclides or non-radioactive elements.

[0086] According to embodiments of this application, the complex may further include at least one of the following technical features: According to embodiments of this application, M is selected from... 67 / 68 Ga、 18 F, 99m Tc, 89Zr、 124 I, 76 Br、 43 Sc、 111 In、 45 Ti、 52 Mn, 59 Fe、 94 mTc, 67 Ga、 71 / 72 / 74 As、 82m Rb、 86 Y、 177 Lu、 90 Y、 131 I, 153 Sm、 60 / 61 / 62 / 64 / 67 Cu、 89 Sr、 166 Ho、 177 Yb、 47 Sc、 186 / 188 Re、 212 / 213 Bi、 149 Pm, 212 Pb, 211 At、 223 Ra、 161 Tb, 225 Ac or 227 Th.

[0087] According to embodiments of this application, M is selected from... 68 Ga、 18 F, 89 Zr、 99m Tc or 177 Lu.

[0088] According to embodiments of this application, the radionuclide 18 F is through 18 FAl is formed by complexing with the compound.

[0089] According to embodiments of this application, M is selected from... 68 Ga、 89 Zr、 18 F or 177 Lu.

[0090] According to embodiments of this application, M is selected from... 68 Ga or 177 Lu.

[0091] Furthermore, those skilled in the art will understand that the features and advantages described above for the compound also apply to this metal complex, and will not be repeated here.

[0092] Pharmaceutical Composition In a third aspect of this application, a pharmaceutical composition is provided. According to embodiments of this application, the pharmaceutical composition comprises the compound described in the first aspect or the complex described in the second aspect.

[0093] According to embodiments of this application, the pharmaceutical composition may further include pharmaceutically acceptable excipients, carriers, and mediators.

[0094] In one optional embodiment of this application, pharmaceutically acceptable excipients refer to pharmaceutical excipients that are conventional in the pharmaceutical field, such as absorption enhancers, isotonic agents, stabilizers, regulators, etc.

[0095] In one alternative embodiment of this application, a pharmaceutically acceptable carrier refers to a drug carrier conventional in the pharmaceutical field.

[0096] In one alternative embodiment of this application, pharmaceutically acceptable mediators refer to pharmaceutical mediators conventional in the pharmaceutical field, such as solutions (e.g., water).

[0097] In one alternative embodiment of this application, examples of suitable pharmaceutically acceptable carriers, excipients, and mediators are well known in the art. Pharmaceutical compositions comprising such carriers, excipients, and mediators can be formulated using known conventional methods.

[0098] In some alternative embodiments, the pharmaceutical composition of this application may also contain other active ingredients for treatment.

[0099] The pharmaceutical composition of this application can be administered via various routes (e.g., orally or intravenously). Preferably, the pharmaceutical composition of this application is in solution form. Clinical dosing regimens are determined by the attending physician and clinical factors. As is known in the medical field, the dosage for any given patient depends on many factors, including patient size, body surface area, age, the drug to be administered, sex, time and route of administration, general health, and other concurrently administered medications. The pharmaceutical composition of this application can be administered topically or systemically. Preferably, it can be administered intravenously or subcutaneously. The pharmaceutical composition of this application can also be administered directly to the target site, for example, by targeted delivery to internal or external target sites.

[0100] Furthermore, those skilled in the art will understand that the features and advantages described above for the compounds and metal complexes also apply to this pharmaceutical composition, and will not be repeated here.

[0101] use In a fourth aspect of this application, the uses of the compound described in the first aspect, the complex described in the second aspect, and the pharmaceutical composition described in the third aspect are proposed as follows: In one aspect, this application proposes the use of the compound described in the first aspect, the complex described in the second aspect, or the pharmaceutical composition described in the third aspect in the preparation of a medicament for the diagnosis and / or treatment of folic acid receptor overexpression diseases.

[0102] On the other hand, this application proposes the use of the compounds described in the first aspect, the complexes described in the second aspect, or the pharmaceutical compositions described in the third aspect in the diagnosis and / or treatment of folic acid receptor overexpression diseases.

[0103] In another aspect, this application proposes the compounds described in the first aspect, the complexes described in the second aspect, or the pharmaceutical compositions described in the third aspect for the diagnosis and / or treatment of folic acid receptor overexpression diseases.

[0104] According to embodiments of this application, the diseases are brain tumors, breast cancer, ovarian cancer, gastric cancer, lung cancer, kidney cancer, mesothelial carcinoma, endometrial cancer, colorectal cancer, cervical cancer, head and neck tumors, and testicular cancer.

[0105] Furthermore, those skilled in the art will understand that the features and advantages described above for the compounds, complexes and pharmaceutical compositions also apply to this use, and will not be repeated here.

[0106] method In a fifth aspect of this application, a method for diagnosing and / or treating folic acid receptor overexpression disorders is provided. According to embodiments of this application, the method comprises administering to a subject a pharmaceutically acceptable dose of the compound described in the first aspect, the complex described in the second aspect, or the pharmaceutical composition described in the third aspect.

[0107] In one alternative embodiment of this application, the pharmaceutically acceptable dose may be selected from the effective dose (or effective amount).

[0108] The effective amount of the compound described in this application may vary depending on the administration method and the severity of the disease to be treated. A preferred effective amount can be determined by those skilled in the art based on various factors (e.g., through clinical trials). These factors include, but are not limited to: pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, and half-life; the severity of the disease to be treated, the patient's weight, the patient's immune status, and the route of administration. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0109] The compounds or pharmaceutical compositions of this application may be incorporated into suitable pharmaceuticals, which may be prepared in various forms, such as liquids. Various routes of administration of the compounds, pharmaceutical compositions, or pharmaceuticals of this application are contemplated, including intravenous, intramuscular, and subcutaneous injection, but this application is not limited to these exemplified routes of administration.

[0110] Furthermore, those skilled in the art will understand that the features and advantages described above for compounds, metal complexes, and pharmaceutical compositions also apply to this method, and will not be repeated here.

[0111] The following will explain the solution of this application with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0112] The specific substances corresponding to the abbreviations of chemical substance names in the embodiments of this application are shown in the following table: .

[0113] The structures of Fmoc-D-Lys(Dde)-OH, Fmoc-D-Tyr(tBu)-OH, Fmoc-D-Lys(Alloc)-OH, and Fmoc-D-Glu(tBu)-OH mentioned in the embodiments of this application are as follows: , , , , , , , .

[0114] The synthetic methods for the compounds mentioned in the embodiments of this application are all based on solid-phase synthesis strategies, which involve progressively extending peptide chains on a resin and ultimately cleaving them to obtain the target product. The methods described in these embodiments can be used to prepare polypeptide compounds with the structures described in this application, and are reproducible and operable.

[0115] Example 1: Synthesis of Compound 1

[0116] Compound 1 was synthesized using standard Fmoc chemical methods, with the following specific steps:

[0117] 1) Weigh 2-CTC resin (degree of substitution Sub = 0.50 mmol / g, 1.00 eq) and Fmoc-D-Lys (Dde)-OH (1.00 eq) into the reaction column. Add 10.0 mL of DCM and then add DIEA (4.00 eq) dropwise to carry out the condensation reaction. Add MeOH dropwise into the reaction column and drain the waste until no liquid flows out. Add DMF to wash the resin.

[0118] 2) Deprotection: Piperidine / DMF was added to the resin to remove the Fmoc protecting group at the amino terminus. The resin was washed five times with DMF to obtain the deprotected resin intermediate.

[0119] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (3.00 eq) and HBTU (2.85 eq) into the above resin, add 30.0 mL of DMF, and then add DIEA (6.00 eq) dropwise into the reaction column. After the reaction is complete, remove the reaction solution and wash with DMF.

[0120] Repeat steps 2)-3) above to couple the following amino acids:

[0121] Weigh 2.00 eq of dicolic acid and dissolve it in 4.00 mL of DMSO. Add 1.90 eq of DEPBT and sonicate. Then add 4.00 eq of DIEA and stir for one hour. Pour the reaction solution into the above resin and react overnight. Remove the reaction solution and wash with DMF.

[0122] Shrink the resin with MeOH, discharge the waste until no more liquid flows out, pour out the resin and dry it for later use.

[0123] Note: Alloc / Allyl removal conditions were: PhSiH3 (5.00 mmol, 10.0 eq), Pd (PPh3)4 (0.05 mmol, 0.10 eq), 10 min * 3 times; The conditions for Dde removal were: 3% hydrazine hydrate / DMF, 15 min * 2 times.

[0124] 4) Peptide cleavage: At room temperature, the dried resin was added to a prepared cleavage solution (90% TFA / 2.5% H2O / 5% TIS / 2.5% 3-Mpr), and ultrasonically heated to cleave the peptide chain from the resin, simultaneously removing side-chain protecting groups. The solution was filtered, and the filtrate was added to ice-cold isopropyl ether for sedimentation and centrifugation. The crude peptide was then dried under vacuum.

[0125] 5) Peptide purification: The crude peptide was purified by preparative high-performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile) to obtain the final product compound 1. LC-MS analysis showed that its molecular weight was consistent with the theoretical value, confirming the successful acquisition of the target compound. Its purity, determined by HPLC, was greater than 95%.

[0126] Example 2: Synthesis of Compound 2

[0127] Compound 1 was synthesized using standard Fmoc chemical methods, with the following specific steps:

[0128] 1) Weigh 2-CTC resin (degree of substitution Sub = 1.00 mmol / g, 1.00 eq) and Fmoc-D-Lys(Dde)-OH (1.00 eq) into a reaction column, add 20.0 mL of DCM, and then add DIEA (4.00 eq) dropwise to initiate the condensation reaction. After the reaction, wash with DMF.

[0129] 2) Deprotection: Add piperidine / DMF solution to the resin and agitate with nitrogen. Wash the resin five times with DMF and dry it to obtain the final resin.

[0130] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (3.00 eq) and HATU (2.85 eq) into the above resin, add DMF, and then add DIEA (6.00 eq) dropwise into the reaction column. Adjust the nitrogen gas to make the resin bulge evenly. After the reaction is complete, remove the reaction solution and add DMF to wash.

[0131] Repeat steps 2)-3) above to couple the following amino acids:

[0132] Weigh 2.00 eq of dicolic acid and dissolve it in 4.00 mL of DMSO. Add 1.90 eq of DEPBT and sonicate. Then add 4.00 eq of DIEA and stir for one hour. Pour the reaction solution into the above resin and react overnight. Remove the reaction solution and wash with DMF.

[0133] Shrink the resin with MeOH (20.0 mL), discharge the waste, pour out the resin and dry it for later use.

[0134] Note: The conditions for Dde removal are: 3% hydrazine hydrate / DMF.

[0135] 4) Peptide cleavage: At room temperature, the dried resin was added to a prepared cleavage solution (92.5% TFA / 2.5% H2O / 2.5% TIS / 2.5% 3-MPR, 20.0 mL) to cleave the peptide from the resin and simultaneously remove the side-chain protecting groups. The reaction solution was then added to frozen isopropyl ether, centrifuged to settle, and dried to obtain the crude product.

[0136] 5) Peptide purification: The crude product was purified by preparative high-performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile) to obtain the final product compound 2. LC-MS analysis showed that its molecular weight was consistent with the theoretical value, confirming the successful acquisition of the target compound. Its purity, determined by HPLC, was greater than 95%.

[0137] Example 3: Synthesis of Compound 3

[0138] Step 1:

[0139] Compound 3-1 (1.00 eq) was dissolved in NaOH solution (15.5 ppm) at 25 °C. eq The reaction solution was reacted at 100 °C for 36 h. After the reaction temperature dropped to 20 °C, impurities were filtered out, and the filtrate was freeze-dried to obtain compound 3-2.

[0140] Step Two

[0141] Compound 3-2 (1.00 eq) was dissolved in EtOH (560 mL), and SOCl2 (4.00 eq) was slowly added at 0 °C. eq The reaction solution was reacted at 80 °C for 72 h. The reaction solution was then cooled to 25 °C and concentrated under vacuum to obtain a crude product. The crude product was directly prepared into a yellow solid compound 3-3 under a TFA system.

[0142] Step 3: Compound 3-3 was directly chirally resolved in a 0.1% NH3·H2O system to yield compounds 3-4 and 3-5.

[0143] Step Four:

[0144] Compound 4 (1.00 eq) was dissolved in MeOH solution, and LiOH·H2O (4.00 eq) was added at 25 °C. The reaction solution was reacted at 70 °C for 7 h. The reaction solution was directly cooled to 20 °C, concentrated under vacuum and filtered. After filtration, solid Int 1 (purity: 98.9%) was prepared in a TFA system.

[0145] Step Four:

[0146] This step involves synthesis using standard Fmoc chemical methods: 1) Resin Preparation: Weigh 2-CTC resin (degree of substitution Sub = 0.50 mmol / g, 1.00 eq) and Fmoc-Lys(Dde)-OH (1.00 eq) into the reaction column. Add 20 mL of DCM, then add DIEA (4.00 eq) dropwise. Purge the resin with nitrogen to ensure uniform agitation. After the reaction is complete, add MeOH dropwise to the reaction column, purge with nitrogen, and remove waste. Wash with DMF.

[0147] 2) Deprotection: Add 20% piperidine / DMF solution to the resin and purge with air. Wash the resin five times with DMF and dry it to obtain the final resin.

[0148] 3) Coupling of amino acids: Weigh out Fmoc-Tyr(tBu)-OH (3.00) eq ) and HATU (2.85) eq Add 20.0 mL of DMF to the above resin, then add DIEA (0.60 mmol, 6.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure the resin agitates evenly. After the reaction is complete, remove the reaction solution, add DMF to wash and discharge waste.

[0149] Repeat steps 2)-3) above to couple the following amino acids (3-10):

[0150] 4) Peptide cleavage and purification: The dried resin was added to a prepared cleavage solution (90.0% TFA / 2.5% H2O / 5.0% TIS / 2.5% 3-Mpr) to cleave the peptide from the resin and simultaneously remove side-chain protecting groups. The solution was filtered, and the filtrate was added to ice-cold isopropyl ether for sedimentation and centrifugation, followed by washing with isopropyl ether. The solution was dried under vacuum for 2 hours to obtain the crude peptide. The crude peptide was purified by preparative high-performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile) to obtain the final product compound 3 (purity 97.2%). LC-MS analysis confirmed that the molecular weight was consistent with the theoretical value, confirming the successful acquisition of the target compound. Its purity was determined by HPLC.

[0151] Example 4: Synthesis of Compound 4 Step 1:

[0152] Compound 4 (1.00 eq) was dissolved in MeOH, and LiOH·H2O (4.00 eq) dissolved in H2O was added at 25 °C. eq The reaction solution was reacted at 70 °C for 7 h. The reaction solution was then directly cooled to 20 °C, concentrated under vacuum, and the pH was adjusted to 5-6 with 1N HCl. After filtration and concentration, Int 2 was obtained.

[0153] Step Two:

[0154] Synthesized using standard Fmoc chemical methods: 1) Resin Preparation: Weigh 1 / 2-CTC resin (degree of substitution Sub = 0.50 mmol / g, 1.00 eq) and Fmoc-Lys(Dde)-OH (1.00 eq) into the reaction column. Add 20 mL of DCM, then add DIEA (4.00 eq) dropwise. Adjust the nitrogen atmosphere to ensure uniform resin agitation. Add MeOH dropwise to the reaction column, purge with nitrogen, and purge waste until no liquid flows out. Add DMF for washing.

[0155] 2) Deprotection: Add a 20% piperidine / DMF solution to the resin and agitate with nitrogen. Wash the resin with DMF and dry it under vacuum to obtain the final resin.

[0156] 3) Coupling of amino acids: Weigh out Fmoc-Tyr(tBu)-OH (3.00g) eq ) and HATU (2.85) eq Add 20.0 mL of DMF to the above resin, then add DIEA (6.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure the resin agitates evenly. React at 20°C for 30 minutes. Remove the reaction solution, add DMF to wash and discharge waste.

[0157] Repeat steps 2)-3) above to couple the following amino acids:

[0158] 4) Peptide cleavage and purification: The dried resin was added to a prepared cleavage buffer (90.0% TFA / 2.5% H2O / 5.0% TIS / 2.5% 3-Mpr, 10.00 mL) to cleave the peptide from the resin and simultaneously remove side-chain protecting groups. The mixture was filtered, and the filtrate was added to ice-cold isopropyl ether for sedimentation and centrifugation, followed by washing with isopropyl ether. The crude peptide was then dried under vacuum.

[0159] The crude peptide was purified by preparative high performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile) to obtain the final product compound 4 (purity 95.0%). The target compound was successfully obtained by LCMS and HPLC identification.

[0160] Example 5: Synthesis of Compound 5

[0161] The synthesis of compound 5 was the same as that of compound 1, except that the coupled amino acid DOTA(tBu)3 was replaced with Nota(tBu)2. LC-MS analysis showed that its molecular weight was consistent with the theoretical value, proving that the target compound was successfully obtained. Its purity, determined by HPLC, was greater than 95%.

[0162] Example 6: Radioactive Labeling 1. 68 Labeling process of Ga-compound 1 / compound 2 / compound 3 / compound 4 Add 1 mL of sodium acetate / acetic acid buffer solution (pH=7.2) to a vial, then add 60 μL of the precursor aqueous solution of the example compound (containing 60 μL of compound 1), mix thoroughly, and then add 1 mL of... 68 The GaCl3 solution was reacted with 0.1 M hydrochloric acid at 80 °C for 10 min, the reaction was terminated, and the product was purified by C18 column analysis. The radiochemical purity of the product was determined by Radio-iTLC, and the radiochemical purity was >95%.

[0163] 2. 18 F-compound 5 labeling process Add 2.5 mL of DMSO solution, 55 μL of AlCl3, 7 μL of glacial acetic acid, 2 mg of gentian acid, and 40 μL of an aqueous solution of precursor compound 11 (containing 5200 μg of precursor compound) to a vial, then add to the reaction flask and shake well. Take a certain amount of the generated fluorine...18 The radioactivity of fluorine [18F] aqueous solution was measured and recorded using an activity meter (fluorine [18F] aqueous solution can be generated by a cyclotron). 18 The aqueous solution was added to the pretreated QMA column, followed by elution with 0.5 mL of physiological saline. The eluent flowed directly into the reaction flask, which was then capped with a rubber stopper. The reaction flask was placed at 70°C for 15 min. After cooling to room temperature, the reaction solution was diluted with sterile water for injection and purified using a C18 column. The eluent was discarded, and the C18 column was slowly eluted with 1.5 mL of 70% ethanol. The eluent was collected into the product bottle, diluted with 9 mL of physiological saline, and filtered through a sterile membrane into a sterile vacuum bottle. The radiochemical purity of the product was determined using Radio-iTLC, and the radiochemical purity was >95%.

[0164] Preclinical trials Experiment 1: In vivo experiment Experimental steps: KB cells in the logarithmic growth phase were selected, routinely digested, and seeded into 12-well plates at 5×10^5 cells / well, and cultured overnight at 37°C and 5% CO2.

[0165] The culture medium was discarded the following day, and the cells were washed with PBS. After recording the cell count in the control wells, 1 µCi of [a specific ingredient] was added to each well. 68 The Ga-labeled test compound was incubated at 37°C for 1 h.

[0166] After incubation, cells were washed with pre-cooled PBS, followed by lysis with lysis buffer and collection of all lysis products. The radioactivity count (CPM) of the lysis buffer was measured using a gamma counter, and the cell uptake rate (%AD) was calculated by comparing it with the total CPM of the added drug. The results were then normalized to the actual cell count.

[0167] The obtained %AD was used to evaluate the uptake capacity of this compound in KB cells, and the results are shown in Table 1 and 2. Figure 1 Show.

[0168] It can be seen that the compound 68 Ga-compound 1, 68 Ga-compound 3. 68 Ga-compound 4 showed high uptake levels in KB cells, indicating that the compound could be effectively taken up by KB cells and had good cellular uptake capacity.

[0169] Table 1: Cellular uptake results

[0170] Experiment 2: Tissue distribution and targeting of the example compound in a mouse tumor model Mouse model: KB Model: A subcutaneous ectopic xenograft model established based on B-NDG severely immunodeficient mice, in which the tumor cells used are human cervical cancer-related cells, manufactured by Biocytogen (Beijing) Pharmaceutical Technology Co., Ltd.

[0171] SKOV-3 model: Establishing a mouse subcutaneous xenograft tumor model based on human ovarian cancer cell lines (such as SKOV-3). PET / CT scan steps: Animals were randomly selected for the experiment. Before scanning, animals were given isoflurane inhalation anesthesia to achieve a stable state of anesthesia, and the radioactive compound to be tested was injected via the tail vein. PET / CT data were acquired at preset time points after administration (dynamic or static scanning, including 1 h, 2 h, 4 h, etc.). The acquired image data were reconstructed using the equipment software, then processed and analyzed to generate tissue distribution maps and quantitatively analyze the radioactive uptake values ​​of each tissue and organ (expressed as %ID / g).

[0172] 1. Two SKOV-3 model mice were selected, and each mouse was injected with 80 μCi. 68 Ga-compound 1, scan time: dynamic 1h, static 2h, experimental results are shown in Table 2 and... Figure 2 .

[0173] The results of the uptake values ​​of each organization showed that 68 Following administration, Ga-compound 1 rapidly enters the target tissue and exhibits detectable radioactive accumulation at that site, while uptake in non-target tissues is low. The compound is primarily cleared by the kidneys. These results indicate... 68 Ga-compound 1 exhibits good in vivo targeted distribution characteristics and acceptable pharmacokinetic characteristics.

[0174] Table 2: Different time points after drug administration 68 Uptake of Ga-compound 1 in different tissues of model mice

[0175] 2. The experiment was divided into 4 groups, with 4 KB model mice selected for each group. The four groups were injected with... 68 Ga-compound 1, 68 Ga-compound 2, 68 Ga-compound 3. 68 Ga-compound 4, 18 F-Compound 5. Each vial was injected with 80 μCi. Scan times: dynamic 1 h, static 2 h, 4 h (if applicable). Experimental results are shown in Tables 3-7 and examples. Figures 3-6 .

[0176] Table 3: Different time points after drug administration 68Uptake of Ga-compound 1 in different tissues of model mice;

[0177] Table 4: Different time points after drug administration 68 Uptake of Ga-compound 2 in different tissues of model mice

[0178] Table 5: Different time points after drug administration 68 Uptake of Ga-compound 3 in different tissues of model mice

[0179] Table 6: Different time points after drug administration 68 Uptake of Ga-compound 4 in different tissues of model mice

[0180] Table 7: Different time points after drug administration 18 Uptake of F-compound 5 in different tissues of model mice

[0181] Experimental results show that 68 Ga-compound 1, 68 Ga-compound 2, 68 Ga-compound 3. 68 Ga-compound 4, 18 Compound F-5 showed high radioactive uptake at tumor sites approximately 0.5 hours after administration, while radioactive uptake in other non-target tissues gradually decreased over time; among them 68 Ga-compound 1, 18 The radioactive signal of compound F-5 persisted in the tumor region after administration and did not show a significant decrease during the observation period (up to 4 hours). Imaging results further demonstrated that the tested compound could form clear tumor images approximately 0.5 hours after administration, with good contrast and clear distinction between the radioactive signal in the tumor region and the surrounding background tissue throughout the imaging process.

[0182] Experiment 3: 177 Distribution of Lu-compound 1 in KB model ex vivo tissue experiments Experimental steps: Nine mice were selected as the KB animal model. Each animal was given... 68300 μCi of Ga-compound 1 was administered, and three animals were dissected at 1 h, 4 h, and 48 h after administration. Tissues and organs including the thyroid gland, brain, heart, kidneys, large intestine, small intestine, liver, lungs, pancreas, gonads, skeletal muscle, spleen, stomach, fat, and tumors were collected, and gamma radiation counts were measured. Results are shown in Table 8. Figure 7 Table 8 lists the radioactivity levels at different time points and in different tissues. 177 Lu-compound 1 showed high radioactive enrichment in tumor tissue 4 hours after administration. 24 hours after administration, no significant decrease in radioactive signal was observed in the tumor tissue. 48 hours after administration, the tumor tissue maintained a high uptake level, while radioactive uptake in other non-target organs was relatively low. These results indicate that... 177 Lu-compound 1 can specifically target tumors in vivo and maintain uptake at the tumor site for a certain period of time. At the same time, it can be gradually eliminated through in vivo metabolic pathways. It has good tumor accumulation ability and long tumor retention time in vivo, while exhibiting low non-target organ background, showing favorable in vivo distribution characteristics.

[0183] Table 8

[0184] Experiment 4: 177 Lu-compound 1 Tumor Therapy Experiment Twelve KB animal model mice were randomly selected and divided into two groups of six mice each: a control group and an experimental group. The experimental group received the following treatment per animal: 177 Lu-compound 1 drug, 2 mCi, was administered once per mouse via tail vein injection; the control group received the same volume of physiological saline as the experimental group. Mouse body weight and tumor volume were measured before the experiment, and twice weekly after administration. The major and minor axes of the tumor were measured to calculate tumor volume using the following formula: Tumor volume (TV) = a × b 2 / 2 (a is the major axis, b is the minor axis). And calculate its tumor growth inhibition rate (TGI).

[0185] Thirteen days after administration, the TGI value in the experimental group was 60.3%. Figure 8 It can be seen that, compared to the saline control group, 177 Lu-compound 1 significantly controlled tumor growth and exhibited good in vivo antitumor activity. During the experimental observation period, no significant abnormal fluctuations were observed in the body weight of mice in each group, indicating that the compound had good in vivo tolerance under the experimental conditions and no obvious signs of systemic toxicity were observed.

[0186] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0187] Although embodiments of this application have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting this application. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of this application.

Claims

1. A compound having the structure shown in formula (I) or an isotopic variant thereof, a hydrate, an ester or solvate, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof: (I)； in: Z is selected from a chelating group; L is selected from ; R1 and R2 are each independently empty, H, and -C. 1~3 Alkyl or -C 1~3 Halogenated alkyl groups; It can be a single bond or a double bond; R3 is -C 1~3 alkylene-(6-12 aryl) or -C 1~3 alkylene-(5-12-membered heteroaryl); R4, R5, R6, and R7 are each independently -C 1~6 Alkylene; n is 0 or 1.

2. The compound according to claim 1, characterized in that, N connected to R1 When it is a double bond, R1 is empty, and it is connected to N via R2. When it is a double bond, R2 is empty; Optionally, N is connected to R1. N connected to R2 Both are double bonds, with R1 and R2 both empty; or N connected to R1 N connected to R2 All are single bonds, R1 is H, -C 1~3 Alkyl or -C 1~3 For alkyl halogens, R2 is always H.

3. The compound according to any one of claims 1 to 2, characterized in that, The compound satisfies one or more of the following conditions: 1) R3 is -C 1~3 alkylene-(8-12 aryl) or -C 1~3 alkylene-(8-12-membered heteroaryl); Optionally, R3 is a -methylene-10-membered aromatic group; 2) R4 is -C 3~6 Alkylene; 3) R5 is -C 1~3 Alkylene; 4) R6 is -C 3~6 Alkylene; 5) R7 is -C 1~3 Alkylene.

4. The compound according to any one of claims 1 to 3, characterized in that, The compound satisfies one or more of the following conditions: 1) R3 is -methylene-naphthyl; 2) n is 0.

5. The compound according to any one of claims 1 to 3, characterized in that, The compound satisfies one or more of the following conditions: 1) L is selected from or ; Optionally, L is selected from or ; 2) Structure selected from , , , or .

6. The compound according to any one of claims 1 to 3, characterized in that, The chelating group is derived from a chelating agent; The chelating agent is selected from 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid (DOTA). N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC) 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA), 1,4,7-Triazacyclononanephosphonic acid (TRAP) 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO) Diethyltriaminepentaacetic acid (DTPA) trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA) 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A) p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isocyanothiobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isocyanothiobenzyl)-4-methyl-DTPA (1M3B), 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA), [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA), 6-Hydroxypyridine-3-carboxylic acid (HYNIC) 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA), or 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA); Preferably, Z is selected from DOTA NOTA、 NODAGA、 DOTAGA, HBED-CC, p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA and p-SCN-Bn-DOTA; Optionally, Z is selected from DOTA, or NOTA.

7. A compound having the structure shown in formula (II) or an isotopic variant thereof, a hydrate, an ester or solvate, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof: (II); in, R1 and R2 are each independently empty, H, and -C. 1~3 Alkyl or -C 1~3 Halogenated alkyl groups; It can be a single bond or a double bond; R3 is -C 1~3 alkylene-(6-12-membered aromatic group); R4 is -C 1~6 Alkylene; n is 0 or 1; Z is selected from chelating groups.

8. The compound according to claim 7, characterized in that, The compound satisfies one or more of the following conditions: 1) Connect N to R1 When it is a double bond, R1 is empty, and it is connected to N via R2. When it is a double bond, R2 is empty; Optionally, N is connected to R1. N connected to R2 Both are double bonds, with R1 and R2 both empty; or N connected to R1 N connected to R2 All are single bonds, R1 is H, -C 1~3 Alkyl or -C 1~3 Haloalkyl groups, where R2 is always H; 2) n is 1, and R3 is a -methylene-10-membered aromatic group; Preferably, n is 1, and R3 is -methylene-naphthyl; 3) n is 0; 4) The chelating group is derived from a chelating agent; The chelating agent is selected from 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid (DOTA). N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC) 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA), 1,4,7-Triazacyclononanephosphonic acid (TRAP) 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO) Diethyltriaminepentaacetic acid (DTPA) trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA) 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A) p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isocyanothiobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isocyanothiobenzyl)-4-methyl-DTPA (1M3B), 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA), [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA), 6-Hydroxypyridine-3-carboxylic acid (HYNIC) 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA), or 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA); Preferably, Z is selected from DOTA NOTA、 NODAGA、 DOTAGA, HBED-CC, p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA and p-SCN-Bn-DOTA; Optionally, Z is selected from DOTA, or NOTA; 4） Structure selected from , , , or .

9. A compound that is, in the form of, an isotopic variant of, a hydrate, an ester or solvate, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof: , , , , , , , ,or .

10. A complex, characterized in that, Includes the compound according to any one of claims 1 to 9, and M complexed with said compound; M is selected from radioactive nuclides or non-radioactive elements; Optionally, M is selected from 67 / 68 Ga、 18 F, 99m Tc, 89 Zr、 124 I, 76 Br、 43 Sc、 111 In、 45 Ti、 52 Mn, 59 Fe、 94m Tc, 71 / 72 / 74 As、 82m Rb、 86 Y、 177 Lu、 90 Y、 131 I, 153 Sm、 60 / 61 / 62 / 64 / 67 Cu、 89 Sr、 166 Ho、 177 Yb、 47 Sc、 186 / 188 Re、 212 / 213 Bi、 149 Pm, 212 Pb, 211 At、 223 Ra、 161 Tb, 225 Ac or 227 Th; Optionally, M is selected from... 68 Ga、 18 F, 89 Zr、 99m Tc or 177 Lu; Optionally, the radionuclide 18 F is through 18 Formed by the complexation of FAl with the compound; Optionally, M is selected from... 68 Ga、 89 Zr、 18 F or 177 Lu; Optionally, M is selected from... 68 Ga or 177 Lu.

11. A pharmaceutical composition, characterized in that, It includes the compound according to any one of claims 1 to 9, or the complex according to claim 10, and optionally pharmaceutically acceptable excipients, carriers, or mediators.

12. Use of the compound of any one of claims 1 to 9, the complex of claim 10, or the pharmaceutical composition of claim 11 in the preparation of a medicament for the diagnosis and / or treatment of folic acid receptor overexpression diseases.

13. The use according to claim 12, characterized in that, The diseases mentioned are brain tumors, breast cancer, ovarian cancer, stomach cancer, lung cancer, kidney cancer, mesothelial carcinoma, endometrial cancer, colorectal cancer, cervical cancer, head and neck tumors, and testicular cancer.

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