Novel compounds and their therapeutic uses

Abstract

This invention provides novel compounds useful in the treatment of proliferative disorders, particularly cancer. [Solution] A compound represented by the following formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided. JPEG2026143429000098.jpg95170

Description

[Technical Field]

[0001] [preface] This invention relates to novel compounds useful in treating proliferative disorders, such as cancer. Specifically, the present invention relates to novel compounds in the form of ligands and ligand-containing complexes. These ligands exhibit the ability to self-assemble with certain metals and anions to form complexes. The present invention also relates, in particular, to the therapeutic use of compounds for the treatment of proliferative disorders, such as cancer. To relate to. [Background technology]

[0002] Modern medicine ranges from relatively simple things, such as lithium salts used to treat bipolar disorder, to... Large, complex organic structures for cancer therapy that can contain hundreds of atoms and dozens of chiral centers. It extends to. 1 However, despite this great diversity, all of these modern medicines are They share commonalities, that is, they are all chemically prepared through repetitive synthesis procedures. These are often separate molecular species that must be manufactured. This different approach to medicine This is the use of self-assembly, where a specific pre-programmed set of components is used between the constituent components themselves. As a result of the interaction, the disordered system of existing compounds forms a tissue structure. This is the process. 2、3、4、5、6、7、8、9 Self-assembly is a phenomenon in which chemists have observed different molecules. Molecules that can all possess different biological activities without needing to be synthesized by conventional methods. This provides easy and rapid access to libraries of extremely complex structures and novel compounds. .

[0003] Despite self-assembly being a mature area of ​​scientific research, artificial self Interest in the potential therapeutic applications of assembly systems has been relatively limited. 10、1 1、12、13、14 However, notable progress has been made in this area For example, Hannon demonstrated that iron(II)-containing dinuclear triple helicates (e.g., L3Fe2 4+ ) strongly interact with double-stranded DNA and bind in the major groove, exhibiting therapeutic properties. 15、16、17 Other iron(II)-containing species include, for example, S cott and co-workers' "head-to-head-to-tail" helicates (“head-to-head-to-tail” heli cates). These helicates show in vitro cytotoxic activity against various cancer cell lines, with lower IC 50 values than cisplatin. 18 Some ruthenium-containing transition metal heli cates and mesocates have also been shown to possess interesting biological properties, indicating higher cytotoxicity against p53-deficient cancer cells. 19 Metallacycles and metallacages have also been shown to have useful properties. Han's [Pd2L4 4+ cage exhibits cytotoxicity against an array of different human cancer cell lines. 20 Not surpris ingly, many of such active assemblies contain Pt 2+ , whose cytotoxic effects are well known, and these have been shown to be active against many cancer cell lines , and some assemblies have been used for encapsulation and targeted delivery of cisplatin. 21

[0004] Notwithstanding the progress described above, there remains a need in the treatment of proliferative disorders, particularly cancer,​ Useful new compounds are needed.

[0005] This invention was made with the above in mind. [Overview of the Initiative]

[0006] To our surprise, the inventors have found that the compounds of formula I described herein are compatible with certain metals and In the presence of anions, they self-assemble into mononuclear complexes and trinuclear complexes (formula II as described herein) It functions as a tripod-type ligand capable of forming compounds of type III. We found that this complex is encapsulated by it. Organophosphate dianions (i.e., ROPO3) 2- ) is phosphate (i.e., PO4 3 - It exhibits phosphatase activity that allows it to be easily hydrolyzed by ).

[0007] In cell research, this complex is used in various human cancer cell lines and glioblastoma cancer stem cell models. It is highly toxic to Dell. 22、23 Similar to its efficacy, this complex is effective against healthy, non-cancerous cells (A RPE19, 24 MCF10a, 25 and NP1 22、23 (compared to non-cancer cell models) It exhibits remarkable selective activity against cancer cells (up to 2000 times). Several A Encapsulating anions (especially phosphate anions or sulfate anions) enhances their potency and selectivity. Selectivity is further regulated. Studies on the mechanism of action have shown that this complex acts on multiple kinases. Selective inhibition of cancer cells, ATP depletion, autophagy, and cancer cytotoxicity are all mediated by the phosphorus. Selective phosphatase for phosphatine, phosphotyrosine, and phosphothreonine amino acids It has been shown to have enzyme activity. Kinase inhibition by certain complexes is not due to dephosphorylation. It is hypothesized that this occurs by binding to phosphoamino acids. These are selective tumor cells. It exhibits a highly novel mechanism of action, possessing the ability to target multiple kinases while maintaining cytotoxicity. This is expected to suppress the emergence of resistant cancer cell subpopulations. It is a characteristic feature.

[0008] According to one aspect of the present invention, a compound having the structure of formula I as defined herein, or A pharmaceutically acceptable salt, hydrate, or solvate thereof is provided, provided that this compound is Compound Ia as defined herein, or its pharmaceutically acceptable salts, hydrates, or solvates thereof. It's not an object.

[0009] According to a further aspect of the present invention, a compound having the structure of formula II as defined herein , or pharmaceutically acceptable salts, hydrates or solvates thereof are provided. Appropriately, This compound is compound IIa as defined herein or a pharmaceutically acceptable salt or hydrate thereof. Or it is not a solvate. More appropriately, M is Zn 2+ Mn 2+ Fe 2+ Co 2+ and Ni 2+ It is selected from the group consisting of the following.

[0010] According to a further aspect of the present invention, a compound having the structure of formula III as defined herein A substance, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided, however this The compound does not have the structure of formula IIIa as defined herein. Where appropriate, M is Zn 2+ Mn 2+ Fe 2+ Co2+ and Ni 2+ It is selected from the group consisting of the following.

[0011] According to a further aspect of the present invention, a compound having the structure of formula I as defined herein, Or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, of M. A source, and a medical device containing one or more pharmaceutically acceptable diluents, excipients, or carriers. A pharmaceutical composition is provided. The pharmaceutical composition may further provide a source of Q as defined herein. It is included in.

[0012] According to a further aspect of the present invention, a compound having the structure of formula II as defined herein , or pharmaceutically acceptable salts, hydrates or solvates thereof, and one or more thereof. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient, or carrier is provided. The pharmaceutical composition further comprises a source of Q as defined herein.

[0013] According to a further aspect of the present invention, a compound having the structure of formula III as defined herein The substance or its pharmaceutically acceptable salts, hydrates, or solvates, and one or more thereof. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient, or carrier is provided.

[0014] According to a further aspect of the present invention, a compound having the structure of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, and as defined herein A kit of parts including the M supplier will be provided.

[0015] According to a further aspect of the present invention, a compound having the structure of formula II as defined herein , or pharmaceutically acceptable salts, hydrates or solvates thereof, and as defined herein A kit of parts including the source of the Q is provided.

[0016] According to a further aspect of the present invention, for use as a pharmaceutical, M as defined herein A compound of formula I as defined herein, combined with a source of, or pharmaceutically acceptable The salt, hydrate, or solvate thereof is provided. The compound of formula I and M are supplied as appropriate. The source is further combined with the source of Q as defined herein.

[0017] According to a further aspect of the present invention, the formula defined herein for use as a pharmaceutical product Compounds of type II, or pharmaceutically acceptable salts, hydrates, or solvates thereof, are provided. Appropriately, the compound of formula II is combined with a source of Q as defined herein.

[0018] According to a further aspect of the present invention, the formula defined herein for use as a pharmaceutical product Compounds of type III, or pharmaceutically acceptable salts, hydrates, or solvates thereof are provided. ru.

[0019] According to a further aspect of the present invention, for use as a pharmaceutical, as defined herein, A pharmaceutical composition, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided.

[0020] According to a further aspect of the present invention, for use in the treatment of proliferative disorders (e.g., cancer) The compound of formula I as defined herein, combined with a source of M as defined herein. , or pharmaceutically acceptable salts, hydrates or solvates thereof are provided. Appropriately, The compound of formula I and the source of M are further combined with the source of Q as defined herein. It is.

[0021] According to a further aspect of the present invention, for use in the treatment of proliferative disorders (e.g., cancer) The compounds of formula II as defined herein, or pharmaceutically acceptable salts and hydrates thereof. Or a solvate is provided. Appropriately, the compound of formula II is a supply of Q as defined herein. It is combined with the power source.

[0022] According to a further aspect of the present invention, for use in the treatment of proliferative disorders (e.g., cancer) The compound of formula III as defined herein, or a pharmaceutically acceptable salt or hydrate thereof. Alternatively, a solvate is provided.

[0023] According to a further aspect of the present invention, for use in the treatment of proliferative disorders (e.g., cancer) The pharmaceutical composition as defined herein, or a pharmaceutically acceptable salt, hydrate, or A solvate is provided.

[0024] According to a further aspect of the present invention, proliferative disorders (e.g., in patients requiring such treatment) For example, a method for treating cancer is provided, and this method combines a source of M as defined herein with In combination, the compounds of formula I as defined herein, or pharmaceutically acceptable salts and hydrates thereof. Alternatively, the procedure may include administering a therapeutically effective dose of the solvate to the patient. Appropriately, the compound of formula I. The substance and the source of M are administered in combination with the source of Q.

[0025] According to a further aspect of the present invention, proliferative disorders (e.g., in patients requiring such treatment) For example, a method for treating cancer is provided, and this method involves a compound of formula II as defined herein. or administer to the patient a therapeutically effective dose of a pharmaceutically acceptable salt, hydrate, or solvate thereof. The procedure includes the following steps: The compound of formula II is administered in combination with a source of Q. ru.

[0026] According to a further aspect of the present invention, proliferative disorders (e.g., in patients requiring such treatment) For example, a method for treating cancer is provided, and this method involves the compound of formula III as defined herein. Administer a therapeutically effective dose of the substance, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to the patient. This includes the step of giving.

[0027] According to a further aspect of the present invention, proliferative disorders (e.g., in patients requiring such treatment) For example, a method for treating cancer is provided, and this method treats the pharmaceutical composition as defined herein. The procedure includes the step of administering a therapeutically effective dose to the patient.

[0028] According to a further aspect of the present invention, in the manufacture of a pharmaceutical product, the chemical of formula I, II, or III The use of a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided. In appropriate cases, pharmaceuticals are intended for the treatment of proliferative disorders (e.g., cancer).

[0029] In the above aspects of the present invention, the proliferative disorder is appropriately cancer, and cancer is appropriately hi It is a type of cancer. Specifically, the compounds according to the present invention are useful in treating any type of cancer. Mismatch repair inhibition is beneficial. Any suitable cancer can be targeted (e.g., glandular cancer). Cystic carcinoma, adrenal tumor, amyloidosis, anal cancer, appendiceal cancer, astrocytoma, telangiectasia Ataxia tonic, Beckwith-Weidemann syndrome, cholangiocarcinoma (cholangiocarcinoma), Bart - Hogg-Duvet syndrome, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, Carney Complex tumors, central nervous system tumors, cervical cancer, colorectal cancer, Cowden's disease, craniopharyngioma, fibroblastic cancer Adult infantile ganglioglioma, ventriculependymoma, esophageal cancer, Ewing's sarcoma, eye cancer, eyelid cancer, family Gonadontic polyposis, familial GIST, familial malignant melanoma, familial non-VHL clear cell angioplasia Renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, pregnancy-related Gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyoma Hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary renal cell carcinoma Cancer, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumors, laryngeal and hypopharyngeal cancer, leukemia (acute) Lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell prolymphoblastic leukemia Leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CLL) ML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia, Lie-Fraumeni syndrome, liver Cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), lymphoma (Hodgkin's, non-Hodgkin's) Lynch syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia 1 Type 1 and Type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndrome Plastic syndromes (MDS), nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors Neurofibromatosis types 1 and 2 (e.g., of the gastrointestinal tract, lungs, or pancreas), nevus basal cell carcinoma Syndrome, oral or oropharyngeal cancer, osteosarcoma, ovarian / Falopian duct / peritoneal cancer, pancreatic cancer, para Thyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma, paraganglioma, pituitary tumor Surgery, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (for example, Kaposi's positivity (or soft tissue cancer), skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma. Thyroid cancer, tuberous sclerosis, uterine cancer, vaginal cancer, von Hippel-Lindau syndrome, external Vaginal cancer, Waldenström's macroglobulinemia, Werner syndrome, Wilms' tumor (Cervical ulcers and xeroderma pigmentosum). The specific cancers targeted include blood cancers, such as lymphoma ( Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's disease Leukemia (including BL lymphoma and angioimmunoblastic T-cell lymphoma (AITL)), Lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML), multiple bone Myeloma, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, stomach-esophagus cancer Cancer, neuroendocrine cancer, osteosarcoma, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, This includes cholangiocarcinoma, CNS cancer, thyroid cancer, head and neck cancer, esophageal cancer, and ovarian cancer. ru.

[0030] The constituent components used in combination with each other (for example, compounds of formula I, II, or III) The sources of M and Q can be administered simultaneously, separately, or sequentially. One aspect of the present invention In this context, "in combination with" refers to simultaneous administration. In another aspect of the present invention, "in combination with" "Together" refers to separate administrations. In a further aspect of the present invention, "in combination with" means This refers to sequential administration. If the administration is sequential or separate, the second (and any Any delay in administering the subsequent components would result in the loss of the beneficial effects of the combination. It shouldn't be done.

[0031] With respect to one aspect of the present invention, the features include optional, appropriate, and preferred features. With respect to any other aspect of the present invention, optional, suitable and preferred features are included. It could also be considered a characteristic. [Modes for carrying out the invention]

[0032] [Definition] Unless otherwise stated, the following terms used in this specification and in the claims have the same meaning as: It has the meaning of:

[0033] "To treat" or "treatment" includes prevention and alleviation of established symptoms of a condition. It is understood that this means "to treat the situation, disability or condition." The term "treatment" of a situation, disability, or condition includes (1) suffering from a situation, disability, or condition. It may be possible or predisposing to the condition, but the clinical or subclinical symptoms of the situation, disorder, or condition A situation, disorder or (2) to prevent or delay the appearance of clinical symptoms of a condition, a condition, or a disorder To suppress, that is, (in the case of maintenance therapy) the occurrence or reduction of the disease or its recurrence. To stop, reduce, or delay at least one of its clinical or subclinical symptoms. , or (3) to alleviate or reduce a disease, i.e., a condition, disability or state or including the reduction of at least one of its clinical or subclinical symptoms. It can be done.

[0034] "Therapeutic dose" is the amount administered to a mammal to treat a disease. This refers to the amount of compound sufficient to perform the treatment. "Therapeutic dose" means the amount of compound, the amount of treatment The treatment method varies depending on the disease of the mammal being treated, its severity, age, weight, and other factors. For example, in humans or other mammals, the therapeutically effective dose is determined in a laboratory or clinical setting. The effective dose that can be experimentally determined, or the therapeutic dose, for a particular disease to be treated. And the guidelines of the U.S. Food and Drug Administration (FDA) or the corresponding foreign regulatory agency for the subject matter. It should be understood that the amount may be determined by the drug. Appropriate dosage form, administration The determination of dosage and route of administration is within the scope of the skills of those skilled in the pharmaceutical and medical fields. What I'm saying should be understood.

[0035] "Subject(s)" and "Patients(s)" can be used individually or individually or in combination with other terms. When used herein in conjunction with the term, the term refers to animals (e.g., mammals), in particular humans. Appropriately, "subject(s)" and "patient(s)" can refer to non-human animals (e.g., It could be livestock or a pet, or a human.

[0036] "Pharmacologically acceptable" can be used alone or in conjunction with one or more other terms. When used in detailed writing, it generally refers to chemically affecting other components (e.g., in relation to formulations). and / or physically compatible, and / or generally, its recipient (e.g., opposite This refers to materials that are physiologically compatible with animals (such as elephants).

[0037] In this specification, "alkyl" includes linear and branched alkyl groups. As a reference to alkyl groups, for example, "propyl" is specific only to the linear version. For example, as a reference to individual branched alkyl groups, "isopropyl" is a branched bar It is specific only to alkyl groups. For example, "(1-6C) alkyl" has (1-4C) alkyl groups. It contains methyl, (1-3C) alkyl, propyl, isopropyl, and t-butyl.

[0038] "(m~nC)" or "(m~nC) base" can be used alone or as a prefix. This refers to any group having m to n carbon atoms.

[0039] The "alkylene" group is located between two other chemical groups and helps to bond them together. It is an alkyl group. Therefore, "(1-6C)alkylene" has 1-6 carbon atoms. This is a linear saturated divalent hydrocarbon group or a branched saturated divalent carbon group of 3-6 carbon atoms. Hydrogenated groups, for example, methylene (-CH2-), ethylene isomer (-CH(CH3)-, and (-CH2CH2-), propylene isomer (-CH(CH3)CH2-, -CH(CH2 CH3)-, -C(CH3)2-, and -CH2CH2CH2-), pentylene(-C It means H2CH2CH2CH2CH2-, etc.

[0040] "Alkenyl" refers to linear and branched alkyl groups containing two or more carbon atoms. An alkenyl group refers to a group that contains at least one carbon-carbon double bond. This includes, for example, ethenyl, propenyl, and buta-2,3-enyl, and all This includes possible geometric (E / Z) isomers.

[0041] "Alkynyl" refers to linear and branched alkyl groups containing two or more carbon atoms. At the very least, one carbon-carbon triple bond exists within the group. For example, an alkynyl group has It contains acetylenyl and propynyl.

[0042] "(m~nC)cycloalkyl" refers to a saturated hydrocarbon ring system containing m to n carbon atoms. This means that. Exemplary cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, and bicyclo[2.2.1]heptyl It contains chill.

[0043] "Alkoxy" refers to oxygen-linked linear and branched alkyl groups. The alkoxy group includes: Examples include methoxy, ethoxy, and t-butoxy.

[0044] In this specification, "haloalkyl" means that one or more hydrogen atoms are halogens (e.g., This refers to alkyl groups that are replaced by fluorine atoms. Often, haloalkyl groups are... , fluoroalkyl. Haloalkyl groups include, for example, -CH2F, -CHF2 and This includes B-CF3.

[0045] "Halo" or "halogeno" refers to fluoro, chloro, bromo, and iodine, appropriately, Fluoro, chloro, and bromo, more appropriately, fluoro and chloro.

[0046] "Carbocyclyl," "carbocyclic," or "carbocyclic" refers to a non-aromatic saturated or partial This refers to a fractionally saturated monocyclic, condensed, bridged, or spirodicyclic carbon-containing ring system (multiple systems are possible). Monocyclic and carbocyclic rings contain approximately 3 to 12 (or, more appropriately, 3 to 7) ring atoms. A bicyclic carbocyclic ring contains atoms with 6 to 17 members, and preferably 7 to 12 members. A cyclic carbocyclic ring(s) can be a condensed, spirocyclic, or bridging ring system. Examples include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl and It contains spiro[3.3]heptanil.

[0047] "Heterocyclyl," "heterocyclic," or "heterocyclic" refers to a non-aromatic saturated or partially saturated compound. This refers to a ring system (multiple rings) that is partially saturated, such as monocyclic, condensed, bridged, or spirodicyclic / heterocyclic rings. Monocyclic and heterocyclic rings contain approximately 3 to 12 (or, appropriately, 3 to 7) ring atoms, ~5 (or possibly 1, 2, or 3) heteroatoms in the ring are nitrogen, oxygen, or sulfur. They are selected. A bicyclic heterocycle contains 7-17 member atoms, or optionally 7-12 member atoms. It contains. Bicyclic and heterocyclic rings (multiple rings) can be condensed, spirocyclic, or bridging ring systems. Heterocyclic groups include, for example, cyclic ethers, such as oxyranyl, oxetanyl, and tetracycline. This includes lahydrofuranyl, dioxanyl, and substituted cyclic ethers, etc. It contains nitrogen. Examples of heterocycles include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and te It contains trahydrotriazinyl, tetrahydropyrazolyl, etc. It is a typical sulfur-containing compound. The heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, and tetrahydro This includes -2H-thiopyran and hexahydrothiepine. Other heterocycles include dihydrs Lo-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, Tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazolyl Nyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydro- Limidinil, dioxolinyl, octahydrobenzofuranil, octahid It contains robenzimidazolyl and octahydrobenzothiazolyl. It contains sulfur. In the case of heterocycles, sulfur oxide heterocycles containing SO or SO2 groups are also included. For example, For example, tetrahydrothienyl and thiomorpholinyl sulfoxides and sulfones Forms, for example, tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1- Dioxides are included. Heterocycles have one or two oxo (=O) or thioxo May contain (=S) substituents. One or two oxo (=O) or thioxo (=S) substitutions. Suitable values ​​for heterocyclyl groups containing the group include, for example, 2-oxopyrrolidinyl, 2 - Thioxopyrrolidinil, 2-oxoimidazolidinil, 2-thioxoimidazolidinil , 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidaz It is lysinyl or 2,6-dioxopiperidinyl. Certain heterocyclyl groups are nitrogen A saturated monoring containing one, two, or three heteroatoms selected from oxygen or sulfur. Heterocyclyls with 3 to 7 members, e.g., azetidinil, tetrahydrofuranil, tetrahydrofuranil Dropyranil, pyrrolidinil, morpholinil, tetrahydrothienyl, tetrahydrothienyl Nyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, pi Peridinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. As you should understand, any heterocycle can be composed of any suitable atom, for example, carbon. Alternatively, it can be linked to another group by a nitrogen atom. However, piperidino or morphol The references herein to No are piperidine-1-yl linked by a ring nitrogen or This refers to the morpholine-4-yl ring.

[0048] A "bridged ring system" refers to a ring system in which two rings share two or more atoms, for example, Adv anced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages See 131-133, 1992. Examples of bridged heterocyclyl ring systems include, Zarbicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane Butane, azabicyclo[2.2.2]octane, azabicyclo[3.2.1]octa It contains quinuclidine and quinuclidine.

[0049] "Spiro bi-cyclic ring systems" are two ring systems that form one Sharing a common spirocarbon, that is, a heterocyclic ring, a single common spirocarbon This means that atoms are linked to further carbocyclic or heterocyclic rings. Examples of spiro ring systems include 6-azaspiro[3,4]octane and 2-oxa-6-azas Pyro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azas Pyro[3.3]heptane, 7-oxa-2-azapiro[3.5]nonane, 6-oxa- 2-Azaspiro[3.4]octane, 2-Oxa-7-Azaspiro[3.5]nonane It contains 2-oxa-6-azaspiro[3.5]nonane.

[0050] "Aromatic" is used herein, either alone or in conjunction with one or more other terms. When used, monocyclic and polycyclic forms containing 4n+2π electrons (where n is an integer) are used. This refers to a cyclic ring system. Aromatic compounds are ring systems containing only carbon atoms (i.e., "aryl" rings). Furthermore, a ring system containing at least one heteroatom selected from N, O, or S ( That is, it refers to and includes "aromatic heterocycles" or "heteroaryls". It should be understood that the aromatic ring system may be substituted or unsubstituted. That's fine.

[0051] "Non-aromatic" is used herein by itself or by another term or When used in conjunction with multiple terms, at least one that is not part of a broad conjugated π system This refers to a monocyclic or polycyclic ring system having a double bond. As used herein, it refers to a non-aromatic ring system. This refers to a ring system containing only carbon atoms and at least one selected from N, O, or S. This refers to ring systems containing heteroatoms, and non-aromatic ring systems containing them are substituted. It may be present, or it may not be substituted.

[0052] "Aryl" refers to a cyclic or polycyclic aromatic ring containing 5 to 12 carbon atoms. Aryl groups include monovalent and divalent species. For example, this This includes, but is not limited to, phenyl, biphenyl, naphthyl, and the like. A detailed embodiment So, aryl is phenyl.

[0053] "Heteroaryl" or "aromatic heterocyclic" is selected from nitrogen, oxygen, or sulfur. It incorporates one or more heteroatoms (e.g., 1 to 4, especially 1, 2, or 3). It refers to a monocyclic, bicyclic, or polycyclic aromatic ring. The term heteroaryl has one This includes valence and divalent species. Examples of heteroaryl groups have 5 to 12 ring members, more commonly Heteroaryl groups are typically monocyclic and bicyclic groups containing 5 to 10 ring members. For example, a monoring ring with 5 or 6 members or a biring ring with 9 or 10 members, for instance It can be a bicyclic structure formed from 5- and 6-membered fused rings or two 6-membered fused rings. Each ring typically contains up to four heteroatoms selected from nitrogen, sulfur, and oxygen. Yes, it is possible. Typically, a heteroaryl ring has up to 3 heteroatoms, more commonly up to 2. For example, it contains a single heteroatom. In one embodiment, the heteroaryl ring is at least It contains one ring nitrogen atom. The nitrogen atom in the heteroaryl ring is imidazole or pi Even if it is basic, as in the case of lysine, or essential, as in the case of indole or pyrrole nitrogen It may also be non-basic. Generally, hetero-amino compounds including any amino group substituent on the ring. The number of basic nitrogen atoms present in the le group is less than 5.

[0054] Examples of heteroaryl compounds include furyl, pyrrolyl, thienyl, oxazolyl, isoxa Zolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, Thiadianzolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl Pyrazinyl, 1,3,5-triazeninyl, benzofuranyl, indolyl, isoindolyl Benzothienyl, Benzoxazolyl, Benzimidazolyl, Benzothiazolyl, Nzothiazolyl, indazolyl, prinyl, benzoflazanil, quinolyl, isoquinolyl , quinazolinyl, quinoxalinyl, synnolinyl, pteridinyl, naphth Lidinyl, Carbazolyl, Phenazinyl, Benzisoquinolinyl, Pyridopyrazinyl, Chi Eno[2,3-b]furanyl, 2H-flo[3,2-b]-pyranyl, 5H-pyrido[2 ,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H- Imidazolyl[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[ It contains 2,1-b]thiazolyl and imidazo[1,2-b][1,2,4]triazinyl. Furthermore, "heteroaryl" partially encompasses aromatic bicyclic- or polycyclic ring systems. At least one ring is an aromatic ring, and one or more of the other rings are A non-aromatic, saturated or partially saturated ring, wherein at least one ring is nitrogen It contains one or more heteroatoms selected from oxygen or sulfur. Partially Examples of aromatic heteroaryl groups include tetrahydroisoquinolinyl, tetrahydrox Norinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzie Nyl, dihydrobenzfuranil, 2,3-dihydro-benzo[1,4]dioxynyl, be Nzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl Lu, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-te Trahydro-1,8-naphthilidinyl, 1,2,3,4-tetrahydropyrido[2,3- [b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxa It contains Zinyl.

[0055] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, Thienyl, imidazolyl, flazanil, oxazolyl, oxadiazolyl, oxatria Zolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl It contains a tetrazolyl group.

[0056] Examples of six-membered heteroaryl groups include, but are not limited to, pyridyl and pyrazinyl groups. This includes pyridazinil, pyrimidinil, and triazinil.

[0057] Bicyclic heteroaryl groups are, for example, benzene condensed into a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms. ring; Pyridine condensed into a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms. ring; A pyrimidine ring condensed into a 5- or 6-membered ring containing one or two ring heteroatoms. ; Pyrroles are condensed into a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms. ring; A pyrazole ring condensed to a 5- or 6-membered ring containing one or two ring heteroatoms. ; A pyrazine ring condensed to a 5- or 6-membered ring containing one or two ring heteroatoms; Imidazoles condensed into a 5- or 6-membered ring containing one or two ring heteroatoms. ring; Oxazoles condensed into a 5- or 6-membered ring containing one or two ring heteroatoms. ring; Isooxazo condensed into a 5- or 6-membered ring containing one or two ring heteroatoms ring; A thiazole ring condensed to a 5- or 6-membered ring containing one or two ring heteroatoms. ; An isothiazo condensed into a 5- or 6-membered ring containing one or two ring heteroatoms. Lu-ring; A thiophene condensed into a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms. Ring; A furan ring condensed into a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms. ; Condensed into a 5- or 6-membered aromatic heterocycle containing 1, 2, or 3 ring heteroatoms , a cyclohexyl ring; and Condensed into a 5- or 6-membered aromatic heterocycle containing 1, 2, or 3 ring heteroatoms It can also be a group selected from the cyclopentyl ring.

[0058] Bicyclic heteroaryl groups containing a six-membered ring condensed onto a five-membered ring include, for example, not limited to, Although not specified, benzfuranyl, benzthiophenyl, benzimimidazolyl, benzoxy Sazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isoben Zofranil, indolyl, isoindolyl, indolidinyl, indolinyl, isoindo Linyl, prinyl (e.g., adeninyl, guaninyl), indazolyl, be It contains nzodioxolyl and pyrazolopyridinyl groups.

[0059] Bicyclic heteroaryl groups containing two six-membered fused rings include, for example, and are not limited to, However, quinolinyl, isoquinolinyl, chromanil, thiochromanil, chromenil, iso Clomenil, Chromanil, Isochromanil, Benzodioxanil, Quinolidinil, Benz Oxazinyl, benzodiadinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, It contains synnolinyl, phthalazinyl, naphthilidinyl, and pteridinyl groups.

[0060] This specification also describes groups containing two or more functional groups using several compound terms. Such terms will be understood by those skilled in the art. For example, (3-6C)cycloalkyl(m- nC) alkyl is substituted with (3-6C) cycloalkyl (m-nC) alkyl Includes kills.

[0061] "Optionally substituted" means that the base or structure being substituted is... It refers to a structure, or molecule, and an unsubstituted group, structure, or molecule. For example, "In the formula, R 1 One of the CH, CH2, CH3 groups or heteroatoms (i.e., NH) within the group, "It is replaced by R" 1 One of the hydrogen groups of the group is related to the group This appropriately means that it is substituted by a defined group.

[0062] If an optional substituent is selected from "one or more" groups, this definition includes the designation All substituents selected from one of the selected groups or two of the specified groups It should be understood that the selected substituents are included. In one embodiment, "one or more" means one, two, or three. In another embodiment, "One or more" means one or two. In one detailed embodiment, one or more This refers to one thing.

[0063] "Compounds according to the present invention" collectively and specifically refers to the compounds disclosed herein. It means.

[0064] When used herein, "about" is used in conjunction with a measurable value, such as a quantity or duration. "This includes, for example, a reasonable variation in the value that is permissible for experimental errors during the measurement of the aforementioned value. It means to do something.

[0065] [Compounds according to the present invention] Unless otherwise specified, all references to compounds according to the present invention herein refer to (all Any one of the compounds of formula I, II, or III (including the subformula), or pharmaceutical It is understood that this refers to the salt, hydrate, or solvate of which is permissible. Similarly, this specification References to compounds according to the present invention in this document refer to formulas I, II and (including all subformulas). Compounds of type III, as well as pharmaceutically acceptable salts, hydrates, or solvates thereof, are collected. It is understood that it refers to something comprehensively.

[0066] [Compounds of formula I] In one embodiment, the present invention relates to the following formula I: [ka] [In the formula, R 1 N, CR 2 aryl, heteroaryl, carbocykrill and heterocyclyl Selected from the group consisting of R 1 Any aryl, heteroaryl, or carbocykrill in the middle Or heterocyclines are one or more R 3 It may be replaced in some cases; Each R 3 These are hydroxy, cyano, halogen, (1-4C) alkyl, and (1-4C) halo Lukil, (2~4C) Alkenil, (2~4C) Alkinil, Ariel, Ariel (1~ 3C) alkyl, heteroaryl, heteroaryl(1-3C) alkyl, carbocyclyte Carbocyclyl(1-3C) alkyl, heterocyclyl, heterocyclyl(1-3C) ) alkyl, -OR 3a , -NR 3a R 3b , -C(O)-R 3a , -C(O)-OR 3 a -OC(O)-R 3a -C(O)-NR 3a R 3b , -N(R 3a )C(O)- R 3b and -S(O) 0-2 R 3a Independently selected from the group consisting of, R3 Any ( (1-4C) alkyl, (1-4C) haloalkyl, (2-4C) alkenyl, (2-4C ) Alkynyl, aryl, aryl(1-3C)alkyl, heteroaryl, heteroaryl Alkyl (1-3C) alkyl, carbocyrill, carbocyrill (1-3C) alkyl, Telocyryl or heterocyclyl(1-3C) alkyl groups consist of one or more R 3c in Substituted depending on the circumstances; R 3a and R 3b is hydrogen, (1-3C) alkyl and (1-3C) haloalkyl or Each of the following groups is independently selected; Each R 3c These are hydroxy, halogen, cyano, amino, (1-3C)alkyl, (1-3 Independently selected from the group consisting of C) alkoxy and (1-3C) haloalkyl; R 2 These are hydrogen, hydroxyl, cyano, halogen, (1-4C) alkyl, and (1-4C) halogen. Roalkyl, (2-4C)alkenyl, (2-4C)alkynyl, aryl, aryl( 1-3C) alkyl, heteroaryl, heteroaryl(1-3C) alkyl, carbosis Krill, carbocyclyl(1-3C) alkyl, heterocyclyl, heterocyclyl(1- 3C) alkyl, -OR 2a , -NR 2a R 2b , -C(O)-R 2a , -C(O)-O R 2a -OC(O)-R 2a -C(O)-NR 2a R 2b , -N(R 2a )C(O )-R 2b and -S(O) 0-2 R 9a Selected from the group consisting of R 2Any (1) inside (~4C) alkyl, (1~4C) haloalkyl, (2~4C) alkenyl, (2~4C) Alkynyl, aryl, aryl(1-3C)alkyl, heteroaryl, heteroaryl (1-3C)alkyl, carbocyrill, carbocyrill(1-3C)alkyl, hete Rocyclyl or heterocyclyl (1-3C) alkyl groups consist of one or more R 2c de ba Replaced by; R 2a and R 2b is hydrogen, (1-3C) alkyl and (1-3C) haloalkyl or Each of the following groups is independently selected; Each R 2c These are hydroxy, halogen, cyano, amino, (1-3C)alkyl, (1-3 Independently selected from the group consisting of C) alkoxy and (1-3C) haloalkyl; Each L 1 teeth, -(W) n -(X) m -(Y) o -(Z) p - is a base, n and o are independently 0, 1, or 2, and m and p are independently , is either 0 or 1, except when both m and p are 1, in which case o is not 0; Each W is (1-3C) alkylene, (2-3C) alkenylene, (2-3C) alkinile It consists of arn, arylene, heteroarylene, carbocyrene and heterocyclene. Selected from the group, any (1-3C)alkylene, (2-3C)alkene, ( 2-3C) Alkynylene, arylene, heteroarylene, carbocyrylene or hetero Rocyclylene contains one or more W a In some cases, it is replaced, and each W a , hydroxy, cyano, halogen, amino, (1-2 C) alkoxy and (1-2 C) haloalkyl are selected from the group independently; X is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O) 0-2 -, -C(O)-N(R x )-, -N(R x )-C(O)-, -NR x -, -N(R x ) -C(O)-NR x -, -SO2N(R x )-, and -N(R x )SO2 , and each R x is independently selected from the group consisting of hydrogen, hydroxy, cyano, (1-4C)alkyl, (2-4C )alkenyl and (2-4C)alkynyl; each Y is selected from the group consisting of (1-3C)alkylene, (2-3C)alkenylene, (2-3C)alkynyle ne, arylene, heteroarylene, carbocyclylene and heterocyclylene , and any (1-3C)alkylene, (2-3C)alkenylene, ( 2-3C)alkynylene, arylene, heteroarylene, carbocyclylene or hete rocyclylene in Y is optionally substituted with one or more Y a , and each Y a is independently selected from the group consisting of hydroxy, cyano, halogen, amino, (1-2 C) alkoxy and (1-2 C) haloalkyl the group independently; Z is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O) 0-2 -, -C(O)-N(R z )-, -N(R z )-C(O)-, -NR z -, -N(R z ) -C(O)-NR z-, -SO2N(R z )-, and -N(R z ) A group consisting of SO2 Selected from, each R z These are hydrogen, hydroxyl, cyano, (1-4C)alkyl, (2-4C Independently selected from the group consisting of alkenyls and (2-4C)alkynyls; X a It is a ring heteroatom located within the A ring, selected from N and O; Each A ring is a monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocyclic, or bicyclic heterocyclic ring. It is an elementary ring, and at least one of them is one or more R 4 It is replaced depending on the case, each R 4 These are hydroxy, cyano, halogen, (1-6C) alkyl, and (1-6C) haloal Kill, (2-6C) Alkenil, (2-6C) Alkinil, Ariel, Ariel (1-3 C) Alkyl, heteroaryl, heteroaryl(1-3C)alkyl, carbocyrill Carbocyclyl(1-3C) alkyl, heterocyclyl, heterocyclyl(1-3C) Alkyl, -R 4a -OR 4b , -R 4a -NR 4b R 4c , -R 4a -C(O)-R 4 b , -R 4a -C(O)-OR 4b , -R 4a -OC(O)-R 4b , -R 4a -C( O)-NR 4b R 4c , -R 4a -N(R 4b )C(O)-R 4c and -R 4a -S( O) 0-2 R 4b Independently selected from the group consisting of, R4 Any (1-6C) alkyl group within (1-6C) Haloalkyl, (2-6C) Alkenyl, (2-6C) Alkinyl, Ali Alkyl, aryl(1-3C)alkyl, heteroaryl, heteroaryl(1-3C) Lukil, carbocyclyl, carbocyclyl(1-3C) alkyl, heterocyclyl or Heterocyclyl(1-3C)alkyl groups consist of one or more R 4d It may be replaced in some cases. ; R 4a It is either absent, or selected from the group consisting of hydroxy, halo, and amino. (1-3C) alkylenes that are substituted with one or more substituents. and; R 4b and R 4c is hydrogen, (1-3C) alkyl and (1-3C) haloalkyl or Each of the following groups is independently selected; Each R 4d These are hydroxy, halogen, cyano, amino, (1-3C)alkyl, (1-3 Independently selected from the group consisting of C) alkoxy and (1-3C) haloalkyl; X b It is a ring heteroatom located within the B ring, selected from N and O. Each B ring is a monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocyclic, or bicyclic heterocyclic ring. It is an elementary ring, and at least one of them is one or more R 5 It is replaced depending on the case, each R 5 These are hydroxy, cyano, halogen, (1-6C) alkyl, and (1-6C) haloal Kill, (2-6C) Alkenil, (2-6C) Alkinil, Ariel, Ariel (1-3 C) Alkyl, heteroaryl, heteroaryl(1-3C)alkyl, carbocyrill Carbocyclyl(1-3C) alkyl, heterocyclyl, heterocyclyl(1-3C) Alkyl, -R 5a -OR 5b , -R 5a -NR 5b R 5c , -R 5a -C(O)-R 5 b , -R 5a -C(O)-OR 5b , -R 5a -OC(O)-R 5b , -R 5a -C( O)-NR 5b R 5c , -R 5a -N(R 5b )C(O)-R 5c and -R 5a -S( O) 0-2 R 5b Independently selected from the group consisting of, R 5 Any (1-6C) alkyl group within (1-6C) Haloalkyl, (2-6C) Alkenyl, (2-6C) Alkinyl, Ali Alkyl, aryl(1-3C)alkyl, heteroaryl, heteroaryl(1-3C) Lukil, carbocyclyl, carbocyclyl(1-3C) alkyl, heterocyclyl or Heterocyclyl(1-3C)alkyl groups consist of one or more R 5d It may be replaced in some cases. ; R 5a It is either absent, or selected from the group consisting of hydroxy, halo, and amino. It is a (1-3C) alkylene which is optionally substituted with one or more substituents; R 5b and R 5c It is hydrogen, (1-5) alkyl (e.g., (1-3C) alkyl) Each is independently selected from the group consisting of (1-3C) haloalkyl groups; Each R 5dThese are hydroxy, halogen, cyano, amino, (1-3C)alkyl, (1-3 Independently selected from the group consisting of C) alkoxy and (1-3C) haloalkyl; Each L 2 (When ring A is directly bonded to ring B) is absent, (1-2C) alkylene Selected from the group consisting of ethenylene and ethinylene, L 2 Any (1~2C) inside Lukilen, ethenylene, and ethinylene are hydroxy, halogen, cyano, amino, ( Composed of (1-3C) alkyl, (1-3C) alkoxy, and (1-3C) haloalkyl The structure is optionally substituted with one or more substituents selected from the group. Compounds containing, or pharmaceutically acceptable salts, hydrates, or solvates thereof, However, the compound of formula I is the following compound Ia: [ka] , or compounds other than pharmaceutically acceptable salts, hydrates or solvates thereof, or drugs Provides scientifically acceptable salts, hydrates, or solvates thereof.

[0067] The specific compounds according to the present invention include, for example, compounds of formula I, or pharmaceutically acceptable compounds. These include salts, hydrates, and / or solvates, and unless otherwise stated, R 1 , L 1 A, X a , L 2 , B and X b Each of these, as well as any related subgroups , any of the meanings defined above or any of the following paragraphs (1) to (80) They possess either one. (1) Each A ring consists of a total of 1, 2, or 3 rings, independently selected from N, O, and S. A 5-7 member monocyclic heteroaryl containing a heteroatom, or independently of N, O, and S. Selected are 5-7 member monocyclic heteroatoms containing a total of 1, 2, or 3 ring heteroatoms. It is an elementary ring, and each A ring has one or more R 4 It is sometimes replaced. (2) Each A ring consists of a total of 1, 2, or 3 rings, independently selected from N, O, and S. A 5-6 member monocyclic heteroaryl containing a heteroatom, or independently of N, O, and S. Selected are 5-6 member monocyclic heteroatoms containing a total of 1, 2, or 3 ring heteroatoms. It is an elementary ring, and each A ring has one or more R 4 It is sometimes replaced. (3) Each A ring is based on the following group: [ka] [In the formula, a is either 0 or 1.] (4) Each A ring is based on the following group: [ka] That is the case. (5)X a The A ring is N, and the A ring is selected from N, O, and S, with 0, 1, or 2 elements. It contains further ring heteroatoms. (6)X a The A ring is N, and the A ring is selected from N, O, and S, with 0 or 1 additional It contains a ring heteroatom. (7)X a L 1 It is located directly adjacent to the carbon atom to which it is bonded. (8)Each R 4 These are hydroxy, halogen, (1-6C)alkyl, and (1-6C)haloal Kill, (2-6C)alkenyl, phenyl, phenyl(1-3C)alkyl, 5-6 member Heteroaryl, 5-6 member heteroaryl(1-3C)alkyl, -R4a -OR 4b , -R 4a -NR 4b R 4c , -R 4a -C(O)-R 4b , -R 4a -C(O)-OR 4b , -R 4a -OC(O)-R 4b , -R 4a -C(O)-NR 4b R 4c , -R 4 a -N(R 4b )C(O)-R 4c and -R 4a -S(O) 0-2 R 4b A group consisting of They were independently selected, R 4 Any (1-6C) alkyl, (1-6C) haloalkyl, (2-6C) alkenyl, phenyl, phenyl(1-3C) alkyl, 5-6 member heterozygotes Aryl or 5-6 member heteroaryl(1-3C)alkyl groups include one or more R 4d It is sometimes replaced. (9)Each R 4 These are hydroxy, halogen, (1-3C)alkyl, and (1-3C)haloal Kill, (2-3C)alkenyl, phenyl and -R 4a -OR 4b Independent from the group consisting of Selected for R 4 Any (1-3C) alkyl, (1-3C) haloalkyl, (2- 3C) Alkenyl or phenyl is one or more R 4d In some cases, it is replaced. ru. (10)Each R 4 These are hydroxy, halogen, (1-3C)alkyl, and (1-3C)halo It is independently selected from the group consisting of lukyl and phenyl. (11)Each R 4 These include hydroxy, halogen, (1-2C)alkyl and (1-2C) It is independently selected from the group consisting of rhalkyl groups. (12)Each R 4a It is either absent or methylene. (13)R 4b and R 4c These are independently selected from the group consisting of hydrogen, methyl, and ethyl. Selected. (14)Each R 4d These are hydroxy, halogen, amino, (1-2C)alkyl, (1-2 C) Independently selected from the group consisting of alkoxy and (1-2C) haloalkyl. (15)Each R 4d These include halogens, (1-2C)alkyls, and (1-2C)haloalkyls. They are independently selected from the group consisting of [the specified elements]. (16) Each B ring is i) A total of 1, 2, or 3 ring heteroatoms independently selected from N, O, and S A monocyclic heterocyclic ring containing 5 to 7 members; ii) A total of 1, 2, or 3 ring heteroatoms independently selected from N, O, and S. A 5-7 member monocyclic heteroaryl containing; iii) A total of 1, 2, 3, or 4 ring hete selected independently from N, O, and S A bicyclic heterocycle with 8 to 10 members containing a 10-member atom; or iv) A total of 1, 2, 3, or 4 ring heterozygotes independently selected from N, O, and S. 8-10 membered bicyclic heteroaryls containing atoms And, Any ring in B is one or more R 5 It is sometimes replaced. (17) Each B ring is i) A total of 1, 2, or 3 ring heteroatoms independently selected from N, O, and S A monocyclic heterocycle containing 5-6 members; ii) A total of 1, 2, or 3 ring heteroatoms independently selected from N, O, and S. A 5-6 member monocyclic heteroaryl containing; iii) A total of 1, 2, or 3 ring heterogens independently selected from N, O, and S. A bicyclic heterocycle of 9-10 members containing a child; or iv) One, two, or three ring heterogenes selected independently from N, O, and S. A 9-10 member bicyclic heteroaryl containing chromosomes. And, Any ring in B is one or more R 5 It is sometimes replaced. (18) Each B ring is as follows: [ka] [In the formula, b 1 is 0, 1, 2, or 3, b 2 It is one of the following: 0, 1, 2, 3, or 4. (19) Each B ring is as follows: [ka] [In the formula, b 1 is 0, 1, or 2, b 2 It is one of the following: 0, 1, 2, or 3. (20) Each B ring is as follows: [ka] It is one of the following. (21) Each B ring is as follows: [ka] It is one of the following. (22)X bThe A ring is N, and the A ring is 0, 1, or 2 selected from N, O, and S. It contains further ring heteroatoms. (23)X b The A ring is N, and the A ring is 0 or 1 further selected from N, O, and S. It contains a ring heteroatom. (24)X b L 2 It is located directly adjacent to the carbon atom to which it is bonded. (25)Each R 5 These are hydroxy, halogen, (1-6C)alkyl, and (1-6C)halo Lukyl, (2-6C)alkenyl, phenyl, phenyl(1-3C)alkyl, 5-6 member heteroaryl, 5-6 member heteroaryl (1-3C) alkyl, -R 5a -OR 5 b , -R 5a -NR 5b R 5c , -R 5a -C(O)-R 5b , -R 5a -C(O)-O R 5b , -R 5a -OC(O)-R 5b , -R 5a -C(O)-NR 5b R 5c , -R 5a -N(R 5b )C(O)-R 5c and -R 5a -S(O) 0-2 R 5b A group consisting of Selected independently from, R 5 Any (1-6C) alkyl or (1-6C) haloalkyl group within the group. (2-6C) alkenyl, phenyl, phenyl(1-3C) alkyl, 5-6 member hete A loaryl or 5-6 member heteroaryl(1-3C)alkyl group is one or more R 5d It is sometimes replaced. (26)Each R 5 These are hydroxy, halogen, (1-6C)alkyl, and (1-6C)halo Lukyl, (2-6C)alkenyl, phenyl, phenyl(1-3C)alkyl, 5-6 member heteroaryl, 5-6 member heteroaryl (1-3C) alkyl, -R 5a -OR 5 b , -R 5a -C(O)-R 5b , -R 5a -C(O)-OR 5b , -R 5a -OC( O)-R 5b Independently selected from the group consisting of, R 5 Any (1-6C) alkyl group in the middle, ( (1-6C) Haloalkyl, (2-6C) Alkenyl, Phenyl, Phenyl (1-3C) Lukil, 5-6 member heteroaryl or 5-6 member heteroaryl (1-3C) alkyl Lu is 1 or more R 5d It is sometimes replaced. (27)Each R 5 These are hydroxy, halogen, (1-6C)alkyl, and (1-6C)halo Lukyl, phenyl, 5-6 member heteroaryl, -R 5a -OR 5b , -R 5a -C(O )-R 5b , -R 5a -C(O)-OR 5b , -R 5a -OC(O)-R 5b Consists of Independently selected from the group, R 5 Any (1-6C) alkyl, (1-6C) haloalkyl R, phenyl, or 5-6 member heteroaryl compounds, one or more R 5d Depending on the circumstances It has been replaced. (28)Each R 5These are hydroxy, halogen, (1-3C)alkyl, and (1-3C)halo Lukyl, phenyl, 5-6 member heteroaryl, -R 5a -OR 5b , -R 5a -C(O )-R 5b , -R 5a -C(O)-OR 5b , -R 5a -OC(O)-R 5b Consists of Independently selected from the group, R 5 Any (1-3C) alkyl, (1-3C) haloalkyl R, phenyl, or 5-6 member heteroaryl compounds, one or more R 5d Depending on the circumstances It has been replaced. (29)Each R 5 These are hydroxy, halogen, (1-3C)alkyl, and (1-3C)halo Lukil, -R 5a -OR 5b , -R 5a -C(O)-R 5b , -R 5a -C(O)-OR 5b , -R 5a -OC(O)-R 5b Independently selected from the group consisting of, R 5 Any inside (1-3C) alkyl or (1-3C) haloalkyl is one or more R 5d de ba It is replaced by a combination. (30)Each R 5 Independently, -R 5a -OC(O)-R 5b That is the case. (31)Each R 5a It is either absent or methylene. (32)R 5b and R 5c These are hydrogen, methyl, ethyl and pentyl (for example, hydrogen, Each is independently selected from the group consisting of methyl and ethyl. (33)Each R 5d These are hydroxy, halogen, amino, (1-2C)alkyl, (1-2 C) Independently selected from the group consisting of alkoxy and (1-2C) haloalkyl. (34)Each R 5d These include halogens, (1-2C)alkyls, and (1-2C)haloalkyls. They are independently selected from the group consisting of [the specified elements]. (35) Each W is (1-3C) alkylene, phenylene, 5-6 member heteroarylene, Selected from the group consisting of 5-6 member carbocyclylenes and 5-6 member heterocyclylenes. , any (1-3C) alkylene, phenylene, 5-6 member heteroarylene in W, 5 ~6-membered carbocyclylene or 5-6 membered heterocyclylene, one or more W a It is sometimes replaced. (36) Each W is selected from the group consisting of (1-3C) alkylene or phenylene, Any (1-3C) alkylene or phenylene in the mixture contains one or more W a In the case It is being replaced by [something else]. (37)Each W a These include hydroxy, halogen, (1-2)alkoxy and (1-2C)halogen. It is independently selected from the group consisting of rhalkyl groups. (38)X is -O-, -C(O)-, -C(O)-O-, -OC(O)-, -C(O )-N(R x )-,-N(R x )-C(O)- and -NR x - Selected from the group consisting of ru. (39)X is -C(O)-N(R x )-,-N(R x )-C(O)- and -NR x - It is selected from the group consisting of the following. (40)X is -NR x - is (41)Each R x These are independently selected from the group consisting of hydrogen, hydroxyl, and (1-4C)alkyl. Selected. (42)Each R x This is independently selected from the group consisting of hydrogen, hydroxyl, and methyl. (43)Each R x It is hydrogen. (44) Each Y is (1-3C) alkylene, phenylene, 5-6 member heteroarylene, Selected from the group consisting of 5-6 member carbocyclylenes and 5-6 member heterocyclylenes. , any (1-3C) alkylene, phenylene, 5-6 member heteroarylene in W, 5 ~6-membered carbocyclylene or 5-6 membered heterocyclylene contains one or more Y a It is sometimes replaced. (45) Each Y is selected from the group consisting of (1-3C) alkylene or phenylene, and W Any (1-3C) alkylene or phenylene in the group may contain one or more Y a In the case It is being replaced by [something else]. (46) Each Y a These include hydroxy, halogen, (1-2)alkoxy and (1-2C)halogen. It is independently selected from the group consisting of rhalkyl groups. (47)Z is -O-, -C(O)-, -C(O)-O-, -OC(O)-, -C(O )-N(R z )-,-N(R z )-C(O)- and -NR z - Selected from the group consisting of ru. (48)Z is -C(O)-N(R z )-,-N(R z )-C(O)- and -NR z - It is selected from the group consisting of the following. (49)Z is -NR z - is (50)Each R z These are independently selected from the group consisting of hydrogen, hydroxyl, and (1-4C)alkyl. Selected. (51)Each R z This is independently selected from the group consisting of hydrogen, hydroxyl, and methyl. (52)Each R z It is hydrogen. (53) n is either 0 or 1, and o is either 0 or 1. (54) m is 0 and p is 1. (55) At least one of m, n, o, and p is not 0 (i.e., L 1 is simply a single bond (Not.) (56) n is 0 or 1, m is 1, o is 0 or 1, and p is 1. (57) n is 0 or 1, m is 0, o is 0 or 1, and p is 1. (58)L 1 The following: [ka] [In the formula, each r is independently either 0 or 1; Each s is independently 0, 1, or 2. It has one of the following structures: (59)L 1 The following: [ka] It has one of the following structures. (60)L 1 The following: [ka] [In the formula, each r is independently either 0 or 1.] It has one of the following structures. (61)L 1 The following: [ka] It has one of the following structures. (62)L 1 The following: [ka] It has one of the following structures. (63)L 2 (B is directly bonded to A) non-existent and (1-2C) alkyle Selected from the group consisting of N, L 2 Any (1-2C) alkylene in the middle is hydroxyl, ha Rogen, amino, (1-2C)alkyl, (1-2C)alkoxy and (1-2C) Optionally substituted with one or more substituents selected from the group consisting of r-alkyl groups. ru. (64)L 2 It is selected from the group consisting of non-existent and (1-2C)alkylenes, L 2 Medium Any (1-2C)alkylene is hydroxy, halogen, and (1-2C)haloal It may be substituted with one or more substituents selected from the group consisting of kill. (65)L 2 This is selected from the group consisting of non-existence, methylene, and ethylene. (66)L 2 (Ring A does not exist in such a way that it is directly bonded to Ring B.) (67)R 1 N, CR 2 phenyl, 6-membered heteroaryl, 6-membered carbocyclyl and selected from the group consisting of 6-membered heterocyclines, R 1 Any phenyl, 6 members inside A heteroaryl, a 6-membered carbocyclyl, or a 6-membered heterocyclyl is one or more. R 3 It is sometimes replaced. (68)R 1 N, CR 2 Selected from the group consisting of phenyl and cyclohexyl, R1 Any phenyl or cyclohexyl in it is one or more R 3 Depending on the situation, place It has been replaced. (69)R 1 The following: [ka] It has one of the following structures. (70)R 1 The following: [ka] It has a structure based on the following. (71)R 2 These are hydrogen, hydroxyl, halogen, (1-4C) alkyl, and (1-4C) halogen. Roalkyl and -OR 2a Selected from the group consisting of R 2 Any (1-4C) inside Kill or (1-4C) haloalkyl is one or more R 2c It may be replaced in some cases. It is. (72)R 2 R is selected from the group consisting of hydrogen and (1-3C)alkyl groups. 2 inside Any (1-4C) alkyl group may have one or more R 2c It is sometimes replaced. (73)R 2 This is selected from the group consisting of hydrogen, methyl, or ethyl. (74)Each R 2a This is independently selected from the group consisting of hydrogen and methyl. (75)Each R 2b This is independently selected from the group consisting of hydrogen and methyl. (76)Each R 2c These include hydroxy, halogen, amino, (1-2C)alkoxy and ( 1-2C) Independently selected from the group consisting of haloalkyls. (77)Each R 3These are hydroxy, halogen, (1-4C)alkyl, and (1-4C)halo Lukil and -OR 3a Independently selected from the group consisting of, R 3 Any (1-4C) inside Lukyl or (1-4C) haloalkyl, one or more R 3c In some cases, it may be replaced. It is being done. (78)Each R 3a This is independently selected from the group consisting of hydrogen and methyl. (79)Each R 3b This is independently selected from the group consisting of hydrogen and methyl. (80)Each R 3c These include hydroxy, halogen, amino, (1-2C)alkoxy and ( 1-2C) Independently selected from the group consisting of haloalkyls.

[0068] Each A-ring may appropriately include one of the numbered paragraphs (2) to (4) above. As defined above. Most appropriately, each A ring is as described in paragraph (4) numbered above. As defined in [the document].

[0069] each X a This is defined as, appropriately, in paragraph (6) or (7) numbered above. It is. Most appropriately, each X a This refers to paragraphs (6) and (7) numbered as above. As defined in both sections.

[0070] Each R 4 The appropriate option is one of the paragraphs numbered above (9) to (11). As defined in the section, most appropriately, each R 4 This refers to the paragraph numbered above (1 As defined in 1).

[0071] R 4dThis is defined appropriately in paragraph (15) numbered above.

[0072] Each B-ring may appropriately be one of the paragraphs (17) to (21) numbered above. As defined in paragraph 1. Furthermore, each B ring may be appropriately defined in the paragraph numbered above. As defined in any one of (19) to (21). Most appropriately, each B ring This is defined in paragraph (21) numbered above.

[0073] each X b This is defined appropriately in paragraph (23) or (24) numbered above. As stated above, most appropriately, each X b This refers to the paragraphs numbered above (23) and ( As defined in both of 24).

[0074] Each R 5 The appropriate answer is one of the paragraphs numbered above (27) to (30). As defined in Section 1. Furthermore, as appropriate, each R 5 The paragraphs numbered above As defined in (29) or (30). Most appropriately, each R 5 The above number As defined in the attached paragraph (30).

[0075] R 5d This is defined appropriately in paragraph (34) numbered above.

[0076] Each W is defined as appropriately in paragraph (36) numbered above.

[0077] X is defined as appropriately in paragraphs (39) or (40) numbered above. Therefore, most appropriately, X is defined as in paragraph (40) numbered above. That is the case.

[0078] Each R x This is defined appropriately in paragraph (42) or (43) numbered above. As stated above, most appropriately, each R x This is defined in paragraph (43) numbered above. As stated above.

[0079] Each Y is defined as appropriately in paragraph (45) numbered above.

[0080] Z is defined as appropriately in paragraphs (48) or (49) numbered above. Therefore, most appropriately, Z is defined as in paragraph (49) numbered above. That is the case.

[0081] Each R z This is defined appropriately in paragraph (51) or (52) numbered above. As stated above, most appropriately, each R z This is defined in paragraph (52) numbered above. As stated above.

[0082] n, m, o, and p are appropriately referred to in paragraphs (55), (56) and the above-mentioned numbered paragraphs. As defined in (57). Most appropriately, n, m, o and p are the numbers above. This is defined in paragraph (57) marked with an asterisk.

[0083] L 1 Appropriately, one of the paragraphs numbered above (58) to (62) As defined in section 2. Furthermore, L 1 This refers to the paragraph numbered above (6 As defined in any one of items 0) to (62). Most appropriately, L 1 is, up As defined in paragraph (62) with the specified number.

[0084] L 2 This is defined appropriately in paragraphs (65) or (66) numbered above. That's correct. Most appropriately, L 2 This is defined in paragraph (66) numbered above. That's right.

[0085] R 1 This is defined appropriately in paragraphs (69) or (70) numbered above. That's correct. Most appropriately, R 1 This is defined in paragraph (70) numbered above. That's right.

[0086] R 2 This is defined appropriately in paragraphs (72) or (73) numbered above. That's correct. Most appropriately, R 2 This is defined in paragraph (73) numbered above. That's right.

[0087] In a particular group of the compound according to the present invention, the compound is (a sub-definition of formula I) of the following formula II: [ka] [In the formula, R 1 , L 1 , R 4 a, B, X b and any related subgroups are as follows: As defined in one of the paragraphs marked with a number. ] Structure by, It has pharmaceutically acceptable salts, hydrates, and / or solvates thereof.

[0088] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the solvate, R 1 This refers to paragraphs (68) to (70) numbered above. This is as defined in any one of the paragraphs.

[0089] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / Or, in the case of a solvate, W is defined as in paragraph (36) numbered above. And X is defined in the numbered paragraphs (38), (39), or (40) above. As described above, Y is defined in paragraph (45) numbered above, Z is defined as described in paragraphs (47), (48), or (49) numbered above. And m, n, o, and p are defined as in the numbered paragraph (55) above. That is the case.

[0090] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / Or, in the case of a solvate, W is defined as in paragraph (36) numbered above. And X is defined in the numbered paragraphs (38), (39), or (40) above. As described above, Y is defined in paragraph (45) numbered above, Z is defined as described in paragraphs (47), (48), or (49) numbered above. And m, n, o and p are in paragraphs (56) or (57) numbered as above. It is as defined.

[0091] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, L 1This refers to paragraphs (58) to (62) numbered above. This is as defined in any one of the paragraphs.

[0092] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the solvate, R 4 This refers to the paragraphs (9) to (11) numbered above. As defined in one of the paragraphs.

[0093] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the solvate, each X b This refers to paragraphs (23) and (24) numbered above. This is as defined in both of the following sections.

[0094] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / Or, in the solvate, each B ring is in paragraphs (19) to (21) numbered above. As defined in one of the following paragraphs.

[0095] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 1 This is defined in one of the paragraphs numbered above (58) to (62). That is correct.

[0096] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As stated above.

[0097] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, L 1 This is defined in one of the paragraphs numbered above (58) to (62). As it was; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As stated above.

[0098] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, L 1 This is defined in one of the paragraphs numbered above (58) to (62). As it was; each X b This is defined in both paragraphs (23) and (24) numbered above. That is the case.

[0099] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; each X b This is defined in both paragraphs (23) and (24) numbered above. That is the case.

[0100] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1This is defined in paragraphs (69) or (70) numbered above; L 1 This is defined in one of the paragraphs numbered above (58) to (62). As it was; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As stated above.

[0101] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 1 This is defined in one of the paragraphs numbered above (60) to (62). As it was; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As stated above.

[0102] In one embodiment, the compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 1 This is defined in one of the paragraphs numbered above (60) to (62). As it was; Each B ring is defined as described in paragraph (20) or (21) indicated above. .

[0103] In a particular group of the compound according to the present invention, the compound is (a sub-definition of formula I) of the following formula I-II: [ka] [In the formula, Each R 5 This is defined in one of the numbered paragraphs above, and These are two R atoms located at adjacent carbon atoms. 5 The group is a field that combines with the atoms attached to it. In total, this is one or more R 5 It forms a condensed benzene ring which may be substituted by the group. They are connected in such a way; R 1 , L 1 A, X a , b 1 And any related subgroups are numbered above. As defined in one of the Lagraf standards. ] Structure, or pharmaceutically acceptable It has a salt, hydrate, and / or solvate thereof.

[0104] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a vi / or solvate, R 1 This refers to paragraphs (68) to (70) numbered as above. As defined in one of the following paragraphs.

[0105] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a solvate, W is defined as in paragraph (36) numbered above. And X is defined in paragraphs (38), (39), or (40) numbered above. As stated above, Y is defined in paragraph (45) numbered above. Z is defined in paragraphs (47), (48), or (49) numbered above. And m, n, o and p are defined in the paragraph (55) numbered above. It is.

[0106] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a solvate, W is defined as in paragraph (36) numbered above. And X is defined in paragraphs (38), (39), or (40) numbered above. As stated above, Y is defined in paragraph (45) numbered above. Z is defined in paragraphs (47), (48), or (49) numbered above. And m, n, o and p are in paragraphs (56) or (57) numbered above. As defined in [the document].

[0107] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a solvate, L 1 This refers to paragraphs (58) to (62) numbered above. As defined in one of the following paragraphs.

[0108] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a vi / or solvate, R 5 This refers to paragraphs (27) to (30) numbered as above. As defined in any one of the items, or two R atoms located on adjacent carbon atoms 5 When the group is combined with the atoms attached to it, it corresponds to the numbered paragraph (27) above. )~(30) one or more R as defined in any of these 5 Substituted in the base depending on the case They are linked together to form a condensed benzene ring.

[0109] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a solvate, each X aParagraphs (6) and (7) numbered above This is as defined in both sections.

[0110] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the bi / or solvates, each A ring is part of the numbered paragraphs (2) to (4) above. This is as defined in any one of the paragraphs.

[0111] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 1 This is defined in one of the paragraphs numbered above (58) to (62). That is correct.

[0112] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. That's right.

[0113] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, L 1 This is defined in one of the paragraphs numbered above (58) to (62). As it was; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. That's right.

[0114] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, L 1 This is defined in one of the paragraphs numbered above (58) to (62). As it was; each X a This is defined in both paragraphs (6) and (7) numbered above. ru.

[0115] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; each X a This is defined in both paragraphs (6) and (7) numbered above. ru.

[0116] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 1 This is defined in one of the paragraphs numbered above (58) to (62). As it was; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. That's right.

[0117] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L1 This is defined in one of the paragraphs numbered above (60) to (62). As it was; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. That's right.

[0118] In one embodiment, compounds of formulas I-II, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 1 This is defined in one of the paragraphs numbered above (60) to (62). As it was; Each A ring is defined as described in paragraph (3) or (4) indicated above.

[0119] In a particular group of the compound according to the present invention, the compound is (a sub-definition of formula I) of the following formula I-III: [ka] [In the formula, Each R 5 This is defined in one of the numbered paragraphs above, and These are two R atoms located at adjacent carbon atoms. 5 The group is a field that combines with the atoms attached to it. In addition, one or more R as defined in any of the paragraphs numbered above. 5 base They are linked to form a fused benzene ring which may be substituted in some cases; R 1 , L 1 , R 4 , a, L 2 , b 1 And any related subgroups are numbered as above. As defined in one of the paragraphs below: ] Structure, or pharmaceutical It has salts, hydrates, and / or solvates of which are permissible.

[0120] In one embodiment, compounds of formulas I-III, or pharmaceutically acceptable salts or hydrates thereof In the case of the solvate, R 1 This refers to paragraphs (68) to (70) numbered above. As defined in one of the following paragraphs.

[0121] In one embodiment, compounds of formulas I-III, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, W is defined in the paragraph (36) numbered above. As such, X is in paragraphs (38), (39), or (40) numbered above. As defined above, Y is as defined in paragraph (45) numbered above. Z is defined in paragraphs (47), (48), or (49) numbered above. As such, m, n, o, and p are defined in the numbered paragraph (55) above. That's right.

[0122] In one embodiment, compounds of formulas I-III, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, W is defined in the paragraph (36) numbered above. As such, X is in paragraphs (38), (39), or (40) numbered above. As defined above, Y is as defined in paragraph (45) numbered above. Z is defined in paragraphs (47), (48), or (49) numbered above. As such, m, n, o and p refer to the numbered paragraphs (56) or (57) above. As defined in ).

[0123] In one embodiment, compounds of formulas I-III, or pharmaceutically acceptable salts or hydrates thereof In the case of the solvate, L 1 This refers to paragraphs (58) to (62) numbered as above. As defined in one of the following paragraphs.

[0124] In one embodiment, compounds of formulas I-III, or pharmaceutically acceptable salts or hydrates thereof In the case of the solvate, R 4 This refers to paragraphs (9) to (11) numbered above. As defined in one of the following paragraphs.

[0125] In one embodiment, compounds of formulas I-III, or pharmaceutically acceptable salts or hydrates thereof In the case of the solvate, R 5 This refers to paragraphs (27) to (30) numbered above. As defined in any one of the following clauses, or two adjacent carbon atoms R 5 When the group is combined with the atoms attached to it, it corresponds to the numbered paragraph (2) above. 7) One or more R as defined in any of (30) 5 Substitute in the base depending on the case They are linked together to form a condensed benzene ring.

[0126] In one embodiment, compounds of formulas I-III, or pharmaceutically acceptable salts or hydrates thereof In the solvates, each L 2 This refers to the paragraph numbered above (65) or ( As defined in 66).

[0127] In one embodiment, compounds of formulas I-III, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 1 This is defined in one of the paragraphs numbered above (58) to (62). That is correct.

[0128] In one embodiment, compounds of formulas I-III, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 2 This is defined in paragraphs (65) or (66) numbered above.

[0129] In one embodiment, compounds of formulas I-III, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, L 2 This is defined in paragraphs (65) or (66) numbered above; L 1 This is defined in one of the paragraphs numbered above (58) to (62). That is correct.

[0130] In one embodiment, compounds of formulas I-III, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 1 This is defined in one of the paragraphs numbered above (58) to (62). As it was; L 2 This is defined in paragraphs (65) or (66) numbered above.

[0131] In one embodiment, compounds of formulas I-III, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 1 This is defined in one of the paragraphs numbered above (60) to (62). As it was; L 2 This is defined in paragraphs (65) or (66) numbered above.

[0132] In one embodiment, compounds of formulas I-III, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 1 This is defined in one of the paragraphs numbered above (60) to (62). As it was; L 2 This is defined in paragraph (66) numbered above.

[0133] In a particular group of the compound according to the present invention, the compound is (a sub-definition of formula I) of the following formula I-IV: [ka] [In the formula, Each R 5 This is defined in one of the numbered paragraphs above, and These are two R atoms located at adjacent carbon atoms. 5 The group is a field that combines with the atoms attached to it. In addition, one or more R as defined in any of the paragraphs numbered above. 5 base They are linked to form a fused benzene ring which may be substituted in some cases; R 1 , L 1 , R 4 a, b 1 And any related subgroups are numbered above. As defined in one of the Lagraf standards. ] Structure, or pharmaceutically acceptable It has a salt, hydrate, and / or solvate thereof.

[0134] In one embodiment, compounds of formulas I-IV, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a vi / or solvate, R 1 This refers to paragraphs (68) to (70) numbered as above. As defined in one of the following paragraphs.

[0135] In one embodiment, compounds of formulas I-IV, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a solvate, W is defined as in paragraph (36) numbered above. And X is defined in paragraphs (38), (39), or (40) numbered above. As stated above, Y is defined in paragraph (45) numbered above. Z is defined in paragraphs (47), (48), or (49) numbered above. And m, n, o and p are defined in the paragraph (55) numbered above. It is.

[0136] In one embodiment, compounds of formulas I-IV, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a solvate, W is defined as in paragraph (36) numbered above. And X is defined in paragraphs (38), (39), or (40) numbered above. As stated above, Y is defined in paragraph (45) numbered above. Z is defined in paragraphs (47), (48), or (49) numbered above. And m, n, o and p are in paragraphs (56) or (57) numbered above. As defined in [the document].

[0137] In one embodiment, compounds of formulas I-IV, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a solvate, L 1 This refers to paragraphs (58) to (62) numbered above. As defined in one of the following paragraphs.

[0138] In one embodiment, compounds of formulas I-IV, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a vi / or solvate, R 4 This refers to paragraphs (9) to (11) numbered above. This is as defined in any one of the paragraphs.

[0139] In one embodiment, compounds of formulas I-IV, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a vi / or solvate, R 5 This refers to paragraphs (27) to (30) numbered as above. As defined in any one of the items, or two R atoms located on adjacent carbon atoms 5 When the group is combined with the atoms attached to it, it corresponds to the numbered paragraph (27) above. )~(30) one or more R as defined in any of these 5 Substituted in the base depending on the case They are linked together to form a condensed benzene ring.

[0140] In one embodiment, compounds of formulas I-IV, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1This is defined in one of the paragraphs numbered above (68) to (70). As it was; L 1 This is defined in one of the paragraphs numbered above (58) to (62). That is correct.

[0141] In one embodiment, compounds of formulas I-IV, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 1 This is defined in one of the paragraphs numbered above (60) to (62). That is correct.

[0142] In a particular group of the compound according to the present invention, the compound is (a sub-definition of formula I) of the following formula IV: [ka] [In the formula, R 1 ,W,X,Y,m,n,o,A,X a , L 2 B, X b and any related The subgroups are defined in one of the numbered paragraphs above. The structure, or pharmaceutically acceptable salts, hydrates, and / or solvates thereof. It holds.

[0143] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the solvate, R 1 This refers to paragraphs (68) to (70) numbered above. This is as defined in any one of the paragraphs.

[0144] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / Or, in the case of a solvate, W is defined as in paragraph (36) numbered above. And X is defined in the numbered paragraphs (38), (39), or (40) above. As described above, Y is defined in paragraph (45) numbered above.

[0145] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / Or, in the case of a solvate, W is defined as in paragraph (36) numbered above. And X is defined in the numbered paragraphs (38), (39), or (40) above. As described above, Y is defined in paragraph (45) numbered above, m, n, and o are defined in the paragraphs (56) or (57) numbered above. It is.

[0146] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the solvate, each X a This refers to paragraphs (6) and (7) numbered as above. As defined in both sections.

[0147] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / Or, in the solvate, each A ring is one of the paragraphs (2) to (4) numbered above. As defined in one of the paragraphs.

[0148] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the solvate, each X b This refers to paragraphs (23) and (24) numbered above. This is as defined in both of the following sections.

[0149] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / Or, in the solvate, each B ring is in paragraphs (19) to (21) numbered above. As defined in one of the following paragraphs.

[0150] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the solvate, each L 2 This refers to the paragraphs numbered above (65) or (66) As defined in ).

[0151] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; Each B ring is defined as described in paragraphs (19) or (21) numbered above. .

[0152] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; each X b This is defined in both paragraphs (23) and (24) numbered above. That is the case.

[0153] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1This is defined in paragraphs (69) or (70) numbered above; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. That's right.

[0154] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; each X a This is defined in both paragraphs (6) and (7) numbered above. ru.

[0155] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; W is defined as in paragraph (36) numbered above, and X is numbered above As defined in the attached paragraphs (38), (39), or (40), Y is above As defined in paragraph (45) with the specified number.

[0156] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, each X a This is defined in both paragraphs (6) and (7) numbered above. the law of nature; each X b This is defined in both paragraphs (23) and (24) numbered above. and; W is defined as in paragraph (36) numbered above, and X is numbered above As defined in the attached paragraphs (38), (39), or (40), Y is above As defined in paragraph (45) with the specified number.

[0157] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, Each A ring is defined in one of the paragraphs (2) to (4) numbered above. It is a street; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As described above; W is defined as in paragraph (36) numbered above, and X is numbered above As defined in the attached paragraphs (38), (39), or (40), Y is above As defined in paragraph (45) with the specified number.

[0158] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; each X a This is defined in both paragraphs (6) and (7) numbered above. the law of nature; each X b This is defined in both paragraphs (23) and (24) numbered above. and; W is defined as in paragraph (36) numbered above, and X is numbered above As defined in the attached paragraphs (38), (39), or (40), Y is above As defined in paragraph (45) with the specified number.

[0159] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. It is a street; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As stated above; W is defined as in paragraph (36) numbered above, and X is numbered above As defined in the attached paragraphs (38), (39), or (40), Y is above As defined in paragraph (45) with the specified number.

[0160] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, L 2 This is defined in paragraphs (65) or (66) numbered above; each X a This is defined in both paragraphs (6) and (7) numbered above. the law of nature; each X b This is defined in both paragraphs (23) and (24) numbered above. and; W is defined as in paragraph (36) numbered above, and X is numbered above As defined in the attached paragraphs (38), (39), or (40), Y is above As defined in paragraph (45) with the specified number.

[0161] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, L 2 This is defined in paragraphs (65) or (66) numbered above; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. It is a street; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As described above; W is defined as in paragraph (36) numbered above, and X is numbered above As defined in the attached paragraphs (38), (39), or (40), Y is above As defined in paragraph (45) with the specified number.

[0162] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 2 This is defined in paragraphs (65) or (66) numbered above; each X a This is defined in both paragraphs (6) and (7) numbered above. the law of nature; each X b This is defined in both paragraphs (23) and (24) numbered above. and; W is defined as in paragraph (36) numbered above, and X is numbered above As defined in the attached paragraphs (38), (39), or (40), Y is above As defined in paragraph (45) with the specified number.

[0163] In one embodiment, the compound of formula IV, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 2 This is defined in paragraphs (65) or (66) numbered above; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. It is a street; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As described above; W is defined as in paragraph (36) numbered above, and X is numbered above As defined in the attached paragraphs (38), (39), or (40), Y is above As defined in paragraph (45) with the specified number.

[0164] In a particular group of the compound according to the present invention, the compound is (a sub-definition of formula I) of the following formula I-VI: [ka] [wherein q is 0, 1, 2, or 3; R 1 A, X a , L 2 B, X b And any related subgroups are numbered as above. As defined in one of the paragraphs above. ] Structure, or pharmaceutically It has acceptable salts, hydrates, and / or solvates thereof.

[0165] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and For the bi / or solvate, q is 0, 1, or 2.

[0166] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a vi / or solvate, R 1 This refers to paragraphs (68) to (70) numbered as above. As defined in one of the following paragraphs.

[0167] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a solvate, each X a Paragraphs (6) and (7) numbered above This is as defined in both sections.

[0168] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the bi / or solvates, each A ring is part of the numbered paragraphs (2) to (4) above. This is as defined in any one of the paragraphs.

[0169] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a solvate, each X b This refers to paragraphs (23) and (2) numbered above. As defined in both of 4).

[0170] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the bi / or solvates, each B ring is as described in paragraphs (19) to (21) numbered above. As defined in one of the following paragraphs.

[0171] In one embodiment, in Japanese products, each L 2 This refers to the paragraph numbered above (65) or ( As defined in 66).

[0172] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; Each B ring is defined as described in paragraphs (19) or (21) numbered above. .

[0173] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; each X b This is defined in both paragraphs (23) and (24) numbered above. That is the case.

[0174] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. That's right.

[0175] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; each X a This is defined in both paragraphs (6) and (7) numbered above. ru.

[0176] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; each X a This is defined in both paragraphs (6) and (7) numbered above. the law of nature; each X b This is defined in both paragraphs (23) and (24) numbered above. That is the case.

[0177] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. It is a street; Each B ring is defined as described in paragraphs (19) or (21) numbered above. .

[0178] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, L 2 This is defined in paragraphs (65) or (66) numbered above; each X a This is defined in both paragraphs (6) and (7) numbered above. the law of nature; each X b This is defined in both paragraphs (23) and (24) numbered above. That is the case.

[0179] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, L 2 This is defined in paragraphs (65) or (66) numbered above; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. It is a street; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As stated above.

[0180] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 2 This is defined in paragraphs (65) or (66) numbered above; each X a This is defined in both paragraphs (6) and (7) numbered above. the law of nature; each X b This is defined in both paragraphs (23) and (24) numbered above. That is the case.

[0181] In one embodiment, compounds of formulas I-VI, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; L 2 This is defined in paragraphs (65) or (66) numbered above; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. It is a street; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As stated above.

[0182] In a particular group of the compound according to the present invention, the compound is (a sub-definition of formula I) of the following formula I-VII: [ka] [In the formula, L 1 A, X a , L 2 B, X b and any related subgroups are as follows: As defined in one of the paragraphs marked with a number. ] Structure by, It has pharmaceutically acceptable salts, hydrates, and / or solvates thereof.

[0183] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, W is defined in the paragraph (36) numbered above. As such, X is in paragraphs (38), (39), or (40) numbered above. As defined above, Y is as defined in paragraph (45) numbered above. Z is defined in paragraphs (47), (48), or (49) numbered above. As such, m, n, o, and p are defined in the numbered paragraph (55) above. That's right.

[0184] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, W is defined in the paragraph (36) numbered above. As such, X is in paragraphs (38), (39), or (40) numbered above. As defined above, Y is as defined in paragraph (45) numbered above. Z is defined in paragraphs (47), (48), or (49) numbered above. As such, m, n, o and p refer to the numbered paragraphs (56) or (57) above. As defined in ).

[0185] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of the solvate, L 1 This refers to paragraphs (58) to (62) numbered as above. As defined in one of the following paragraphs.

[0186] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the solvates, each X a This refers to paragraphs (6) and (7) numbered above. This is as defined in both of the following sections.

[0187] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the and / or solvates, each A ring is one of the numbered paragraphs (2) to (4) above. As defined in one of the following paragraphs.

[0188] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the solvates, each X b This refers to the paragraphs numbered above (23) and ( As defined in both of 24).

[0189] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the solvates, each B ring is located in paragraphs (19) to (21) numbered above. ) as defined in any one of the following paragraphs.

[0190] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of the solvate, each L 2 This refers to the paragraph numbered above (65) or ( As defined in 66).

[0191] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, L 1 This is defined in one of the paragraphs numbered above (58) to (62). As it was; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As stated above.

[0192] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, L 1 This is defined in one of the paragraphs numbered above (58) to (62). As it was; each X b This is defined in both paragraphs (23) and (24) numbered above. That is the case.

[0193] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, L 1 This is defined in one of the paragraphs numbered above (58) to (62). As it was; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. That's right.

[0194] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, L 1 This is defined in one of the paragraphs numbered above (58) to (62). As it was; each X a This is defined in both paragraphs (6) and (7) numbered above. ru.

[0195] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, L 1 This is defined in one of the paragraphs numbered above (58) to (62). As it was; each X a This is defined in both paragraphs (6) and (7) numbered above. the law of nature; each X b This is defined in both paragraphs (23) and (24) numbered above. That is the case.

[0196] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, L 1 This is defined in one of the paragraphs numbered above (58) to (62). As it was; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. It is a street; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As stated above.

[0197] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, L 2 This is defined in paragraphs (65) or (66) numbered above; each X a This is defined in both paragraphs (6) and (7) numbered above. the law of nature; each X b This is defined in both paragraphs (23) and (24) numbered above. That is the case.

[0198] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, L 2 This is defined in paragraphs (65) or (66) numbered above; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. It is a street; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As stated above.

[0199] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, L 1 This is defined in one of the paragraphs numbered above (60) to (62). As it was; L 2 This is defined in paragraphs (65) or (66) numbered above; each X a This is defined in both paragraphs (6) and (7) numbered above. the law of nature; each X bThis is defined in both paragraphs (23) and (24) numbered above. That is the case.

[0200] In one embodiment, compounds of formulas I-VII, or pharmaceutically acceptable salts or hydrates thereof In the case of a solvate, L 1 This is defined in one of the paragraphs numbered above (60) to (62). As it was; L 2 This is defined in paragraphs (65) or (66) numbered above; Each A ring is defined in one of the paragraphs (2) to (4) numbered above. It is a street; Each B-ring is defined in one of the numbered paragraphs (19) to (21) above. As stated above.

[0201] In a particular group of the compound according to the present invention, the compound is (a sub-definition of formula I) of the following formula I-VIII: [ka] [In the formula, each R 5 This is defined in one of the numbered paragraphs above. or two R located at adjacent carbon atoms 5 The group combines with the atoms attached to them. If combined, one or more of the paragraphs numbered above will be defined in one of them. R 5 Linked to form a condensed benzene ring which may be substituted by a group; R 1 W, X, Y, m, n, o, R 4 , a, L 2 , b 1 and any related subgroups P is defined as described in one of the numbered paragraphs above. It has a structure, or pharmaceutically acceptable salts, hydrates, and / or solvates thereof.

[0202] In one embodiment, compounds of formulas I-VIII, or pharmaceutically acceptable salts or hydrates thereof and / or in solvates, R 1 This refers to paragraphs (68) to (70) numbered above. ) as defined in any one of the following paragraphs.

[0203] In one embodiment, compounds of formulas I-VIII, or pharmaceutically acceptable salts or hydrates thereof And / or in the solvates, W is defined in the numbered paragraph (36) above. As stated above, X is in paragraphs (38), (39), or (40) numbered as above. As defined above, Y is as defined in paragraph (45) numbered above. be.

[0204] In one embodiment, compounds of formulas I-VIII, or pharmaceutically acceptable salts or hydrates thereof And / or in the solvates, W is defined in the numbered paragraph (36) above. As stated above, X is in paragraphs (38), (39), or (40) numbered as above. As defined above, Y is as defined in paragraph (45) numbered above. Yes, m, n, and o are defined in the numbered paragraphs (56) or (57) above. As stated above.

[0205] In one embodiment, compounds of formulas I-VIII, or pharmaceutically acceptable salts or hydrates thereof and / or in solvates, R 4 This refers to paragraphs (9) to (11) numbered above. As defined in one of the following paragraphs.

[0206] In one embodiment, compounds of formulas I-VIII, or pharmaceutically acceptable salts or hydrates thereof and / or in the solvate, R 5 This refers to paragraphs (27) to (30) numbered above. ) as defined in any one of the items, or two adjacent carbon atoms R 5 The group, when combined with the atoms attached to them, corresponds to the numbered paragraphs above. One or more R as defined in any one of items 27) to (30) 5 Depending on the circumstances They are linked in such a way that they form a substituted condensed benzene ring.

[0207] In one embodiment, compounds of formulas I-VIII, or pharmaceutically acceptable salts or hydrates thereof and / or in the solvate, each L 2 This refers to the paragraph numbered above (65) or As defined in (66).

[0208] Compounds of formulas I-VIII, or pharmaceutically acceptable salts, hydrates, and / or In solvates, R 1 This is defined in paragraphs (69) or (70) numbered above; L 2 This is defined in paragraphs (65) or (66) numbered above.

[0209] In one embodiment, compounds of formulas I-VIII, or pharmaceutically acceptable salts or hydrates thereof and / or in solvates, R 1 This is defined in paragraphs (69) or (70) numbered above; W is defined as in paragraph (36) numbered above, and X is numbered above As defined in the attached paragraphs (38), (39), or (40), Y is above As defined in paragraph (45) with the specified number.

[0210] In one embodiment, compounds of formulas I-VIII, or pharmaceutically acceptable salts or hydrates thereof and / or in solvates, L 2 This is defined in paragraphs (65) or (66) numbered above; W is defined as in paragraph (36) numbered above, and X is numbered above As defined in the attached paragraphs (38), (39), or (40), Y is above As defined in paragraph (45) with the specified number.

[0211] In one embodiment, compounds of formulas I-VIII, or pharmaceutically acceptable salts or hydrates thereof and / or in solvates, R 1 This is defined in paragraphs (69) or (70) numbered above; L 2 This is defined in paragraphs (65) or (66) numbered above; W is defined as in paragraph (36) numbered above, and X is numbered above As defined in the attached paragraphs (38), (39), or (40), Y is above As defined in paragraph (45) with the specified number.

[0212] In a particular group of the compound according to the present invention, the compound is (a sub-definition of formula I) of the following formula I-IX: [ka] [In the formula, q is 0 (in this case, R 1 (is directly bonded to N), is 1, 2, or 3; Each R 5 This is defined in one of the numbered paragraphs above, and These are two R atoms located at adjacent carbon atoms. 5 The group is a field that combines with the atoms attached to it. In addition, one or more R as defined in any of the paragraphs numbered above. 5 base They are linked to form a fused benzene ring which may be substituted in some cases; R 1 , R 4 a, b 1 And any related subgroups are paragraphs numbered above. As defined in one of the following: ] structure, or pharmaceutically acceptable It has a salt, hydrate, and / or solvate thereof.

[0213] In one embodiment, compounds of formulas I-IX, or pharmaceutically acceptable salts, hydrates thereof, and For the bi / or solvate, q is 0, 1, or 2.

[0214] In one embodiment, compounds of formulas I-IX, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a vi / or solvate, R 1 This refers to paragraphs (68) to (70) numbered as above. As defined in one of the following paragraphs.

[0215] In one embodiment, compounds of formulas I-IX, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a vi / or solvate, R 4 This refers to paragraphs (9) to (11) numbered above. This is as defined in any one of the paragraphs.

[0216] In one embodiment, compounds of formulas I-IX, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a vi / or solvate, R 5 This refers to paragraphs (27) to (30) numbered as above. As defined in any one of the items, or two R atoms located on adjacent carbon atoms 5 When the group is combined with the atoms attached to it, it corresponds to the numbered paragraph (27) above. ) ~ (30) one or more R as defined in any one of these items 5 Depending on the circumstances, They are linked in such a way that they form a fused benzene ring.

[0217] In one embodiment, compounds of formulas I-IX, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; R 4 This is defined in one of the paragraphs (9) to (11) numbered above. That's right.

[0218] In one embodiment, compounds of formulas I-IX, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; R 5 This is defined in one of the paragraphs numbered above (27) to (30). As shown, or two R located at adjacent carbon atoms 5 The base is the base that adheres to these When combined with the child, any of the paragraphs numbered above (27) to (30) or one or more R as defined in item 1 5 A condensed benzene ring that is optionally substituted with a group. They are connected in such a way that they form a structure.

[0219] In one embodiment, compounds of formulas I-IX, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 4 This is defined in one of the paragraphs (9) to (11) numbered above. It is a street; R 5 This is defined in one of the paragraphs numbered above (27) to (30). As shown, or two R located at adjacent carbon atoms 5 The base is the base that adheres to these When combined with the child, any of the paragraphs numbered above (27) to (30) or one or more R as defined in item 1 5 A condensed benzene ring that is optionally substituted with a group. They are connected in such a way that they form a structure.

[0220] In one embodiment, compounds of formulas I-IX, or pharmaceutically acceptable salts, hydrates thereof, and In the case of a diuretic / solvate, R 1 This is defined in paragraphs (69) or (70) numbered above; R 4 This is defined in one of the paragraphs (9) to (11) numbered above. It is a street; R 5 This is defined in one of the paragraphs numbered above (27) to (30). As shown, or two R located at adjacent carbon atoms 5 The base is the base that adheres to these When combined with the child, any of the paragraphs numbered above (27) to (30) or one or more R as defined in item 1 5 A condensed benzene ring that is optionally substituted with a group. They are connected in such a way that they form a structure.

[0221] In one embodiment, in a specific group of the compound according to the present invention, the compound is (sub-group of formula I). (This is correct) Equation IX below: [ka] [In the formula, q is 0 (in this case, R 1 It is directly bonded to N; ), 1, 2, or 3; Each R 5 This is defined in one of the numbered paragraphs above, and These are two R atoms located at adjacent carbon atoms. 5 The group is a field that combines with the atoms attached to it. In addition, one or more R as defined in any of the paragraphs numbered above. 5 base They are linked to form a fused benzene ring which may be substituted in some cases; R 4 a, b 1 And any related subgroups are in the paragraphs numbered above. As defined in one of the following: the structure by [ ], or its pharmaceutically acceptable salt. It has a hydrate and / or solvate.

[0222] In one embodiment, the compound of formula IX, or a pharmaceutically acceptable salt or hydrate thereof, and / Or, in the case of a solvate, q is 0, 1, or 2.

[0223] In one embodiment, the compound of formula IX, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the solvate, R 4 This refers to the paragraphs (9) to (11) numbered above. As defined in one of the paragraphs.

[0224] In one embodiment, the compound of formula IX, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the solvate, R 5 The paragraphs (27) to (30) numbered above are or as defined in any one of the items, or two R located at adjacent carbon atoms 5 When the group is combined with the atoms attached to it, it corresponds to the numbered paragraph (27) above. One or more R as defined in any one of the items (30) 5 Substitute in the base depending on the case They are linked together to form a condensed benzene ring.

[0225] In one embodiment, the compound of formula IX, or a pharmaceutically acceptable salt or hydrate thereof, and / or in the case of a solvate, R 4 This is defined in one of the paragraphs (9) to (11) numbered above. It is a street; R 5 This is defined in one of the paragraphs numbered above (27) to (30). As shown, or two R located at adjacent carbon atoms 5 The base is the base that adheres to these When combined with the child, any of the paragraphs numbered above (27) to (30) or one or more R as defined in item 1 5 A condensed benzene ring that is optionally substituted with a group. They are connected in such a way that they form a structure.

[0226] In one particularly suitable embodiment, the compound of formula I is as follows: [ka] Having any one of the structures in JPEG2026143429000028.jpg86170, or a pharmaceutically acceptable salt, hydrate, or It is a solvate.

[0227] In one embodiment, the compound of formula I is as follows: [ka] It is not one of them.

[0228] [Compound of formula II] In another embodiment, the present invention relates to the following formula II: [ka] [In the formula, M is Zn 2+ Mn 2+ Cu 2+ Fe 2+ Co 2+ and Ni 2+ A group consisting of Selected; R 1 , L 1 A, X a , L 2 B, X b and any related subgroups are chemicals of formula I. The compound is as defined above. A compound having the structure of ], or pharmaceutically The acceptable salts, hydrates, or solvates thereof are provided.

[0229] As mentioned above, the inventors have surprisingly found that the compound of formula I described herein is a certain In the presence of a species of metal, it self-assembles to form a mononuclear complex, i.e., the compound of formula II. We found that it functions as a tripod-type ligand capable of doing so.

[0230] Therefore, R 1 , L 1 A, X a , L 2 B, X b and any related subgroups P is any of the above definitions for compounds of formula I (including subformulas II to IX). It is understood that it may have R. Therefore, in relation to the compound of formula I, 1 , L 1 A, X a , L 2 B, X b A suitable and preferred definition of is in relation to the compound of formula II. R 1 , L 1 A, X a , L 2 B, X b These are suitable and desirable characteristics of the definition.

[0231] The compound of formula II is a positively charged complex, and contains one or more charge equilibrium anions (ch It can be understood that it exists in conjunction with any suitable charge balance anion. Nion can be used.

[0232] In one detailed embodiment, the compound of formula II, a pharmaceutically acceptable salt thereof, hydrate or solution The mediator is the following compound IIa: [ka] Not any pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0233] In one embodiment, M is Zn 2+ Mn 2+ Fe 2+ Co 2+ and Ni 2+ from Selected from the following group. Appropriately, M is Zn 2+ Mn 2+ and Fe 2+ A group consisting of Selected from. Most appropriately, M is Zn 2+ and Mn 2+ Selected from the group consisting of ru.

[0234] In one embodiment, M is Zn 2+ Cu 2+ Mn 2+ Fe 2+ Co 2+ and N i 2+ Selected from the group consisting of . Appropriately, M is Zn 2+ Cu 2+ Mn 2+ Oh Fe 2+ It is selected from the group consisting of . Most appropriately, M is Zn 2+ Cu 2+ and Mn 2+ It is selected from the group consisting of the following.

[0235] M is X a and X b This is related (indicated as "- - - -" in equation II). However, However, depending on the properties of M, M is X a and X b It does not have to be related to all cases. This is understood. For example, oxygenophilic and hard metal cations (e.g., M=Mn 2+ ) is 2X a and 2X b It may only be related to that, and its coordination sphere is a mixed solvent, for example , completed with water. Such forms of solvation of Formula II (including the hydrate) are within the scope of the present invention. It is understood that it is within the enclosure.

[0236] In one detailed embodiment, the compound is as follows: [ka] A structure or pharmaceutically acceptable salt, hydrate, and / or It has a solvate.

[0237] In one embodiment, M is Cu2+ , R 1 , L 1 A, X a , L 2 B, X b , and If they are related subgroups, the structure is as follows: [ka] It does not form compounds containing [the specified element].

[0238] In one embodiment, R 1 , L 1 A, X a , L 2 B, X b , and any related sub The group has the following structure: [ka] It does not form compounds containing [the specified element].

[0239] [Compounds of formula III] In another embodiment, the present invention relates to the following formula III: [ka] [In the formula, M is Zn 2+ Mn 2+ Cu 2+ Fe 2+ Co 2+ and Ni 2+ A group consisting of Selected; Q is a spherical monoanionic anion, a planar triangular anion, or a dianionic tetrahedron anion. , trianionic tetrahedral anions, dianionic octahedral anions and trianionic octahedral anions An anion selected from the group consisting of helical anions; R 1 , L 1 A, X a , L 2 B, X band any related subgroups are chemicals of formula I. The compound is defined as above. ] A compound having the structure of, or pharmaceutically The acceptable salts, hydrates, or solvates thereof are: However, the compound is formula IIIa: [ka] [In the formula, Q is Br - , I - CO3 2- SiF6 2- IO6 3- VO4 3- , W O4 2- , CrO4 2- SO4 2- HSO4 - AsO4 3- , PO4 3- or H PO4 2- Compounds, or pharmaceutically acceptable salts thereof, that do not have the structure of [the compound]. The hydrate or solvate is provided.

[0240] As mentioned above, the inventors have surprisingly found that the compound of formula I described herein is a certain In the presence of species metals and anions, they self-assemble to form trinuclear complexes, i.e., compounds of formula III. We found that it functions as a tripod-type ligand capable of forming a structure.

[0241] Therefore, R 1 , L 1 A, X a , L 2 B, X b and any related subgroups P is any of the above definitions for compounds of formula I (including subformulas II to IX). It is understood that it may have R. Therefore, in relation to the compound of formula I, 1 , L 1 A, Xa , L 2 B, X b A suitable and preferred definition of is in relation to the compound of formula III. te R 1 , L 1 A, X a , L 2 B, X b These are suitable and desirable characteristics of the definition.

[0242] A compound of formula III, which is a positively charged complex, is formed by one or more charge equilibrium anions. It is understood that they exist in association with each other. Any suitable charge equilibrium anion can be used. ru.

[0243] In one embodiment, M is Zn 2+ Mn 2+ Fe 2+ Co 2+ and Ni 2+ from Selected from the following group. Appropriately, M is Zn 2+ Mn 2+ and Fe 2+ A group consisting of Selected from. Most appropriately, M is Zn 2+ and Mn 2+ Selected from the group consisting of ru.

[0244] In one embodiment, M is Zn 2+ Cu 2+ Mn 2+ Fe 2+ Co 2+ and N i 2+ Selected from the group consisting of . Appropriately, M is Zn 2+ Cu 2+ Mn 2+ Oh Fe 2+ It is selected from the group consisting of . Most appropriately, M is Zn 2+ Cu 2+ and Mn 2+ It is selected from the group consisting of the following.

[0245] M is X a and X b This is related (indicated as "- - - -" in Equation III). However, Furthermore, depending on the properties of M, it is understood that M may also be associated with a mixed solvent. For example, oxygenophilic and hard metal cations (e.g., M=Mn 2+ ) is that its coordination sphere is This can be completed with a mixed solvent, such as water. The form of solvation in Equation III is shown below. It is understood that the states (including hydrates) fall within the scope of the present invention.

[0246] In one embodiment, Q is Br - , I - CO3 2- SiF6 2- IO6 3- , VO 4 3- WO4 2- , CrO4 2- SO4 2- HSO4 - AsO4 3- , PO4 3 - or HPO4 2- That is the case.

[0247] In one embodiment, Q is a dianionic tetrahedral anion and a trianionic tetrahedral anion. It is an anion selected from ON. Appropriately, Q is a dianionic tetrahedron oxoanion. It is an anion selected from n and trianionic tetrahedral oxoanions.

[0248] In one detailed embodiment, Q is a sulfate (SO4 2- ), phosphate (PO4 3- )or Organophosphate (RPO4 2- ) In particular, an unspecified example of organophosphates is phosphorus. It contains monophenyl acids.

[0249] In one detailed embodiment, the compound is as follows: [ka] A structure or pharmaceutically acceptable salt, hydrate, and / or It has a solvate.

[0250] In one embodiment, M is Cu 2+ , R 1 , L 1 A, X a , L 2 B, X b , and If they are related subgroups, the structure is as follows: [ka] It does not form compounds containing [the specified element].

[0251] In one embodiment, R 1 , L 1 A, X a , L 2 B, X b , and any related sub The group has the following structure: [ka] It does not form compounds containing [the specified element].

[0252] Various functional groups and substituents for preparing the compounds according to the present invention have a molecular weight of the compound. It is appropriately selected so as not to exceed 1000. More appropriately, the molecular weight of the compound is 9 Less than 00, for example, less than 800, or less than 750, or less than 700, or less than 650 It is full. More preferably, the molecular weight is less than 600, for example, less than 550.

[0253] A pharmaceutically acceptable salt of the compound according to the present invention is, appropriately, for example, sufficiently basic. For example, an acid-addition salt of the compound according to the present invention, for example, an inorganic acid or an organic acid, for example, Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfone It is an acid-addition salt with an acid (methane sulfonate) or maleic acid. Furthermore, it is sufficiently acidic. The pharmaceutically acceptable salts of the compounds according to the present invention are, appropriately, alkali metal salts, e.g. For example, sodium or potassium salts, alkaline earth metals, such as calcium or magnesium. With nesium salts, ammonium salts, or organic bases that produce pharmaceutically acceptable cations Salts, for example, methylamine, dimethylamine, trimethylamine, piperidine, morphol It is a salt of amine or tris-(2-hydroxyethyl)amine.

[0254] They have the same molecular formula, but the properties or arrangement of the bonds between their atoms or in space Compounds with different arrangements of atoms are called "isomers." Isomers with different arrangements of offspring are called "stereoisomers." Stereoisomers that are not mirror images of each other are called stereoisomers. Diastereomers, which are mirror images that cannot be superimposed on each other, These are called "enantiomers." When a compound has a chiral center, for example, it has four different isomers. It is bonded to a certain group, and a pair of enantiomers are possible. The enantiomers are the absolute of their chiral centers. It can be characterized by its arrangement, the R- and S- sequences of Khan and the prelogue. Described by Singh's law, or by the way the molecule rotates the polarized light in a plane, and dextrorotatory or These can be named levorotatory (i.e., (+) or (-)-isomers, respectively). Chiralization Compounds can exist as either enantiomer or as a mixture thereof. A mixture containing identical enantiomers is called a "racemic mixture."

[0255] The compounds according to the present invention may have one or more chiral centers. Such compounds may be used as individual (R)- or (S)-stereoisomers or as mixtures thereof. It can be produced as a compound. Unless otherwise indicated, certain features in this specification and claims The description or naming convention for a given compound includes both individual enantiomers and mixtures thereof. This is intended to include racemic or other methods. Determination of stereochemistry and stereoisomers. Methods for separation include, for example, synthesis from optically active starting materials or racemic mixtures. By division, it is well known in the field of this technology (Chapter 4 of “Advan ced Organic Chemistry”, 4th edition J.Ma rch, John Wiley and Sons, New York, 2001 See what is discussed in [reference]. Some of the compounds according to the present invention are [details omitted]. It can have any isomer centers (E- and Z-isomers).

[0256] This invention relates to all optical, diastereomers and geometric isomers of the compounds according to the present invention. It is understood that this includes mixtures of those which are active.

[0257] The present invention also includes one or more isotopic substitutions as defined herein. It includes compounds. For example, H can be any, including 1H, 2H(D), and 3H(T). It can be in the form of an isotope; C is any isotope, including 12C, 13C, and 14C. It can be in the form of; O can be in any isotope form, including 16O and 18O.

[0258] Some of the compounds according to the present invention are available in solvated and non-solvated forms, for example, hydrated It is understood that the present invention may exist in such forms. It is understood that this encompasses all forms of solvation that have properties.

[0259] Some of the compounds according to the present invention may exhibit polymorphism, and the present invention has activity It is understood that this encompasses all such forms.

[0260] The compounds according to the present invention may exist in many different tautomers, and the compounds according to the present invention References to substances include all such forms. Note that, to avoid misunderstanding, compounds are It can exist in one of several tautomers, and only one in detail. All of the following are described or shown, one being Formula I, II, or III (or parts thereof): It is encompassed by the formula. Tautomers include, for example, the following tautomer pairs: keto / enol ( (As illustrated below), imines / enamines, amides / iminoalcohols, amidines / amidins Regarding nitroso / oxime, thioketone / enthiol, and nitro / acy-nitro This includes the keto form, the enol form, and the enolate form.

[0261] [ka]

[0262] The compounds according to the present invention also contain amine functional groups and can form N-oxides. References herein to compounds containing a mine functional group also include N-oxide It is also included. If the compound contains several amine functional groups, one or two The above nitrogen atoms can be oxidized to form N-oxides. Detailed examples of N-oxides are: It is the N-oxide of a tertiary amine or the nitrogen atom of a nitrogen-containing heterocycle. N-oxides are, This can be addressed with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid). It can be formed by amine treatment, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, See Wiley Interscience, pages for more details. N-oxides are amine compounds, for example, in inert solvents, such as dichloromethane. Then, react it with m-chloroperoxybenzoic acid (mCPBA), LWDeady( It can be prepared by following the procedure in Syn.Comm.1977, 7, 509-514).

[0263] The compound according to the present invention is decomposed in the body of a human or animal, releasing the compound according to the present invention. It can be administered in the form of a prodrug. The prodrug is the physical form of the compound according to the present invention. It can be used to modify the properties and / or pharmacokinetic properties. The compound is a prodrug if it contains a suitable group or substituent to which a characteristic-modifying group can be attached. A prodrug can be formed, for example, a carboxyl group in the compound according to the present invention or Ester derivatives that can be formed with a hydroxyl group and are cleavable in vivo, and In vivo, the compound can be formed by the carboxyl group or amino group in the compound according to the present invention. It contains cleavable amide derivatives.

[0264] Therefore, the present invention includes the possibility of utilizing organic synthesis and its production process. If available for use in the body of a human or animal as a cutting, as defined above, The invention includes compounds produced by organic synthesis means. The compound according to the present invention, and the precursor compound, are produced in the body of a human or animal as a result of metabolism. The compound according to the present invention is a compound produced by synthesis. Alternatively, it may be a compound produced by metabolism.

[0265] A pharmaceutically acceptable prodrug of the compound according to the present invention is, appropriately, an undesirable drug. To be non-physical and non-excessively toxic, and suitable for administration to the human or animal body, It is based on sound medical judgment.

[0266] Various forms of prodrugs are described, for example, in the following literature: a) Methods in Enzymology, Vol.42, p.309- 396, edited by K.Widder, et al.(Academic Press, 1985); b) Design of Pro-drugs, edited by H.Bund Gaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development ment, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 “Design and Appli cation of Pro-drugs”, by H.Bundgaard p.1 13-191 (1991); d) H.Bundgaard, Advanced Drug Delivery R eviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharm aceutical sciences, 77, 285(1988); f) N.Kakeya, et al., Chem.Pharm.Bull., 3 2,692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposiu m Series, Volume 14; and h) E.Roche(editor), “Bioreversible Carri ers in Drug Design”, Pergamon Press, 198 7.

[0267] A pharmaceutically acceptable prodrug of the compound according to the present invention having a carboxyl group is suitable For example, its ester which can be cleaved in vivo. An in vivo cleavable ester of the compound according to the present invention, containing, for example, If, then, it is cleaved in the body of a human or animal to produce a hydrophilic or hydrophilic alcohol, pharmaceutically It is an acceptable ester. For carboxyl compounds, the pharmaceutically acceptable esters are appropriate. This includes (1-6C) alkyl esters, such as methyl, ethyl, and tert-butyl. (1-6C) alkoxymethyl esters, for example, methoxymethyl esters, (1-6C) Alkanoyloxymethyl esters, e.g., pivaloyloxymethyl esters Tel, 3-phthalidyl ester, etc., (3-8C)cycloalkylcarbonyloxy- 1-6C) Alkyl esters, e.g., cyclopentylcarbonyloxymethyl and 1 -Cyclohexylcarbonyloxyethyl esters, etc., 2-oxo-1,3-dioxo Renylmethyl esters, for example, 5-methyl-2-oxo-1,3-dioxolene-4- Ilmethyl esters and (1-6C)alkoxycarbonyloxy-(1-6C) Alkyl esters, for example, methoxycarbonyloxymethyl and 1-methoxycarbon It contains ethyl acetate, etc.

[0268] A pharmaceutically acceptable prodrug of the compound according to the present invention having a hydroxyl group is suitable For example, it is its ester or ether that is cleavable in vivo. A compound according to the present invention containing a hydroxyl group, which is cleavable in vivo. Esters or ethers are cleaved, for example, in the body of a human or animal, and become hydroxyl-based. It is a pharmaceutically acceptable ester or ether that produces a compound. pharmaceutically acceptable esters that form the base include, appropriately, inorganic esters, for example, This includes phosphate esters (including phosphoramido cyclic esters), etc. Hydroxyl group pharmaceutically acceptable esters that form a group for this purpose include, more appropriately, (1-10C) ) Alkanoyl groups, for example, acetyl, benzoyl, phenylacetyl and substituted benzoyl groups (1-10C) alkoxycarbonyl groups such as yl and phenylacetyl groups, for example, Ethoxycarbonyl, N,N-(1~6C)2-carbamoyl, 2-dialkylaminoacetate It contains phenylacetyl and benzoyl groups, among others. Examples of ring substituents in the group include aminomethyl, N-alkylaminomethyl, and N,N -Dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl and 4- (1-4C) alkylpiperazine-1-ylmethyl is included. A group for the hydroxyl group. pharmaceutically acceptable ethers that form may optionally contain α-acyloxyalkyl groups. For example, it includes acetoxymethyl and pivaloyloxymethyl groups.

[0269] A pharmaceutically acceptable prodrug of the compound according to the present invention having a carboxyl group is suitable For example, the cleavable amide in vivo, for example, an amine, for instance For example, ammonia, (1-4C) alkylamines, such as methylamine, [(1 ~4C)alkyl]2amines, for example, dimethylamine, N-ethyl-N-methylamine Or diethylamine, for example, (1-4C)alkoxy-(2-4C)alkylamines. For example, phenyl-(1-4C)alkylamines such as 2-methoxyethylamine, for example , benzylamine and amino acids, for example, glycine or its esters, which are formed by It's Mido.

[0270] A pharmaceutically acceptable prodrug of the compound according to the present invention having an amino group is appropriately For example, its amide derivatives that can be cleaved in vivo. Pharmacologically acceptable amides include, appropriately, (1-10C) alkanoyl Groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl. It contains amides formed with nylacetyl groups. Phenylacetyl and benzoyl groups Examples of ring substituents include aminomethyl, N-alkylaminomethyl, and N,N-dia. Lukylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl and 4-(1~ It contains 4C)alkyl)piperazine-1-ylmethyl.

[0271] The in vivo effect of the compound according to the present invention is observed after administration of the compound according to the present invention. One or more metabolites formed in the body of a human or animal can exert their effects in part. As described below, the in vivo effects of the compounds according to the present invention are also those of precursors. It can also be used as a metabolite for prodrugs.

[0272] The present invention may have optional, preferred, or suitable features, or otherwise. With respect to a particular embodiment, with respect to any compound or a particular group of a compound as defined herein The present invention may be related to any compound or the aforementioned optional, preferred or appropriate Features or certain embodiments may be excluded in particular, and may relate to specific groups of the compound.

[0273] Appropriately, the present invention excludes any individual compound that does not have the biological activity defined herein. Remove it.

[0274] [Synthesis] The compounds according to the present invention can be prepared by any suitable technique known in the art. Certain methods for the preparation of these compounds are further described in the attached examples. It can be done.

[0275] Used in the description of the synthesis method described herein and for preparing the starting materials In any referenced synthesis method, the choice of solvent, reaction atmosphere, reaction temperature, and duration of the experiment are all considered. All proposed reaction conditions, including the work-up procedure, can be selected by those skilled in the art. It is assumed that this is possible.

[0276] Functional groups present in various parts of the molecule are compatible with the reagents and reaction conditions used. Those skilled in the art of organic synthesis will understand that this is necessary.

[0277] In the synthesis of the compounds according to the present invention in the method defined herein, or in some starting During the synthesis of materials, certain substituents are protected to prevent undesirable reactions. It is understood that such protection is sometimes desirable. Skilled chemists will find that such protection is necessary. If required, and how such a protecting group can be introduced and subsequently removed. They understand that.

[0278] In the case of the protecting group example, one of many general texts relating to the subject, for example, 'Pr otective Groups in Organic Synthesis' by Theodora Green (Publisher: John Wiley & Sons) See reference. Protecting groups are described in the literature as appropriate for the removal of the protecting group in question. Alternatively, it can be removed by any convenient method known to a skilled chemist, The method is chosen to remove the protecting group with minimal interference to other groups in the molecule.

[0279] Therefore, the reactants contain, for example, groups such as amino, carboxy, or hydroxyl. If present, this protects the group in some of the reactions listed herein. Sometimes it is desirable.

[0280] Protecting groups for amino or alkylamino groups may, appropriately, be acyl groups, e.g. For example, alkanoyl groups, such as acetyl, and alkoxycarbonyl groups, such as methotrexate. Xycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, arylmethoxy A cyclocarbonyl group, for example, benzyloxycarbonyl, or an alloyl group, for example, benzyloxycarbonyl It is a zoyl. The deprotection conditions for the above protecting group inevitably change depending on the choice of protecting group. Therefore, for example, acyl groups, for example, alkanoyl or alkoxycarbonyl groups Alternatively, the alloyl group can be replaced with, for example, a suitable base, for example, an alkali metal hydroxide, for example, water. It can be removed by hydrolysis with lithium oxide or sodium hydroxide. Alternatively, The tert-butoxycarbonyl group, for example, is used in hydrochloric acid, sulfuric acid, or phosphoric acid. Alternatively, it can be removed by treatment with a suitable acid as trifluoroacetic acid, and arylmethyl Toxycarbonyl groups, such as benzyloxycarbonyl groups, are used in catalysts, for example, By hydrogenation via carbon-supported palladium, or by Lewis acids, such as Tris(Triflu), It can be removed by treatment with boron (oroacetate). Alternative protection for primary amino groups. The base may be, for example, an alkylamine, for example, dimethylaminopropylamine. It is a phthaloyl group that can be removed by rubbing or treatment with hydrazine.

[0281] The protecting group for the hydroxyl group can be, appropriately, an acyl group, for example, an alkanoid group. Aroyl groups, such as acetyl; alloyl groups, such as benzoyl or arylmethyl. The group, for example, benzyl. The deprotection condition for the above protecting group is necessarily the protecting group It depends on the choice. For example, an acyl group, for example, an alkanoyl group, or an alloyl group. The yl group can be a suitable base, such as an alkali metal hydroxide, such as lithium. They can be removed by hydrolysis with sodium hydroxide or ammonia. Alternatively, ants Methyl groups, such as the benzyl group, are used in catalysts, such as carbon-supported palladium. It can be removed by hydrogenation via methods such as [mention specific methods].

[0282] Protecting groups for carboxyl groups can be, appropriately, for example, esterifying groups, bases, etc. Methyl or ethyl groups can be removed, for example, by hydrolysis using sodium hydroxide. or, for example, by treatment with an acid, such as an organic acid, such as trifluoroacetic acid. Removable components include, for example, t-butyl groups, or catalysts such as carbon-supported palladium. These are benzyl groups that can be removed, for example, by hydrogenation, via the like.

[0283] Resins can also be used as protective groups.

[0284] The methodology used to synthesize the compound according to the present invention is R 1 , L 1 A, X a , L 2 B, X b Depending on the properties of M, Q, and any substituent or its related subgroup It will change. Appropriate methods for their preparation are further described in the attached examples.

[0285] The compounds according to the present invention are synthesized by any one of the methods defined herein. After that, those methods then proceed to the following further steps, namely, (i) step of removing any existing protecting groups; (ii) A step of converting a compound according to the present invention into another compound according to the present invention; (iii) the step of forming a pharmaceutically acceptable salt, hydrate or solvate thereof; be / or (iv) the step of forming the prodrug It can also include further...

[0286] An example of (ii) above is that the compound according to the present invention is synthesized, and then R 1 , L 1 A, X a , L 2 B, X b , one or more of the M and Q groups are further reacted, and the group This is a case where the properties can be changed, providing an alternative compound to the present invention.

[0287] The compounds according to the present invention can be isolated and purified using techniques well known in the art.

[0288] The compounds according to the present invention can be synthesized by the synthesis route shown in the Examples section below.

[0289] [Biological activity] Using the bioassays described in the Examples section of this specification, the compounds according to the present invention It allows for the measurement of pharmacological effects.

[0290] The pharmacological properties of the compound according to the present invention change with structural changes, but as expected, the present invention The compound in question is used in the in vitro assay described in the examples, which is effective against healthy, non-cancerous cells. Through comparison, it was found to be selectively active against various human cancer cells.

[0291] [Pharmaceutical composition] According to a further aspect of the present invention, a compound having the structure of formula I as defined herein, Or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, of M. A source, and a medical device containing one or more pharmaceutically acceptable diluents, excipients, or carriers. A pharmaceutical composition is provided. The pharmaceutical composition may further provide a source of Q as defined herein. It is included in.

[0292] According to a further aspect of the present invention, a compound having the structure of formula II as defined herein , or pharmaceutically acceptable salts, hydrates or solvates thereof, and one or more A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient, or carrier is provided. The pharmaceutical composition further comprises a source of Q as defined herein.

[0293] According to a further aspect of the present invention, a compound having the structure of formula III as defined herein The substance or pharmaceutically acceptable salts, hydrates, or solvates thereof, and one or more thereof. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient, or carrier is provided.

[0294] To avoid misunderstanding, a pharmaceutical composition containing the compound of formula I is defined herein as follows: It was understood that this extended to include pharmaceutical compositions containing compound Ia. stomach.

[0295] To avoid misunderstanding, a pharmaceutical composition containing the compound of Formula II is defined herein as follows: It is understood that this extends to pharmaceutical compositions containing compound IIa (i.e., to include them). I want to.

[0296] To avoid misunderstanding, a pharmaceutical composition containing the compound of Formula III is defined herein as follows: The range is extended to include pharmaceutical compositions containing compounds of formula IIIa (i.e., encompassing them), and Q is , Br - , I - CO3 2- SiF6 2- IO6 3- VO4 3- WO4 2- , C rO4 2- SO4 2- HSO4 - AsO4 3- , PO4 3- or HPO4 2- in I want you to understand something.

[0297] Any pharmaceutically acceptable source of M can be used, examples of which are well known to those skilled in the art. Please understand that this is the case. For example, the source of M is an organic salt (for example, a salt of M and Carboxylic acids, for example, M acetate or M propionate, or salts of M and organic sulfurs Fonic acid (e.g., M-trifluoromethanesulfonate) or inorganic salt (e.g., M-perchloride) It may be salts, M nitrates, M tetrafluoroborates. In one detailed embodiment, M The source is M acetate.

[0298] Any pharmaceutically acceptable source of Q can be used, examples of which are well known to those skilled in the art. Please understand that this is the case. For example, the source of Q is organic, for example, Et3NX[formula] In this, X is a halide (i.e., a spherical monoanionic anion) or Bu 4NH2PO4 (in the formula, PO4 3- (is a trianionic tetrahedral anion) or B u4NHSO4(where SO4 is used in the formula) 2- (This may also be a dianionic tetrahedral anion.) Alternatively, the source of Q could be an inorganic substance, for example, Na2SiF6 (where SiF6 is the source of Q). 2- is, (It is a nionic octahedral anion) or Na2O3POPh (wherein PhPO4 is the formula) 2- teeth, It may also be a dianionic tetrahedral anion.

[0299] Please understand that the source of M can also be the source of Q (for example, ZnSO4). In one detailed embodiment, the source of M is also the source of Q.

[0300] The pharmaceutical composition according to the present invention is for oral use (for example, tablets, oral tablets, hard or soft capsules) Cells, aqueous or oily suspensions, emulsions, dispersible powders or granules, and syrups are also included. (or as an elixir), topical use (e.g., cream, ointment, gel, or aqueous solution) Alternatively, administration by inhalation (as an oily solution or suspension, for example, as a finely ground powder) It can be administered by gas injection (for example, as a finely ground powder) or as a liquid aerosol. or parenteral administration (e.g., sterile intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration) It may be in a form suitable as an aqueous solution or oily solution, or as a suppository for rectal administration.

[0301] The pharmaceutical composition according to the present invention uses conventional pharmaceutical excipients that are well known in the art, It can be obtained in order. Therefore, a composition intended for oral use is, for example, one type Alternatively, it may contain multiple colorants, sweeteners, flavoring agents, and / or preservatives.

[0302] The pharmaceutical composition according to the present invention may optionally include the compound according to the present invention, a source of M, and Q The effective amount of the source of the compound according to the present invention for use in therapy is Treating or preventing the proliferative conditions referenced in the specification, slowing their progression and / or a sufficient amount to alleviate the symptoms associated with the condition.

[0303] The amount of the active ingredient that, when combined with one or more excipients, produces a single dosage form is treated. It inevitably varies depending on the individual and the specific route of administration. For example, oral administration to humans The target formulation generally varies, for example, from about 5% to about 98% by weight of the total composition. An effective drug, 0.5 mg to 0.5 g, formulated with appropriate and convenient amounts of possible excipients. (More appropriately, it contains 0.5 to 100 mg, for example, 1 to 30 mg.)

[0304] The dosage size for the therapeutic or prophylactic purposes of the compounds according to the present invention is based on well-known medical standards. In accordance with the principles, the nature and severity of the condition, the age and sex of the animal or patient, and Naturally, this will vary depending on the route of administration.

[0305] When using the compounds according to the present invention for therapeutic or preventive purposes, this generally means, Considering a certain range, for example, when divided doses are required, 0.1 mg per kg of body weight. The administration is carried out at a daily dose of 75 mg / kg. Generally, parenteral routes are used. In such cases, a lower dose is administered. For example, in the case of intravenous or intraperitoneal administration, A range of dosages, for example, 0.1 mg to 30 mg per kg of body weight, is commonly used. Similarly, in the case of administration by inhalation, there is a range, for example, 0.05 mg to 2 kg of body weight. A dose of 5 mg is used. Oral administration, especially in tablet form, may also be appropriate. Typically, each unit dosage form contains approximately 0.5 mg to 0.5 g of the compound according to the present invention.

[0306] [Therapeutic use and application] This invention provides compounds that are active against various human cancer cell lines. The compound also exhibits significant selective activity against cancer cell lines compared to non-cancerous cells. While not bound by the theory, the inventors believe that the activity of this compound is due to the binding of the phosphate anion. This is thought to be attributable to the ability to hydrolyze and / or phosphate esters. These compounds also exhibit selective inhibition of many kinases.

[0307] Therefore, the present invention relates to a source of M as defined herein for use as a pharmaceutical. A compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, in combination with the above. The present invention provides a hydrate or solvate. The compound of formula I and the source of M are appropriately provided. It is used in further combinations with the sources of Q as defined in the details.

[0308] The present invention also relates to use in the treatment of proliferative disorders (e.g., cancer) as described herein. A compound of formula I as defined herein, combined with a source of M as defined herein, or pharmaceutically The following are acceptable salts, hydrates, or solvates thereof. Appropriately, compounds of formula I and The source of M is further combined with the source of Q as defined herein.

[0309] The present invention also treats proliferative disorders (e.g., cancer) in patients requiring such treatment. This specification provides a method for providing treatment, and this method, in combination with a source of M as defined herein, Compounds of formula I as defined in the book, or pharmaceutically acceptable salts, hydrates, or solvates thereof. The procedure includes administering a therapeutically effective dose to the patient. Appropriately, supplying the compound of formula I and M. The source is administered in combination with the Q supply source.

[0310] The present invention also relates to the manufacture of compounds of formula I, or pharmaceutically acceptable salts thereof, in the production of pharmaceuticals. The use of hydrates or solvates is provided as appropriate. The pharmaceutical product may cause proliferative disorders (e.g., It is for the treatment of cancer.

[0311] As mentioned above, the compound of formula I self-assembles with M to form the mononuclear compound of formula II. It demonstrates its ability. When in contact with a suitable anion, it can be observed in vitro or in vivo. For example, in a biological source of phosphate, the compound of formula II is converted into the trinuclear compound of formula III. It can be easily converted. In the data presented herein, the compounds of formulas II and III are various It is active against human cancer cell lines and / or inhibits many kinases. This is shown. Therefore, the therapeutic use of the present invention involves using a compound of formula I, and the compound is M It is understood that it is used in combination with a source of the following: appropriately, a compound of formula I and M The source of is used in combination with the source of Q. Compound of formula I, source of M, in the case Therefore, simultaneous, separate, or sequential use (e.g., administration) of the sources of Q is included. This is understood.

[0312] Exemplary definitions of M and Q, as well as their sources, are discussed above.

[0313] To avoid misunderstanding, the therapeutic use of the compound of formula I is as follows: compound Ia: [ka] It extends to (i.e., encompasses) the therapeutic use of [this].

[0314] The present invention also relates to a compound of formula II as defined herein, for use as a pharmaceutical, The following provides a pharmaceutically acceptable salt, hydrate, or solvate thereof. Appropriately, Formula II The compound is combined with a source of Q as defined herein.

[0315] The present invention also specifies herein its use in the treatment of proliferative disorders (e.g., cancer). The compound of formula II, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is proposed. Provided. Appropriately, the compound of formula II is combined with a source of Q as defined herein. Yes, they are.

[0316] The present invention also treats proliferative disorders (e.g., cancer) in patients requiring such treatment. This invention provides a method for treating a compound of formula II as defined herein, or a pharmaceutically acceptable compound. The procedure includes the step of administering to the patient a therapeutically effective amount of the salt, hydrate, or solvate thereof. Appropriately, the compound of formula II is administered in combination with a source of Q.

[0317] The present invention also relates to the manufacture of a compound of formula II, or a pharmaceutically acceptable compound thereof, in the manufacture of a pharmaceutical product. Provide the use of salts, hydrates, or solvates. Appropriately, the pharmaceutical product may cause proliferative disorders (e.g. It is for the treatment of cancer.

[0318] As described herein, the compound of formula II is used in various human cancer cell lines and / or many It exhibits selective activity for the inhibition of kinases.

[0319] In one detailed embodiment, the compound of formula II is used in combination with a source of Q. As described in the specification, in contact with the source of Q (in vitro or in vivo) In this case, the compound of formula II undergoes a self-assembly process to produce the compound of formula III, and this It exhibits selective activity against various human cancer cell lines and / or many kinases. This embodiment involves the simultaneous, separate, or sequential use of the compound of formula II and the source of Q. It is understood that this includes use (e.g., administration).

[0320] Exemplary definitions of M and Q, as well as their sources, are discussed above.

[0321] To avoid misunderstanding, the therapeutic use of the compound of formula II is as follows: compound IIa: [ka] It extends to (i.e., encompasses) the therapeutic use of [this].

[0322] The present invention also relates to a compound of formula III as defined herein, for use as a pharmaceutical product. Alternatively, the present invention provides a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0323] The present invention also specifies herein its use in the treatment of proliferative disorders (e.g., cancer). Compounds of formula III that are appropriate, or pharmaceutically acceptable salts, hydrates, or solvates thereof provide.

[0324] The present invention also treats proliferative disorders (e.g., cancer) in patients requiring such treatment. This provides a method for treating a compound of formula III as defined herein, or a compound that is pharmaceutically effective. The step includes administering to the patient a therapeutically effective amount of the acceptable salt, hydrate, or solvate thereof. nothing.

[0325] The present invention also relates to the manufacture of a compound of formula III, or a pharmaceutically acceptable compound, in the manufacture of a pharmaceutical product. The use of salts, hydrates, or solvates of is provided. Appropriately, the pharmaceutical is for the treatment of proliferative disorders (e.g. For example, it is for the treatment of cancer.

[0326] As described herein, the compound of Formula III is used in various human cancer cell lines and / or multiple It exhibits selective activity against the inhibition of various kinases.

[0327] Exemplary definitions of M and Q, as well as their sources, are discussed above.

[0328] To avoid misunderstanding, the therapeutic use of the compound of formula III is as follows: [ka] [In the formula, Q is Br - , I - CO3 2- SiF6 2- IO6 3- VO4 3- , W O4 2- , CrO4 2- SO4 2- HSO4 - AsO4 3- , PO4 3- or H PO4 2- That is the case. This extends to (i.e., encompasses) the therapeutic use of the compounds.

[0329] The present invention also relates to pharmaceutical compositions as defined herein for use as pharmaceuticals, or Provides pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0330] The present invention also relates to use in the treatment of proliferative disorders (e.g., cancer) as described herein. Provides a defined pharmaceutical composition, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. do.

[0331] The present invention also treats proliferative disorders (e.g., cancer) in patients requiring such treatment. This invention provides a method of treatment, which involves administering a therapeutically effective amount of the pharmaceutical composition defined herein to a patient. This includes the step of giving.

[0332] "Proliferative disorder," "proliferative state," and "proliferative disease" are used synonymously in this specification. Unwanted, for example, neoplastic or hyperplastic, can occur both in vitro and in vivo. Formative proliferation is the unnecessary or uncontrolled proliferation of excessive or abnormal cells. It is related to.

[0333] In the above aspects of the present invention, the proliferative disorder is appropriately cancer, and cancer is appropriately hi It is a cancer. In particular, the compounds according to the present invention are beneficial for any mismatch repair inhibition. It is useful in the treatment of cancer. Any suitable cancer can be targeted (e.g., adenoid cystic carcinoma). Adrenal tumor, amyloidosis, anal cancer, appendiceal cancer, astrocytoma, telangiectasia Symptoms, Beckwith-Weidemann syndrome, cholangiocarcinoma (cholangiocarcinoma), Bert-Hogg- Duvet syndrome, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, Carney complex, central nervous system Nervous system tumors, cervical cancer, colorectal cancer, Cowden's disease, craniopharyngioma, fibroplastic infantile cancer Desmoplastic infantile ganglioglioma, ventriculependymoma, esophageal cancer, Euin G's sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma Iodine tumor, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor - GIST, germ cell tumors, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, inherited Transmissible diffuse gastric cancer, hereditary leiomyomatosis and renal cell carcinoma, hereditary mixed polyposis syndrome Group cancer, hereditary pancreatitis, hereditary papillary renal cell carcinoma, juvenile polyposis syndrome, renal cancer, lacrimal gland tumors Laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia) AML (amyolytic leukemia), B-cell prolymphocytic leukemia, hairy cell leukemia, chronic lymphocytic leukemia disease (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia Blood diseases), Lie-Fraumeni syndrome, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), Lymphoma (Hodgkin, non-Hodgkin), Lynch syndrome, mastocytosis, medulloblastoma, melanoma, medulloblastoma Symptoms include: mesothelioma, mesothelioma, multiple endocrine neoplasia type 1 and type 2, multiple myeloma, MUTYH (or MYH-associated polyposis, myelodysplastic syndrome (MDS), nasal cavity and paranasal sinus cancer, Pharyngeal cancer, neuroblastoma, neuroendocrine tumors (e.g., of the gastrointestinal tract, lung, or pancreas), neurofibroma Type 1 and 2 basal cell carcinoma syndrome, nevus basal cell carcinoma syndrome, oral or oropharyngeal cancer, osteosarcoma, ovarian / pharyngeal cancer Alopius duct / peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome Pheochromocytoma, paraganglioma, pituitary tumor, pleuroblastoma, prostate cancer, retinoblastoma, rhabdomyoblastoma Myosarcoma, salivary gland cancer, sarcoma (e.g., Kaposi's positivity or soft tissue cancer), skin cancer, small intestine cancer, stomach cancer Cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis, uterine cancer, vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Waldenström's macroglobulin blood (Syndrome, Werner syndrome, Wilms' tumor, and xeroderma pigmentosum). For specific cancers of target This includes hematological cancers, such as lymphoma (diffuse large B-cell lymphoma). Lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL), and hematological lymphoma (including ductal immunoblastic T-cell lymphoma (AITL)), leukemia (acute lymphoblastic leukemia ( ALL (including chronic myeloid leukemia (CML)), multiple myeloma, breast cancer, non-small cell lung cancer. Lung cancer (NSCLC), colorectal cancer, endometrial cancer, gastric-esophageal cancer, neuroendocrine cancer, Osteosarcoma, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, cholangiocarcinoma, CNS cancer This includes thyroid cancer, head and neck cancer, esophageal cancer, and ovarian cancer.

[0334] The compound according to the present invention (used in combination with a source of M and / or Q as needed) In some cases, it can also be used to treat triplet disease or disorder.

[0335] [Route of administration] The compounds according to the present invention or pharmaceutical compositions containing these compounds may be used systemically or peripherally. By any convenient route of administration, either locally or locally (i.e., at the desired site of action) It can be administered to the target.

[0336] The route of administration is not limited to, but may include: oral (e.g., by oral ingestion); oral cavity; sublingual. ; Percutaneous (e.g., including patches, ointments, etc.); Transmucosal (e.g., patches, ointments, etc.) (including, etc.); intranasal cavity (e.g., by nasal spray); eyeball (e.g., by eye drops); Lungs (for example, by using, for example, via an aerosol, for example, by inhaling through the mouth or nose) By insertion or gas injection therapy; rectally (e.g., by suppositories or enemas); transvaginally (e.g., , by pessary; for example, intratumor, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac , subarachnoid space, spinal cord, intra-articular, subcapsular, orbital, abdominal cavity, tracheal, subepidermal, intra-articular, By injection, including subarachnoid and intrasternal injections; for example, subcutaneous or intramuscular injections. The meat contains parenteral medication administered via depot or reservoir implantation.

[0337] [Combination therapy] The compounds according to the present invention (and optionally sources of M and / or Q) are used in single-agent therapy. It may be administered as a medical procedure, and in addition to the compounds according to the present invention, conventional surgical procedures or radiotherapy may be used. Alternatively, chemotherapy or targeted therapy may be used. Such chemotherapy or targeted therapy may be administered as follows: This may include one or more of the following categories: (i) Antiproliferative drugs / antineoplastic drugs and combinations thereof, as used in medical oncology. For example, although not limited to that, alkylating agents (for example, cisplatin, oxali) Platin, carboplatin, cyclophosphamide, nitrogen mustard, melfa Orchid, chlorambucil, busulfan, temozolamide and nitrosauer Rare); antimetabolites (e.g., gemcitabine and folate antimetabolites, e.g., 5-fluorinated folates) Fluoropyrimidines such as loruracil and tegafur, as well as larcitrexed, me Totrexate, cytosine arabinoside, and hydroxyurea; antitumor antibiotics (for example) Adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin Examples include idarubicin, mitomycin-C, dactinomycin, and mithramycin. Anthracycline drugs; mitotic inhibitors (e.g., vincristine, vinblast) Vinca alkaloids such as vindesine and vinorelbine, as well as taxol Taxoids and polokinase inhibitors such as taxotere; and topoisomer Lase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide) Amsacrin, topotecan, and camptothecin; (ii) Cell division inhibitors, for example, not limited to these, but anti-estrogens (for example, Tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene (droloxifene and iodoxyfene), antiandrogens (e.g., (bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonist LHRH agonists (e.g., goserelin, leuprorelin, and buser) Phosphorus), progestogens (e.g., megestrol acetate) and corticosteroids ( For example, steroid hormones including dexamethasone, prednisone, and prednisolone. Mon, (for example, anastrozole, letrozole, borazole and exemestane) Aromatase inhibitors and 5α-reductase inhibitors, such as finasteride etc; (iii) Anti-invasion agent, for example, not limited to that, c- Src kinase family inhibitor 4-(6-chloro-2,3-methylenedioxyanilino )-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyra n-4-yloxyquinazoline (AZD0530; International Patent Application Publication WO01 / 9434) 1) N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethylphenyl) [Tyl]piperazine-1-yl]-2-methylpyrimidine-4-ylaminothiazole- 5-Carboxamide (dasatinib, BMS-354825; J.Med.Chem., 2004, 47, 6658-6661), bosutinib (SKI-606), and Me Taroproteinase inhibitors, such as marimastat, and urokinase-type plasminors Inhibitors of activator receptor function or antibodies against heparanase; (iv) Inhibitors of growth factor function, for example, but not limited to growth factor antibodies and Growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin (Trademark), anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erb itux, C225] and Stern et al. (Critical reviews in oncology / haematology, 2005, Vol.54, pp11 Any growth factor or growth factor receptor antibody disclosed in -29); such inhibitor Other harmful agents include tyrosine kinase inhibitors, for example, inhibitors of the epidermal growth factor family (e.g.) For example, EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-) Luolophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4- Amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis (2-methoxyethoxy)quinazoline-4-amine (erlotinib, OSI-774) 6-acrylamide-N-(3-chloro-4-fluorophenyl)-7-(3-mol (Forinopropoxy)-Quinazoline-4-amine (CI1033), etc., erbB2 tyrosine Hepatocyte growth factor inhibitors, e.g., lapatinib); inhibitors of the hepatocyte growth factor family; Inhibitors of the nsrin growth factor family; inhibitors of the platelet-derived growth factor family, for example. , imatinib and / or nilotinib (AMN107), etc.; serine / threoninequinate Inhibitors of enzymes (e.g., Ras / Raf signaling inhibitors, e.g., Farnesirtra) Insulators, such as sorafenib (BAY43-9006), Typif Anib (R115777) and ronafarnib (SCH66336), MEK and / or inhibitors of AKT kinase-mediated cell signaling, c-kit inhibitors, abl Kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors IGF receptor (insulin-like growth factor) kinase inhibitors; Aurora kinase inhibitors Harmful agents and cyclin-dependent kinase inhibitors, e.g., CDK2 and / or CDK4 This includes inhibitors, etc. (v) Anti-angiogenic drugs, for example, but not limited to, that suppress the effects of vascular endothelial growth factor. For example, the anti-vascular endothelial growth factor antibody bevacizumab (Avastin (commercial (Standard)) and, for example, VEGF receptor tyrosine kinase inhibitors, for example, vandetanib ( ZD6474), batalanib (PTK787), sunitinib (SU11248), Axi Examples include tinib (AG-013736) and pazopanib (GW786034). (vi) Vascular toxic agents, for example, but not limited to, combretastatin A4 and International patent application publications WO99 / 02166, WO00 / 40529, WO00 / 41669 Opened in WO01 / 92224, WO02 / 04434 and WO02 / 08213 The compound shown; (vii) Endothelin receptor antagonists, e.g., dibotentan (ZD4054) or atracentan; (viii) Antisense therapy, for example, but not limited to, the targets shown above Those targeting ISIS2503, anti-ras antisense, etc.; (ix) Immunity, including cancer vaccines, antibodies, and viruses (oncolytic viruses), Therapeutic approaches, as well as increasing the immunogenicity of the patient's tumor cells and / or cell-mediated effects. Small molecule or cell therapy approaches to facilitate the antitumor response. Such therapies are This is not limited to just that, but immune checkpoint inhibitors (e.g., CTLA4, LAG3, P) D1, PD-L1, TIM-3 and / or TIGIT inhibitors), OX40 agonist cGAS-STING agonist, A2a receptor antagonist, PI3 kinase inhibitor Drugs, TLR7 / 8 agonists, IDO inhibitors, immunostimulants (for example, those that enhance antitumor immunity) (4-1BB, OX40, cGAS-STING, CD27, CD40, and DR3) Arginase inhibitors, BTK inhibitors and bromodomain inhibitors; microbial bromodomain inhibitors of cancer antigens Transduction by chemotactic agents, direct transduction of cancer antigens into antigen-presenting cells, and cancer antigen-specific transduction Therapies using immune cells (e.g., CAR-T), antibodies, antibody fragments, and the immune system can help treat tumor cells. This may include treatment with antibody-drug conjugates that enable recognition.

[0338] Such collaborative treatment involves the simultaneous, sequential, or separate administration of the individual components of the treatment. This can be achieved. Such combination products are compounds according to the present invention within the dose range described above. or use other pharmaceutically effective drugs within their approved dosage range.

[0339] According to one aspect of the present invention, the compound according to the present invention as defined above, or pharmaceutically acceptable Cancers (e.g., cancers with solid tumors) containing salts or solvates of the same substance, and antitumor agents. A combination for use in the treatment of is provided. The compounds according to the present invention are, if necessary It is used in combination with sources of M and / or Q.

[0340] According to one aspect of the present invention, the compound according to the present invention as defined above, or pharmaceutically acceptable The salt or solvate thereof, and any of the antitumor agents shown in the above specification. For the treatment of proliferative conditions, including one type, such as cancer (e.g., cancer with solid tumors). A combination for use in the present invention is provided. The compound according to the present invention is M and as needed / It is used in combination with a source of Q.

[0341] In a further aspect of the present invention, the following may be selected from those described in the above specification: Compounds according to the present invention for use in the treatment of cancer, in combination with other antitumor agents. A pharmaceutically acceptable salt or solvate thereof is provided. The compound according to the present invention is necessary It is used in combination with M and / or Q sources as needed.

[0342] In a further aspect of the present invention, the following may be selected from those described in the above specification: The present invention for use in the treatment of cancer in combination with a tyrosine kinase inhibitor. A compound or a pharmaceutically acceptable salt or solvate thereof is provided. The mixture is used in combination with sources of M and / or Q as needed.

[0343] Components used in combination with each other (for example, compounds of formula I, II, or III) Sources of M and Q (antitumor agents and tyrosine kinase inhibitors), simultaneously, separately, These can be administered sequentially. In one aspect of the present invention, "in combination with" refers to simultaneous administration. In another aspect of the invention, "in combination with" refers to separate administrations. In this context, "in combination with" refers to sequential administration. The administration may be sequential or separate. In some cases, delays in administering the second (and any subsequent) component can affect the combination. It should not be something that loses its beneficial effects.

[0344] According to a further aspect of the present invention, in relation to a pharmaceutically acceptable diluent or carrier, Tumor agents (optionally selected from those listed in the above specification) and / or tyrosine The compound according to the present invention, in combination with a kinase inhibitor, or a pharmaceutically acceptable compound thereof A pharmaceutical composition comprising a salt or solvate is provided.

[0345] [Detailed aspects and embodiments] Statements 1 through 118, numbered below, are not claimed, but are alternatives. Specifically, it helps to define a detailed aspect and embodiment of the claimed invention. That is the case. 1. Equation I below: [ka] [In the formula, R 1 N, CR 2 aryl, heteroaryl, carbocykrill and heterocyclyl Selected from the group consisting of R 1 Any aryl, heteroaryl, or carbocykrill in the middle Or heterocyclines are one or more R 3 It may be replaced in some cases; Each R 3 These are hydroxy, cyano, halogen, (1-4C) alkyl, and (1-4C) halo Lukil, (2~4C) Alkenil, (2~4C) Alkinil, Ariel, Ariel (1~ 3C) alkyl, heteroaryl, heteroaryl(1-3C) alkyl, carbocyclyte Carbocyclyl(1-3C) alkyl, heterocyclyl, heterocyclyl(1-3C) ) alkyl, -OR 3a , -NR 3a R 3b , -C(O)-R 3a , -C(O)-OR 3 a -OC(O)-R 3a -C(O)-NR 3a R 3b , -N(R 3a )C(O)- R 3b and -S(O) 0-2 R 3a Independently selected from the group consisting of, R 3 Any ( (1-4C) alkyl, (1-4C) haloalkyl, (2-4C) alkenyl, (2-4C ) Alkynyl, aryl, aryl(1-3C)alkyl, heteroaryl, heteroaryl Alkyl (1-3C) alkyl, carbocyrill, carbocyrill (1-3C) alkyl, Telocyryl or heterocyclyl(1-3C) alkyl groups consist of one or more R 3c in Substituted depending on the circumstances; R 3a and R 3b is hydrogen, (1-3C) alkyl and (1-3C) haloalkyl or Each of the following groups is independently selected; Each R 3c These are hydroxy, halogen, cyano, amino, (1-3C)alkyl, (1-3 Independently selected from the group consisting of C) alkoxy and (1-3C) haloalkyl; R 2 These are hydrogen, hydroxyl, cyano, halogen, (1-4C) alkyl, and (1-4C) halogen. Roalkyl, (2-4C)alkenyl, (2-4C)alkynyl, aryl, aryl( 1-3C) alkyl, heteroaryl, heteroaryl(1-3C) alkyl, carbosis Krill, carbocyclyl(1-3C) alkyl, heterocyclyl, heterocyclyl(1- 3C) alkyl, -OR 2a , -NR 2a R 2b , -C(O)-R 2a ,-C(O)-O R 2a -OC(O)-R 2a -C(O)-NR 2a R 2b , -N(R 2a )C(O )-R 2b and -S(O) 0-2 R 9a Selected from the group consisting of R 2 Any (1) inside (~4C) alkyl, (1~4C) haloalkyl, (2~4C) alkenyl, (2~4C) Alkynyl, aryl, aryl(1-3C)alkyl, heteroaryl, heteroaryl (1-3C)alkyl, carbocyrill, carbocyrill(1-3C)alkyl, hete Rocyclyl or heterocyclyl (1-3C) alkyl groups consist of one or more R 2c de ba Replaced by; R 2a and R 2b is hydrogen, (1-3C) alkyl and (1-3C) haloalkyl or Each of the following groups is independently selected; Each R 2c These are hydroxy, halogen, cyano, amino, (1-3C)alkyl, (1-3 Independently selected from the group consisting of C) alkoxy and (1-3C) haloalkyl; Each L 1 teeth, -(W) n -(X) m -(Y) o -(Z) p - is a base, n and o are independently 0, 1, or 2, and m and p are independently , is either 0 or 1, except when both m and p are 1, in which case o is not 0; Each W is (1-3C) alkylene, (2-3C) alkenylene, (2-3C) alkinile It consists of arn, arylene, heteroarylene, carbocyrene and heterocyclene. Selected from the group, any (1-3C)alkylene, (2-3C)alkene, ( 2-3C) Alkynylene, arylene, heteroarylene, carbocyrylene or hetero Rocyclylene contains one or more W a In some cases, it is replaced, and each W a , hydroxy, From cyano, halogen, amino, (1-2)alkoxy and (1-2C)haloalkyl They are independently selected from the group; X is -O-, -C(O)-, -C(O)-O-, -OC(O)-, -S(O) 0-2 -, -C(O)-N(R x )-,-N(R x )-C(O)-, -NR x -, -N(R x ) -C(O)-NR x -, -SO2N(R x )-, and -N(R x ) A group consisting of SO2 Selected from, each R x These are hydrogen, hydroxyl, cyano, (1-4C)alkyl, (2-4C Independently selected from the group consisting of alkenyls and (2-4C)alkynyls; Each Y is (1-3C) alkylene, (2-3C) alkenylene, (2-3C) alkinile It consists of arn, arylene, heteroarylene, carbocyrene and heterocyclene. Selected from the group, any (1-3C)alkylene, (2-3C)alkene in Y, ( 2-3C)alkynylene, arylene, heteroarylene, carbocyclylene or hetero cyclylene is optionally substituted with one or more Y a , and each Y a is independently selected from the group consisting of hydroxy, cyano, halogen, amino, (1-2C)alkoxy and (1-2C)haloalkyl; independently selected from the group consisting of; Z is selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O) 0-2 -, -C(O)-N(R z )-, -N(R z )-C(O)-, -NR z -, -N(R z ) -C(O)-NR z -, -SO2N(R z )-, and -N(R z )SO2, and each R is independently selected from the group consisting of z hydrogen, hydroxy, cyano, (1-4C)alkyl, (2-4C )alkenyl and (2-4C)alkynyl; X a is a ring heteroatom located in ring A, selected from N and O; each ring A is monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocycle or bicyclic hetero cycle, any one of which is optionally substituted with one or more R 4 , and each R 4 is independently selected from the group consisting of hydroxy, cyano, halogen, (1-6C)alkyl, (1-6C)haloal kyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, aryl(1-3 C)alkyl, heteroaryl, heteroaryl(1-3C)alkyl, carbocyclyl , carbocyclyl(1-3C)alkyl, heterocyclyl, heterocyclyl(1-3C) alkyl, -R 4a -OR4b , -R 4a -NR 4b R 4c , -R 4a -C(O)-R 4 b , -R 4a -C(O)-OR 4b , -R 4a -O-C(O)-R 4b , -R 4a -C( O)-NR 4b R 4c , -R 4a -N(R 4b )C(O)-R 4c and -R 4a -S( O) 0-2 R 4b are each independently selected from the group consisting of, any (1-6C) alkyl in R 4 , (1-6C) haloalkyl, (2-6C) alkenyl, (2-6C) alkynyl, ary l, aryl(1-3C)alkyl, heteroaryl, heteroaryl(1-3C)alk yl, carbocyclyl, carbocyclyl(1-3C)alkyl, heterocyclyl or heterocyclyl(1-3C)alkyl is optionally substituted with one or more R 4d ; ; R 4a is absent, or is (1-3C) alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo and amino; is (1-3C) alkylene optionally substituted with one or more substituents; R 4b and R 4c are each independently selected from the group consisting of hydrogen, (1-3C)alkyl and (1-3C)haloalkyl ; each R 4d is independently selected from the group consisting of hydroxy, halogen, cyano, amino, (1-3C)alkyl, (1-3 C)alkoxy and (1-3C)haloalkyl; ​X b It is a ring heteroatom located within the B ring, selected from N and O. Each B ring is a monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocyclic, or bicyclic heterocyclic ring. It is an elementary ring, and at least one of them is one or more R 5 It is replaced depending on the case, each R 5 These are hydroxy, cyano, halogen, (1-6C) alkyl, and (1-6C) haloal Kill, (2-6C) Alkenil, (2-6C) Alkinil, Ariel, Ariel (1-3 C) Alkyl, heteroaryl, heteroaryl(1-3C)alkyl, carbocyrill Carbocyclyl(1-3C) alkyl, heterocyclyl, heterocyclyl(1-3C) Alkyl, -R 5a -OR 5b , -R 5a -NR 5b R 5c , -R 5a -C(O)-R 5 b , -R 5a -C(O)-OR 5b , -R 5a -OC(O)-R 5b , -R 5a -C( O)-NR 5b R 5c , -R 5a -N(R 5b )C(O)-R 5c and -R 5a -S( O) 0-2 R 5b Independently selected from the group consisting of, R 5 Any (1-6C) alkyl group within (1-6C) Haloalkyl, (2-6C) Alkenyl, (2-6C) Alkinyl, Ali Alkyl, aryl(1-3C)alkyl, heteroaryl, heteroaryl(1-3C) Lukil, carbocyclyl, carbocyclyl(1-3C) alkyl, heterocyclyl or Heterocyclyl(1-3C)alkyl groups consist of one or more R 5d It may be replaced in some cases. ; R 5a It is either absent, or selected from the group consisting of hydroxy, halo, and amino. It is a (1-3C) alkylene which is optionally substituted with one or more substituents; R 5b and R 5c These are hydrogen, (1-5C) alkyl (e.g., (1-3C) alkyl) and independently selected from the group consisting of (1-3C) haloalkyl groups; Each R 5d These are hydroxy, halogen, cyano, amino, (1-3C)alkyl, (1-3 Independently selected from the group consisting of C) alkoxy and (1-3C) haloalkyl; Each L 2 (In this case, the A ring is directly bonded to the B ring) (1-2C)alkylene Selected from the group consisting of ethenylene and ethinylene, L 2 Any (1~2C) inside Lukilen, ethenylene, and ethinylene are hydroxy, halogen, cyano, amino, ( Composed of (1-3C) alkyl, (1-3C) alkoxy, and (1-3C) haloalkyl [The structure is optionally substituted with one or more substituents selected from the group.] A compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, However, the compound of formula I is the following compound Ia: [ka] , or compounds other than pharmaceutically acceptable salts, hydrates or solvates thereof, or drugs A scientifically acceptable salt, hydrate, or solvate thereof. 2. Each A ring is independently selected from N, O, and S, and comprises a total of 1, 2, or 3 rings. A 5-7 member monocyclic heteroaryl containing a telogen atom, or independently of N, O, and S Selected monocyclic complexes containing a total of 1, 2, or 3 ring heteroatoms, 5-7 membered It is a ring, and each A ring is one or more R 4 In some cases, the statements are replaced. Compounds listed in T1, pharmaceutically acceptable salts, hydrates, or solvates. 3. Each A ring is independently selected from N, O, and S, and comprises a total of 1, 2, or 3 rings. A 5-6 member monocyclic heteroaryl containing a telogen atom, or independently of N, O, and S Selected 5-6 member monocyclic complex containing a total of 1, 2, or 3 ring heteroatoms It is a ring, and each A ring is one or more R 4 In some cases, the statements are replaced. Compounds described in (1) or (2), pharmaceutically acceptable salts, hydrates, or solvates. 4.X a The A ring is N, and the A ring is selected from N, O, and S, and has 0, 1, or 2 further Compounds containing a ring heteroatom, as described in Statement 1, 2, or 3, are pharmaceutically acceptable. A salt, hydrate, or solvate of a substance. 5.X a The ring A is N, and the ring A is 0 or 1 further ring selected from N, O, and S. Compounds containing heteroatoms as described in Statement 1, 2, or 3, pharmaceutically acceptable A salt, hydrate, or solvate. 6.X a However, L 1 Located directly adjacent to the carbon atom to which it is bonded, from Statement 1 A compound, pharmaceutically acceptable salt, hydrate, or solvate as described in any of item 5. 7. Each A ring is based on the following: [ka] [wherein a is 0 or 1], according to any one of Statements 1 to 6 compound, a pharmaceutically acceptable salt, hydrate or solvate thereof. 8. Each R 4 is independently selected from hydroxy, halogen, (1-6C)alkyl, (1-6C)haloalkyl , (2-6C)alkenyl, phenyl, phenyl(1-3C)alkyl, 5- to 6-membered he teroaryl, 5- to 6-membered heteroaryl(1-3C)alkyl, -R 4a -OR 4b , -R 4a -NR 4b R 4c , -R 4a -C(O)-R 4b , -R 4a -C(O)-OR 4 b , -R 4a -O-C(O)-R 4b , -R 4a -C(O)-NR 4b R 4c , -R 4a -N(R 4b )C(O)-R 4c and -R 4a -S(O) 0-2 R 4b from the group consisting of each R is independently selected, and any (1-6C)alkyl, (1-6C)haloalkyl, ( 4 in the group 2-6C)alkenyl, phenyl, phenyl(1-3C)alkyl, 5- to 6-membered heteroar yl or 5- to 6-membered heteroaryl(1-3C)alkyl is optionally substituted with one or more R 4 d , the compound, pharmaceutically cally acceptable salt, hydrate or solvate thereof, according to any one of Statements 1 to 7. 9. Each R 4However, hydroxy, halogen, (1-3C)alkyl, (1-3C)haloalkyl Lu, (2-3C) alkenyl, phenyl and -R 4a -OR 4b Independently from the group consisting of Selected, R 4 Any (1-3C) alkyl, (1-3C) haloalkyl, (2-3 C) Alkenyl or phenyl, one or more R 4d It is sometimes replaced by , compounds listed in any of statements 1 to 8, pharmaceutically acceptable salts, hydrates, or solvates. 10.Each R 4a However, it does not exist, or it is methylene, as per any of statements 1 through 9. The compounds, pharmaceutically acceptable salts, hydrates, or solvates described herein. 11.R 4b and R 4c However, independently of each of the groups consisting of hydrogen, methyl, and ethyl A compound selected from any of statements 1 through 10, pharmaceutically acceptable. Salt, hydrate, or solvate. 12.Each R 4d However, hydroxy, halogen, amino, (1-2C)alkyl, (1-2C A stay independently selected from the group consisting of alkoxy and (1-2C)haloalkyl groups. Compounds, pharmaceutically acceptable salts, hydrates, or solutions described in any of the instructions 1 to 11 medium. 13. Each B ring, i) A total of 1, 2, or 3 ring heteroatoms independently selected from N, O, and S A monocyclic heterocyclic ring containing 5 to 7 members; ii) A total of 1, 2, or 3 ring heteroatoms independently selected from N, O, and S. A 5-7 member monocyclic heteroaryl containing; iii) A total of 1, 2, 3, or 4 ring hete selected independently from N, O, and S A bicyclic heterocycle with 8 to 10 members containing a 10-member atom; or iv) A total of 1, 2, 3, or 4 ring heterozygotes independently selected from N, O, and S. 8-10 membered bicyclic heteroaryls containing atoms And, Any ring in B is one or more R 5 The statement is replaced depending on the circumstances. A compound, pharmaceutically acceptable salt, hydrate, or solvate described in any of 1 to 12. 14. Each B ring, i) A total of 1, 2, or 3 ring heteroatoms independently selected from N, O, and S A monocyclic heterocycle containing 5-6 members; ii) A total of 1, 2, or 3 ring heteroatoms independently selected from N, O, and S. A 5-6 member monocyclic heteroaryl containing; iii) A total of 1, 2, or 3 ring heterogens independently selected from N, O, and S. A bicyclic heterocycle of 9-10 members containing a child; or iv) A total of 1, 2, or 3 ring heteroatoms independently selected from N, O, and S. A 9-10 member bicyclic heteroaryl containing And, Any ring in B is one or more R 5 The statement is replaced depending on the circumstances. A compound, pharmaceutically acceptable salt, hydrate, or solvate described in any of 1 to 13. 15.X b The A ring is N, and the A ring is selected from N, O, and S, and 0, 1, or 2 further Compounds containing a ring heteroatom, as described in any of statements 1 to 14, pharmaceutical A generally acceptable salt, hydrate, or solvate. 16.X bThe ring A is N, and the ring A is 0 or 1 further ring selected from N, O, and S. Compounds containing heteroatoms, as described in any of statements 1 to 15, pharmaceutically Permitted salts, hydrates, or solvates. 17.X b However, L 2 A carbon atom that is directly adjacent to the carbon atom to which it is bonded, Statement 1 A compound, pharmaceutically acceptable salt, hydrate, or solvate described in any of the 16 items. 18. Each B ring is as follows: [ka] [In the formula, b 1 is 0, 1, 2, or 3, b 2 It is 0, 1, 2, 3, or 4. ] Statement 1 Compounds, pharmaceutically acceptable salts, hydrates, or solvates listed in any of the following 17. 19. Each B ring is as follows: [ka] [In the formula, b 1 is 0, 1, or 2, b 2 It is 0, 1, 2, or 3. ] Statement 1-1 A compound, pharmaceutically acceptable salt, hydrate, or solvate as described in any of item 8. 20.Each R 5 However, hydroxy, halogen, (1-6C)alkyl, (1-6C)haloal Kill, (2-6C)alkenyl, phenyl, phenyl(1-3C)alkyl, 5-6 member Heteroaryl, 5-6 member heteroaryl(1-3C)alkyl, -R 5a -OR 5b , -R 5a -NR 5b R5c , -R 5a -C(O)-R 5b , -R 5a -C(O)-OR 5b , -R 5a -OC(O)-R 5b , -R 5a -C(O)-NR 5b R 5c , -R 5 a -N(R 5b )C(O)-R 5c and -R 5a -S(O) 0-2 R 5b A group consisting of They were independently selected, R 5 Any (1-6C) alkyl, (1-6C) haloalkyl, (2-6C) alkenyl, phenyl, phenyl(1-3C) alkyl, 5-6 member heterozygotes One or more aryl or 5-6 member heteroaryl(1-3C)alkyl groups 5d Compounds described in any of statements 1 to 19, which may be substituted in some cases. , pharmaceutically acceptable salts, hydrates, or solvates. 21.Each R 5 However, independently, -R 5a -OC(O)-R 5b Is it statement 1? A compound, pharmaceutically acceptable salt, hydrate, or solvate as described in any of the 20 items. 22.Each R 5a However, none of the statements 1 through 21 are present or are methylene. Any of the compounds listed, pharmaceutically acceptable salts, hydrates, or solvates. 23.R 5b and R 5c However, hydrogen, methyl, ethyl and pentyl (for example, hydrogen, methyl Statements 1 to 2 are independently selected from the group consisting of ethyl and ethyl. A compound, pharmaceutically acceptable salt, hydrate, or solvate as described in any of paragraphs 2. 24.Each R 5d However, hydroxy, halogen, amino, (1-2C)alkyl, (1-2C A stay independently selected from the group consisting of alkoxy and (1-2C)haloalkyl groups. Compounds, pharmaceutically acceptable salts, hydrates, or solutions described in any of the instructions 1 to 23 medium. 25. Each W is (1-3C) alkylene, phenylene, 5-6 member heteroarylene, 5 Selected from the group consisting of ~6-membered carbocyclylenes and 5-6 membered heterocyclylenes, Any (1-3C) alkylene, phenylene, 5-6 member heteroarylene in W, 5- One or more W6-membered carbocyclylenes and 5-6 membered heterocyclylenes a in Compounds listed in any of statements 1 through 24, which may be substituted in some cases, pharmaceutical A generally acceptable salt, hydrate, or solvate. 26. Each W is selected from the group consisting of (1-3C) alkylene or phenylene, and in W Any (1-3C) alkylene or phenylene of which one or more W a Depending on the case Compounds described in any of statements 1 to 25 that are substituted are pharmaceutically acceptable. A salt, hydrate, or solvate of a substance. 27.Each W a However, hydroxy, halogen, (1-2)alkoxy and (1-2C)halo A group independently selected from the group consisting of alkyls, as described in any of statements 1 to 26. Compounds, pharmaceutically acceptable salts, hydrates, or solvates thereof. 28.X is -O-, -C(O)-, -C(O)-O-, -OC(O)-, -C(O) -N(R x )-,-N(R x)-C(O)- and -NR x - Selected from the group consisting of , compounds listed in any of Statements 1 to 27, pharmaceutically acceptable salts, hydrates Or a solvate. 29.X is -NR x -A compound described in any of statements 1 to 28, A pharmaceutically acceptable salt, hydrate, or solvate. 30.Each R x However, independently selected from the group consisting of hydrogen, hydroxyl, and (1-4C)alkyl A selected compound, pharmaceutically acceptable salt, from any of the compounds listed in Statements 1 to 29. , hydrate or solvate. 31.Each R x However, hydrogen is a compound listed in any of Statements 1 to 30, a drug A scientifically acceptable salt, hydrate, or solvate. 32. Each Y is (1-3C) alkylene, phenylene, 5-6 member heteroarylene, 5 Selected from the group consisting of ~6-membered carbocyclylenes and 5-6 membered heterocyclylenes, Any (1-3C) alkylene, phenylene, 5-6 member heteroarylene, 5- One or more 6-membered carbocyclylenes or 5-6 membered heterocyclylenes a in Compounds listed in any of Statements 1 to 31, which may be substituted in some cases, pharmaceutical A generally acceptable salt, hydrate, or solvate. 33. Each Y is selected from the group consisting of (1-3C) alkylene or phenylene, and in Y Any (1-3C) alkylene or phenylene of the following: a Depending on the case Compounds described in any of statements 1 to 32 that are substituted are pharmaceutically acceptable. A salt, hydrate, or solvate of a substance. 34. Each Y aHowever, hydroxy, halogen, (1-2)alkoxy and (1-2C)halo A group independently selected from the group consisting of alkyls, as described in any of statements 1 to 33. Compounds, pharmaceutically acceptable salts, hydrates, or solvates thereof. 35.Z is -O-, -C(O)-, -C(O)-O-, -OC(O)-, -C(O) -N(R z )-,-N(R z )-C(O)- and -NR z - Selected from the group consisting of , compounds listed in any of Statements 1 to 34, pharmaceutically acceptable salts, hydrates Or a solvate. 36.Z is -NR z -A compound, drug, as described in any of statements 1 through 35. A scientifically acceptable salt, hydrate, or solvate. 37.Each R z However, independently selected from the group consisting of hydrogen, hydroxyl, and (1-4C)alkyl A selected compound, pharmaceutically acceptable salt, from any of the compounds listed in Statements 1 through 36. , hydrate or solvate. 38.Each R z Compounds listed in any of Statements 1 through 37, in which hydrogen is present, pharmaceutical A generally acceptable salt, hydrate, or solvate. 39. n is 0 or 1; m is 0; o is 0 or 1; Compounds listed in any of statements 1 to 38, where p is 1, are pharmaceutically acceptable. Salt, hydrate, or solvate. 40.n is 0 or 1, and W consists of (1-3C)alkylene or phenylene. Selected from the group, any (1-3C) alkylene or phenylene in W is one or Multiple W a In some cases, it is replaced, and each W aHowever, hydroxy, halogen, (1-2) alcohols Independently selected from the group consisting of xy and (1-2C)haloalkyl; m is 0; o is 0 or 1, and Y is from the group consisting of (1-3C)alkylene or phenylene. Selected, any (1-3C) alkylene or phenylene in Y is one or more Y a It is replaced depending on the case, and each Y a However, hydroxy, halogen, (1-2)alkoxy Independently selected from the group consisting of (1-2C) haloalkyl groups; p is 1 and Z is -NR z - and R z The statement that is hydrogen is from statements 1 through 39. Any of the compounds, pharmaceutically acceptable salts, hydrates, or solvates listed below. 41.L 1 However, the following: [ka] A compound having any one of the structures described in any of statements 1 to 40 Substance, pharmaceutically acceptable salt, hydrate, or solvate. 42.L 2 However, selected from the group consisting of non-existent and (1-2C)alkylenes, L 2 inside Any (1-2C)alkylene can be hydroxy, halogen, amino, or (1-2C)alkylene. Selected from the group consisting of (1-2C)alkoxy and (1-2C)haloalkyl. Any of statements 1 to 41, which may be substituted by one or more substituents Any of the compounds listed, pharmaceutically acceptable salts, hydrates, or solvates. 43.L 2 However, selected from the group consisting of non-existent and (1-2C)alkylenes, L 2 inside Any (1-2C)alkylene can be hydroxy, halogen, and (1-2C)haloalkyl Optionally substituted with one or more substituents selected from the group consisting of , Compounds, pharmaceutically acceptable salts, hydrates, or any of the compounds described in any of Comments 1 to 42 Solvate. 44.L 2 However, a state may be selected from the group consisting of non-existent, methylene, and ethylene. Compounds, pharmaceutically acceptable salts, hydrates, or solvates described in any of points 1 to 43. thing. 45.L 2 Compounds listed in any of statements 1 through 44 that do not exist, pharmaceutical A salt, hydrate, or solvate that is permissible. 46.R 1 However, N, CR 2 phenyl, 6-membered heteroaryl, 6-membered carbocyclyl Selected from a group consisting of 6-membered heterocyclines, R 1 Any phenyl, 6-membered he One or more teloaryls, 6-membered carbocyclyls, or 6-membered heterocyclyls R 3 Compounds described in any of statements 1 to 45, which may be substituted as such. , pharmaceutically acceptable salts, hydrates, or solvates. 47.R 1 However, N, CR 2 Selected from the group consisting of phenyl and cyclohexyl, R 1 Any phenyl or cyclohexyl in it contains one or more R 3 Replace in some cases Compounds described in any of Statements 1 through 46 are pharmaceutically acceptable. Salt, hydrate, or solvate. 48.Each R 3 However, hydroxy, halogen, (1-4C)alkyl, (1-4C)haloal Kill and -OR 3a Independently selected from the group consisting of, R 3 Any (1-4C) inside Kill or (1-4C) haloalkyl, one or more R 3c It may be replaced in some cases. Compounds listed in any of Statements 1 through 47, pharmaceutically acceptable salts, Hydrate or solvate. 49.Each R 3c However, hydroxy, halogen, amino, (1-2C)alkoxy and (1 ~2C) Independently selected from the group consisting of haloalkyls, from statements 1 to 48 Any of the compounds, pharmaceutically acceptable salts, hydrates, or solvates listed below. 50.R 2 However, hydrogen, hydroxyl, halogen, (1-4C)alkyl, (1-4C)halo Alkyl and -OR 2a Selected from the group consisting of R 2 Any (1-4C) Archi inside A (1-4C) haloalkyl group contains one or more R 2c It is replaced in some cases. Compounds listed in any of Statements 1 through 49, pharmaceutically acceptable salts, water A dihydrate or solvate. 51.R 2 However, R is selected from the group consisting of hydrogen and (1-3C)alkyl groups. 2 Internal position The (1-4C) alkyl group is one or more R 2c In some cases, it is replaced by S Compounds, pharmaceutically acceptable salts, hydrates, or any of the compounds listed in Tate 1 to 50. It is a solvate. 52.R 2 However, selected from the group consisting of hydrogen, methyl, or ethyl, Statement 1 Compounds, pharmaceutically acceptable salts, hydrates, or solvates described in any of items 51 to 51. 53.Each R2c However, hydroxy, halogen, amino, (1-2C)alkoxy and (1 ~2C) Independently selected from the group consisting of haloalkyls, from statements 1 to 52 Any of the compounds, pharmaceutically acceptable salts, hydrates, or solvates listed below. 54.R 1 However, the following: [ka] A compound described in any of statements 1 to 53 having any one of the following structures Substance, pharmaceutically acceptable salt, hydrate, or solvate. 55.R 1 However, the following: [ka] Compounds having the structure described in any of statements 1 to 54, pharmaceutically acceptable A salt, hydrate, or solvate of a substance. 56. The compound is, Formula II: [ka] [In the formula, R 1 , L 1 , R 4 a, B, X b and any related subgroups, As defined in the above statement, statement 1 has the structure of ] Compounds, pharmaceutically acceptable salts, hydrates, or solvates listed in any of the following five items. 57. Compounds, Formula I-II: [ka] [In the formula, Each R 5 This is as defined in any of the above statements, or adjacent carbon atoms. Two R's located 5When the group is combined with the atoms attached to it, this one or is multiple R 5 Linked to form a condensed benzene ring which may be substituted by a group; R 1 , L 1 A, X a , b 1 And any related subgroups, any state As defined in the comments, of the statements 1 to 55 have the structure of ]. A compound, pharmaceutically acceptable salt, hydrate, or solvate as described in any one of the items. 58. Compounds, Formulas I-III: [ka] [In the formula, Each R 5 This is as defined in any of the above statements, or adjacent carbon atoms. Two R's located 5 When the group is combined with the atoms attached to it, this one or is multiple R 5 Linked to form a condensed benzene ring which may be substituted by a group; R 1 , L 1 , R 4 , a, L 2 , b 1 and any related subgroups, any of the above As defined in the statement, statements 1-55 have the following structure: A compound, pharmaceutically acceptable salt, hydrate, or solvate as described in any one of the items. 59. Compounds, formulas I-IV: [ka] [In the formula, Each R 5 This is as defined in any of the above statements, or adjacent carbon atoms. Two R's located5 When the group is combined with the atoms attached to it, this one or is multiple R 5 Linked to form a condensed benzene ring which may be substituted by a group; R 1 , L 1 , R 4 a, b 1 And any related subgroups, any state As defined in the comments, of the statements 1 to 55 have the structure of ]. A compound, pharmaceutically acceptable salt, hydrate, or solvate as described in any one of the items. 60. The compound is, Formula IV: [ka] [In the formula, R 1 ,W,X,Y,m,n,o,A,X a , L 2 B, X b and any related The subgroups are as defined in the above statement. A compound having any one of the statements 1 to 55, pharmaceutically acceptable A salt, hydrate, or solvate. 61. Compounds are of formulas I-VI: [ka] [wherein q is 0, 1, 2, or 3; R 1 A, X a , L 2 B, X b and any related subgroups, any of the above status As defined in the comment, statements 1-55 have the structure of ] A compound, pharmaceutically acceptable salt, hydrate, or solvate listed in any one of the following items. 62. Compounds, formulas I-VII: [ka] [In the formula, L 1 A, X a , L 2 B, X b and any related subgroups, As defined in the above statement, statement 1 has the structure of ] Compounds, pharmaceutically acceptable salts, hydrates, or solvents listed in any one of items ~55. Japanese items. 63. Compounds, formulas I-VIII: [ka] [In the formula, Each R 5 This is as defined in any of the above statements, or adjacent carbon atoms. Two R's located 5 When the group is combined with the atoms attached to it, this one or is multiple R 5 Linked to form a condensed benzene ring which may be substituted by a group; R 1 W, X, Y, m, n, o, R 4 , a, L 2 , b 1 and any related subgroups The structure is as defined in any of the above statements. A compound listed in any one of sections 1 to 55, a pharmaceutically acceptable salt, or hydrated A substance or solvate. 64. Compounds are those of formula I-IX: [ka] [In the formula, q is 0, 1, 2, or 3; Each R 5 This is as defined in any of the above statements, or adjacent carbon atoms. Two R's located5 When the group is combined with the atoms attached to it, this one or is multiple R 5 Linked to form a condensed benzene ring which may be substituted by a group; R 1 , R 4 a, b 1 And any related subgroups, any of the above statements As defined in [ ], any of statements 1 to 55 have the structure of ] Any compound, pharmaceutically acceptable salt, hydrate, or solvate described in item 1. 65. Compound, formula IX: [ka] [In the formula, q is 0, 1, 2, or 3; Each R 5 This is as defined in any of the above statements, or adjacent carbon atoms. Two R's located 5 When the group is combined with the atoms attached to it, this one or is multiple R 5 Linked to form a condensed benzene ring which may be substituted by a group; R 4 , a, L 2 , b 1 And any related subgroups, any of the above statements As defined in [ ], any of statements 1 to 55 have the structure of ] Any compound, pharmaceutically acceptable salt, hydrate, or solvate described in item 1. 66. The compound is as follows: [ka] A compound described in Statement 1 having any one of the structures shown in JPEG2026143429000063.jpg86170 is pharmaceutically acceptable. A salt, hydrate, or solvate of a substance. 67. Equation II below: [ka] [In the formula, M is Zn 2+ Mn 2+ Cu 2+ Fe 2+ Co 2+ and Ni 2+ A group consisting of Selected; R 1 , L 1 A, X a , L 2 B, X b And any related subgroups, state As defined in any one of the items 1 to 55. Compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof. 68. Compound IIa: [ka] , or not its pharmaceutically acceptable salt, hydrate or solvate, Statement 6 Compounds, pharmaceutically acceptable salts, hydrates, or solvates described in 7. 69.M is Zn 2+ Mn 2+ Fe 2+ Co 2+ and Ni 2+ Select from the group consisting of Selected compounds, pharmaceutically acceptable salts, hydrates, or solutions listed in Statement 67 medium. 70.M is Zn 2+ Mn 2+ and Fe 2+ Selected from the group consisting of, Compounds, pharmaceutically acceptable salts, hydrates, or solvates listed in Article 67. 71.M is Zn 2+ and Mn 2+Selected from the group consisting of, in statement 67 The listed compounds, pharmaceutically acceptable salts, hydrates, or solvates. 72. The compound is as follows: [ka] Any one of statements 67-71 having any one of the following structures The compounds, pharmaceutically acceptable salts, hydrates, or solvates listed therein. 73. Equation III below: [ka] [In the formula, R 1 , L 1 A, X a , L 2 B, X b And any related subgroups, state As defined in any one of the terms 1-55; M is Zn 2+ Mn 2+ Cu 2+ Fe 2+ Co 2+ and Ni 2+ A group consisting of Selected; Q is a spherical monoanionic anion, a planar triangular anion, or a dianionic tetrahedron anion. , trianionic tetrahedral anions, dianionic octahedral anions and trianionic octahedral anions An anion selected from the group consisting of helical anions. A compound having a structure due to [ ] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, However, the compound is formula IIIa: [ka] [In the formula, Q is Br - , I - CO3 2- SiF6 2-IO6 3- VO4 3- , W O4 2- , CrO4 2- SO4 2- HSO4 - AsO4 3- , PO4 3- or H PO4 2- Compounds or pharmaceutically acceptable salts thereof that do not have the structure of [ ]. , hydrate or solvate. 74.M is Zn 2+ Mn 2+ Fe 2+ Co 2+ and Ni 2+ Select from the group consisting of Selected compounds, pharmaceutically acceptable salts, hydrates, or solutions listed in Statement 73 medium. 75.M is Zn 2+ Mn 2+ and Fe 2+ Selected from the group consisting of, Compounds, pharmaceutically acceptable salts, hydrates, or solvates listed in Article 73. 76.M is Zn 2+ and Mn 2+ Selected from the group consisting of, in statement 73 The listed compounds, pharmaceutically acceptable salts, hydrates, or solvates. 77.Q is sulfate (SO4 2- ), phosphate (PO4 3- ) or organophosphates (for example) It is monophenyl phosphate, as described in any one of statements 73-76. Compounds, pharmaceutically acceptable salts, hydrates, or solvates thereof. 78. The compound has one of the following structures, as stated in Statements 73-77 A compound, pharmaceutically acceptable salt, hydrate, or solvate described in any one of the following items: [ka] 79. Formula I, combined with a source of M for use as a pharmaceutical: [ka] [In the formula, R 1 , L 1 A, X a , L 2 B, X b This is one of statements 1 to 55. As defined in either of the following; M is Zn 2+ Mn 2+ Cu 2+ Fe 2+ Co 2+ and Ni 2+ A group consisting of The following compounds are selected: ] or pharmaceutically acceptable salts, hydrates, or solvates thereof. . 80. Sources and combinations of M for use in the treatment of proliferative disorders (e.g., cancer) Furthermore, the following equation I: [ka] [In the formula, R 1 , L 1 A, X a , L 2 B, X b This is one of statements 1 to 55. As defined in either of the following; M is Zn 2+ Mn 2+ Cu 2+ Fe 2+ Co 2+ and Ni 2+ A group consisting of The following compounds are selected: ] or pharmaceutically acceptable salts, hydrates, or solvates thereof. . 81. The compound is as follows: [ka] JPEG2026143429000073.jpg165170 has one of the structures described in Statement 79 or 80 for use as described in Statement 79 or 80. A compound related to eye. 82. The compound is as follows: [ka] Compounds for use as described in Statement 79 or 80, having the structure of the above. 83. The source of M is organic (e.g., M acetate or M propionate or M triflu). (Oromethanesulfonates) or inorganic (e.g., M perchlorates or M nitrates or M tetraphosphates) Trafluoroborate) as described in any one of statements 79-82. Compounds for use. 84.M is Zn 2+ Mn 2+ Fe 2+ Co 2+ and Ni 2+ Select from the group consisting of A compound for use as described in any one of statements 79-83 is selected. . 85.M is Zn 2+ Mn 2+ and Fe 2+ Selected from the group consisting of, A compound for use as described in any one of items 79 to 83. 86.M is Zn 2+ and Mn 2+ Selected from the group consisting of statements 79~ A compound for use as described in any one of item 83. 87. A compound of formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, Q Further combined with the source of Q, Q is a spherical monoanionic anion, a planar triangular anion dianionic tetrahedron anion, trianionic tetrahedron anion, dianionic octahedron An anion selected from the group consisting of anions and trianionic octahedral anions. , the compound for use as described in any one of statements 79 to 86. 88.Q consists of dianionic tetrahedral anions and trianionic tetrahedral anions. A compound for use as described in Statement 87, which is an anion selected from the group. 89.Q is a dianionic tetrahedral oxoanion and a trianionic tetrahedral oxoanion. An anion selected from the group consisting of ONs, for use as described in Statement 87 A compound of [this]. 90.Q is sulfate (SO4 2- ), phosphate (PO4 3- ) or organophosphates (for example) The compound for use described in Statement 87 is monophenyl phosphate. 91. The proliferative disorder is cancerous, as stated in one of the statements 80-90. Compounds for use. 92. Cancer can occur in the lungs, colon, rectum, breast, ovaries, bladder, kidneys, prostate, liver, pancreas, brain, and bones. Compounds selected from blood and skin cancers, for use as described in Statement 91. 93. Formula II below for use as a pharmaceutical: [ka] [In the formula, R 1 , L 1 A, X a , L 2 B, X b This is one of statements 1 to 55. As defined in either of the following; M is Zn 2+ Mn 2+ Cu 2+ Fe 2+ Co 2+ and Ni 2+ A group consisting of The following compounds are selected: ] or pharmaceutically acceptable salts, hydrates, or solvates thereof. . 94. For use as a pharmaceutical in the treatment of proliferative disorders (e.g., cancer), the following formula II: [ka] [In the formula, R 1 , L 1 A, X a , L 2 B, X b This is one of statements 1 to 55. As defined in either of the following; M is Zn 2+ Mn 2+ Cu 2+ Fe 2+ Co 2+ and Ni 2+ A group consisting of The following compounds are selected: ] or pharmaceutically acceptable salts, hydrates, or solvates thereof. . 95.M is Zn 2+ Mn 2+ Fe 2+ Co 2+ and Ni 2+ Select from the group consisting of A compound selected for use as described in Statement 93 or 94. 96.M is Zn 2+ Mn 2+ and Fe 2+ Selected from the group consisting of, Compounds for use as described in 93 or 94. 97.M is Zn 2+ and Mn 2+ Selected from the group consisting of Statement 93 or compounds for use as described in 94. 98. Compounds of formula II, or pharmaceutically acceptable salts, hydrates, or solvates thereof, When combined with a source of Q, Q becomes a spherical monoanionic anion, a planar triangular anion, Dianionic tetrahedral anions, trianionic tetrahedral anions, dianionic octahedral anions An anion selected from the group consisting of on and trianionic octahedral anions, A compound for use as described in any one of the items 93-97 of the treatment. 99.Q consists of dianionic tetrahedral anions and trianionic tetrahedral anions. A compound for use as described in Statement 98, which is an anion selected from the group. 100.Q is a dianionic tetrahedral oxoanion and a trianionic tetrahedral oxoanion. An anion selected from the group consisting of nions, for use as described in Statement 98 A compound related to eye. 101.Q is sulfate (SO4 2- ), phosphate (PO4 3- ) or organophosphates (e.g.) For example, monophenyl phosphate is a compound for use as described in Statement 98. 102. The proliferative disorder is cancer, according to any one of statements 94-101. Compounds for use as described. 103. Cancer can affect the lungs, colon, rectum, breast, ovaries, bladder, kidneys, prostate, liver, pancreas, brain, and bones. , selected from blood and skin cancers, compounds for use as described in Statement 102 thing. 104. Formula III below for use as a pharmaceutical: [ka] [In the formula, R 1 , L 1 A, X a , L 2 B, X b This is one of statements 1 through 55. As defined in the section; M is Zn 2+ Mn2+ Cu 2+ Fe 2+ Co 2+ and Ni 2+ A group consisting of Selected; Q is a spherical monoanionic anion, a planar triangular anion, or a dianionic tetrahedron anion. , trianionic tetrahedral anions, dianionic octahedral anions and trianionic octahedral anions An anion selected from the group consisting of facet anions. ] Compounds of, or pharmaceutically acceptable The salt, hydrate, or solvate of which is accepted. 105. Formula III below for use in the treatment of proliferative disorders (e.g., cancer): [ka] [In the formula, R 1 , L 1 A, X a , L 2 B, X b This is one of statements 1 through 55. As defined in the section; M is Zn 2+ Mn 2+ Cu 2+ Fe 2+ Co 2+ and Ni 2+ A group consisting of Selected; Q is a spherical monoanionic anion, a planar triangular anion, or a dianionic tetrahedron anion. , trianionic tetrahedral anions, dianionic octahedral anions and trianionic octahedral anions An anion selected from the group consisting of facet anions. ] Compounds of, or pharmaceutically acceptable The salt, hydrate, or solvate of which is accepted. 106.M is Zn 2+ Mn 2+ Fe 2+ Co 2+ and Ni 2+ From a group consisting of A compound selected for use as described in Statement 104 or 105. 107.M is Zn 2+ Mn 2+ and Fe 2+ A state selected from the group consisting of Compounds for use as described in Ment 104 or 105. 10⁸M is Zn 2+ and Mn 2+ A statement 10 is selected from the group consisting of the following: Compounds for use as described in 4 or 105. 109.Q is derived from dianionic tetrahedral anions and trianionic tetrahedral anions. The anion selected from the group is one of statements 104-108. Compounds for use as described in the section. 110.Q is a dianionic tetrahedral oxoanion and a trianionic tetrahedral oxoanion. Anions selected from a group consisting of nions, from statements 104-108 A compound for use as described in any one of the items. 111.Q is sulfate (SO4 2- ), phosphate (PO4 3- ) or organophosphates (e.g.) For example, monophenyl phosphate) is one of statements 104-108. Compounds for use as described in the section. 112. The proliferative disorder is cancer, according to any one of statements 105-111. Compounds for use as described above. 113. Cancer can affect the lungs, colon, rectum, breast, ovaries, bladder, kidneys, prostate, liver, pancreas, brain, and bones. , selected from blood and skin cancers, compounds for use as described in Statement 112 thing. 114. i) Compounds of the following formula I, or pharmaceutically acceptable salts, hydrates, or solvates thereof; call ii) Kit of parts, including M's source: [ka] [In the formula, R 1 , L 1 A, X a , L 2 B, X b This is one of statements 1 through 55. As defined in the section; M is Zn 2+ Mn 2+ Cu 2+ Fe 2+ Co 2+ and Ni 2+ A group consisting of It will be selected. 115. Means to facilitate compliance with dosage regimens (e.g., kits) Statement 114 further includes instructions detailing how to administer the constituent components. A kit containing [something]. 116. Further sources of Q include, where Q is a spherical monoanionic anion, a planar triangular anion. On, dianionic tetrahedral anion, trianionic tetrahedral anion, dianionic octahedral anion An anion selected from the group consisting of solid anions and trianionic octahedral anions. The kit as described in Statement 114 or 115. 117. i) Compounds of formula II below, or pharmaceutically acceptable salts, hydrates, or solvates thereof and ii) Kit of parts, including the source of Q: [ka] [In the formula, R 1 , L 1 A, X a , L 2 B, X bThis is one of statements 1 through 55. As defined in the section; M is Zn 2+ Mn 2+ Cu 2+ Fe 2+ Co 2+ and Ni 2+ A group consisting of Selected; Q is a spherical monoanionic anion, a planar triangular anion, or a dianionic tetrahedron anion. , trianionic tetrahedral anions, dianionic octahedral anions and trianionic octahedral anions It is an anion selected from the group consisting of facet anions. 118. Means to facilitate compliance with dosage regimens (e.g., kits) Statement 117 further includes instructions detailing how to administer the components. The kit.

[0346] The following are examples of one or more embodiments of the present invention, for illustrative purposes only, with reference to the attached figures. This document describes the following. [Brief explanation of the drawing]

[0347] [Figure 1] This diagram shows the mononuclear complex of L. a is the structure of [LZn]2+. b is [LMn(H2O)2]2+. [Figure 2] This figure shows a self-assembled metal-containing complex of L that incorporates SO4 2-. a is the X-ray structure of [L2Zn3(SO4)]4+. b is [L2Zn3(SO4)]4+ with the ligands colored for better visibility. c is the X-ray structure of [L2Mn3(H2O)2(SO4)]4+. d is [L2Mn3(H2O)2(SO4)]4+ with the ligands colored for better visibility. [Figure 3]This figure shows a self-assembled Cu2+ complex of L that incorporates PhOPO3 2. a is the X-ray structure of [L2Cu3(PhOPO3)]4+. b is [L2Cu3(PhOPO3)]4+ with the ligands colored for better visibility. [Figure 4] This figure shows the reactions of [L2Zn3]6+ and [L2Mn3]6+ with PhOPO3 2-. a is the X-ray structure of [L2Zn3(PO4)]3+. b is [L2Zn3(PO4)]3+ with the ligands colored for better visibility. c is the X-ray structure of [L2Mn3(H2O)2(PO4)]3+. d is [L2Mn3(H2O)2(PO4)]3+ with the ligands colored for better visibility. [Figure 5a] This is a diagram showing ESI-MS of [L2Cu3(PhOPO3)](ClO4)4. [Figure 5b] This figure shows the ESI-MS results of [L2Cu3(PhOPO3)](ClO4)4 after heating at 80°C for 1 hour. [Figure 5c] This figure shows the ESI-MS of [L2Zn3(PhOPO3)](ClO4)4. [Figure 5d] This figure shows the ESI-MS results of [L2Zn3(PhOPO3)](ClO4)4 after heating at 80°C for 1 hour. [Figure 6]This figure shows the phosphatase activity of [L2Zn3]6+. These are 31P NMR spectra using different substrates, including PhOPO3 (spectrums A-D), serine phosphate (spectrums E-H), threonine phosphate (spectrums I-L), and tyrosine phosphate (spectrums M-P). Specific details for each 31P NMR spectrum are as follows: Spectra A, E, I, and M show the substrate alone (incubated at 37°C for 44 hours); Spectra B, F, J, and N show the [L2Zn3]6+-plus substrate (t=0 min); Spectra C, G, K, and O show the [L2Zn3]6+-plus substrate incubated at 37°C for 19 hours; Spectra D, H, L, and M show the [L2Zn3]6+-plus substrate incubated at 37°C for 44 hours. The 31P NMR of [L2Zn3(PO4)]3+ produces a signal at 8.6 ppm. Some doubling of the 31P signal in [L2Zn3(PO4)]3+(H,P, and L) is due to the formation of a mixture of diastereoisomers between the racemicryptan and the decomposed chiral amino acid, which forms the ion pair ([L2Zn3(PO4)](RCH(NH2)CO2)2+) and is not produced by achiral phenyl phosphate. [Figure 7]This figure shows the chemosensity responses of a panel of human cancer and non-cancer cell lines to 96 hours of continuous exposure to a self-assembling test compound. 'a' indicates the potency of the test compound against cancer cells (HT-29, DLD-1, HCT116 p53+ / + and p53- / -, PSN1, MiaPaCa2, BxPC3, A549, H460, and GBM1) and non-cancer cells (ARPE-19, MCF10A, and NP1). Each value represents the mean IC50 ± standard deviation obtained from at least three independent experiments. 'b' and 'c' are the selection indices (SI) for [L2Cu3]6+(b) and [L2Zn3]6+(c) with respect to the indicated cancer cell lines; SI is defined as the mean IC50 for a particular non-cancer cell line model divided by the mean IC50 for a particular cancer cell line. An SI value > 1 indicates that the test compound is more active against a particular cancer cell line than against the corresponding non-cancer cells. Since the SI values ​​are calculated using the mean IC50 value, experimental error is not included in these figures. d and e are the IC50 values ​​for clinically approved platinumates (cisplatin, oxaliplatin, and carboplatin) and [L2Mn3]6+ and their corresponding SI results. [Figure 8] This figure shows the effects of complex anions on potency and selectivity. 'a' shows the effects of various anions on the potency of the Zn2+ complex; this is expressed as relative potency, defined as dividing the IC50 of [L2Zn3(PO4)]3+, [L2Zn3(SO4)]4+, or [L2Zn3(O3POPh)]4+ by the IC50 of [L2Zn3]6+ (values ​​<1 and >1 indicate an increase or decrease in potency, respectively). 'b' shows the effects of anions on selectivity; these results are expressed as relative SI, defined as dividing the SI of [L2Zn3(PO4)]3+, [L2Zn3(SO4)]4+, or [L2Zn3(O3POPh)]4+ by the SI of [L2Zn3]6+ (values ​​>1 and <1 indicate an increase or decrease in selectivity, respectively). [Figure 9-1]This figure shows the effects of [L2Zn3]6+ and [L2Cu3]6+ on the activity of purified human kinases. a and b are the inhibition percentages of kinases indicated by [L2Zn3]6+(a) and [L2Cu3]6+(b), respectively, at a concentration of 10 μM; showing sufficient results in ESI. c and d are kinases whose activity is stimulated by the [L2Zn3]6+(c) or [L2Cu3]6+(d) complex. e and f are kinome maps showing kinases inhibited (red) or stimulated (green) by [L2Zn3]6+(e) or [L2Cu3]6+(f). This example is reproduced with permission from Cell Signalling Technology Inc (www.cellsignal.com). [Figure 9-2] This figure shows the effects of [L2Zn3]6+ and [L2Cu3]6+ on the activity of purified human kinases. a and b are the inhibition percentages of kinases indicated by [L2Zn3]6+(a) and [L2Cu3]6+(b), respectively, at a concentration of 10 μM; showing sufficient results in ESI. c and d are kinases whose activity is stimulated by the [L2Zn3]6+(c) or [L2Cu3]6+(d) complex. e and f are kinome maps showing kinases inhibited (red) or stimulated (green) by [L2Zn3]6+(e) or [L2Cu3]6+(f). This example is reproduced with permission from Cell Signalling Technology Inc (www.cellsignal.com). [Figure 10] This figure shows the Western blot analysis of purified recombinant Src and AMPK after exposure to [L2Zn3]6+ and [L2Cu3]6+. The purified enzymes were incubated with the complex (50 μM) in the presence of ATP for 4 hours prior to analysis. [Figure 11]This figure shows the effects of [L2Zn3]6+, [L2Cu3]6+, and [L2Mn3]6+ complexes on autophagy and cellular ATP levels. a is a representative fluorescence image showing CYTO-ID autophagy staining (green) and Hoechst (blue) by bright-field overlay of HCT116 p53- / - cells treated with 3.125 μM [L2Zn3]6+, [L2Cu3]6+, or [L2Mn3]6+ for 40 hours. White arrows indicate intracellular vacuoles. b shows cellular ATP levels in ARPE19 non-cancer cells and HCT116 p53+ / + cancer cells after 20 hours of exposure to [L2Zn3]6+ at the indicated concentrations. [Figure 12] This figure shows immunoblots illustrating the differential effects of [L2Cu3]6+ and [L2Zn3]6+ treatment of HCT116 cancer cells and ARPE19 non-cancer cells on key cellular proteins associated with cellular and metabolic stress. Representative immunoblot images of indicated proteins after 40 hours of cell exposure to 5 μM [L2Cu3]6+ or [L2Zn3]6+. Tyrosine-phosphorylated proteins are indicated using pan-phospho-Tyr antibody; β-actin is used as load control. [Figure 13] This figure shows the anion effects of the potency of [L2Cu3]6+ and [L2Zn3]6+. These results represent the mean IC50 value ± standard deviation for at least three independent experiments. [Figure 14] This figure shows the effect of anions on the selectivity of [L2Cu3]6+ and [L2Zn3]6+. All values ​​provided herein were determined from the average IC50 values ​​in Figure 13 for each non-cancer cell line used in this study. As a result, error bars are not shown here because experimental errors are explained in Figure 13. [Figure 15a] This figure shows the effect of anions on the potency and selectivity of [L2Cu3]6+ and [L2Zn3]6+. Relative potency was determined by dividing the IC50 of the test compound plus each anion by the IC50 values ​​for [L2Cu3]6+ and [L2Zn3]6+. A value > 1 indicates an increase in potency, while a value < 1 indicates a decrease in potency. [Figure 15b] This figure shows the effect of anions on the potency and selectivity of [L2Cu3]6+ and [L2Zn3]6+. The relative selectivity index (SI) value was determined by dividing the SI value of the test compound plus each anion by the SI value for [L2Cu3]6+ and [L2Zn3]6+. A value > 1 indicates an increase in selectivity, while a value < 1 indicates a decrease in selectivity. [Figure 15c] This figure shows the effect of anions on the potency and selectivity of [L2Cu3]6+ and [L2Zn3]6+. The relative selectivity index (SI) value was determined by dividing the SI value of the test compound plus each anion by the SI value for [L2Cu3]6+ and [L2Zn3]6+. A value > 1 indicates an increase in selectivity, while a value < 1 indicates a decrease in selectivity. [Figure 16] This figure shows the effects of [L2Zn3]6+ and [L2Cu3]6+ on the activity of recombinant human kinases. The compounds were submitted to the MRC Protein Phosphorylation and Ubiquitination Unit, International Centre for Kinase Profiling (University of Dundee), and tested at a concentration of 10 μM against 140 human kinases (Premier Screen). [Figure 17] This figure shows the effects of [L2Cu3]6+, [L2Zn3]6+, and [L2Mn3]6+ on cellular vacuole formation and autophagy in HCT116 p53- / - cancer cells. Representative confocal images of HCT116 p53- / - cancer cells are shown after 40 hours of treatment with a vehicle control or 3.125 μM [L2Cu3]6+, [L2Zn3]6+, or [L2Mn3]6+. The top panel shows phase-contrast cell images, with white arrows indicating intracellular vacuoles. The middle panel shows cell staining positivity for autophagy (CYTO-ID autophagy dye, green). The bottom panel shows overlays of phase-contrast cell images with CYTO-ID autophagy staining (green, punctate, cytoplasm) and nuclear counterstaining (Hoechst). [Figure 18]This figure shows the effects of [L2Cu3]6+, [L2Zn3]6+, and [L2Mn3]6+ on cellular vacuole formation and autophagy in HCT116 p53+ / + cancer cells. Representative confocal images of HCT116 p53+ / + cancer cells are shown after 40 hours of treatment with a vehicle control or 3.125 μM [L2Cu3]6+, [L2Zn3]6+, or [L2Mn3]6+. The top panel shows phase-contrast cell images, with white arrows indicating intracellular vacuoles. The middle panel shows cell staining positivity for autophagy (CYTO-ID autophagy dye, green). The bottom panel shows overlays of phase-contrast cell images with CYTO-ID autophagy staining (green, punctate, cytoplasm) and nuclear counterstaining (Hoechst). [Figure 19] This figure shows the effects of [L2Cu3]6+, [L2Zn3]6+, and [L2Mn3]6+ on cell vacuole formation and autophagy in ARPE19 non-cancer cells. Representative confocal images of ARPE19 non-cancer cells are shown after 40 hours of treatment with a vehicle control or 3.125 μM [L2Cu3]6+, [L2Zn3]6+, or [L2Mn3]6+. The upper panel shows cell staining positivity for autophagy (CYTO-ID autophagy dye, green). The lower panel shows an overlay of phase-contrast cell images with CYTO-ID autophagy staining (green, punctate, cytoplasm) and nuclear counterstaining (Hoechst). [Figure 20] This figure shows the effects of [L2Cu3]6+, [L2Zn3]6+, and [L2Mn3]6+ on cellular ATP levels in ARPE19 non-cancer cells and HCT116 p53+ / + cancer cells. The effect of 20 hours of treatment with indicated concentrations of [L2Cu3]6+, [L2Zn3]6+, or [L2Mn3]6+ on total cellular ATP levels, compared to levels in ARPE19 or HCT116+ / + cells treated with a vehicle control. n=3. Biological replicates, Student's t-test (p-value). [Figure 21]This figure shows the activity of [L2Cu3]6+ and [L2Zn3]6+ against primary H460 tumors. The results shown represent the mean tumor weight ± SEM after treatment with three different doses of [L2Cu3]6+ and [L2Zn3]6+: L2Zn3[1]=54μM, L2Zn3[2]=108μM, L2Zn3[3]=216μM; L2Cu3[1]=42μM, L2Cu3[2]=84μM, L2Cu3[3]=168μM. SoC paclitaxel. Statistical analysis by one-way ANOVA (*): 0.05≧p value>0.01; (* *): 0.01≧p value>0.001; (***): 0.001≧p value; (****): 0.0001≧p value. Number of experimental groups n=10~13. [Figure 22] This figure shows the evaluation of the effects of [L2Cu3]6+ and [L2Zn3]6+ on primary H460 metastasis to low CAM cells. Relative ALU expression (relative to chicken GAPDH) as a quantitative marker of human cell metastasis to low CAM cells. L2Zn3[1]=54μM, L2Zn3[2]=108μM, L2Zn3[3]=216μM; L2Cu3[1]=42μM, L2Cu3[2]=84μM, L2Cu3[3]=168μM. SoC paclitaxel. Relative expression ± SEM. Statistical analysis by one-way ANOVA (*): 0.05≧p value>0.01; (**): 0.01≧p value>0.001; (***): 0.001≧p value; (****): 0.0001≧p value. Number of experimental groups n=7~8. [Figure 23] This figure shows the activity of [L2Cu3]6+ and [L2Zn3]6+ against primary HT29 tumors. The results shown represent the mean tumor weight ± SEM after treatment with three different doses of [L2Cu3]6+ and [L2Zn3]6+: L2Zn3[1]=26.6μM, L2Zn3[2]=53.2μM, L2Zn3[3]=106.4μM; L2Cu3[1]=23.8μM, L2Cu3[2]=65.7μM, L2Cu3[3]=131.46μM. SoC doxorubicin. Statistical analysis by one-way ANOVA (*): 0.05≧p value>0.01; (**): 0.01≧p value>0.001; (***): 0.001≧p value; (****): 0.0001≧p value. The number of experimental groups is n=10-14. [Figure 24]This figure shows the activity of [L2Cu3]6+ and [L2Zn3]6+ against primary HCT116 tumors. The results shown represent the mean tumor weight ± SEM after treatment with three different doses of [L2Cu3]6+ and [L2Zn3]6+: L2Zn3[1]=70.5μM, L2Zn3[2]=141μM, L2Zn3[3]=282μM; L2Cu3[1]=75μM, L2Cu3[2]=150μM, L2Cu3[3]=300μM. SoC doxorubicin. Statistical analysis by one-way ANOVA (*): 0.05≧p value>0.01; (**): 0.01≧p value>0.001; (***): 0.001≧p value; (** **): 0.0001≧p value. Number of experimental groups n=12~15. [Figure 25] This figure shows the evaluation of the effects of [L2Cu3]6+ and [L2Zn3]6+ on the metastasis of primary HCT116 to low CAM. Relative ALU expression (relative to chicken GAPDH) as a quantitative marker of human cell metastasis to low CAM. Relative expression ± SEM. L2Zn3[1]=70.5μM, L2Zn3[2]=141μM, L2Zn3[3]=282μM; L2Cu3[1]=75μM, L2Cu3[2]=150μM, L2Cu3[3]=300μM. SoC doxorubicin. Number of experimental groups n=7~8. [Examples]

[0348] <Part A> [Synthesis and Characterization] Unless otherwise stated, all solvents and materials are Sigma Aldrich, F Purchase from Isher Scientific or Fluorochem, without purification. It was used. 1 H, 13 C, DEPT-135 and DEPT-90 NMR data The Bruker Fourier 300MHz or Bruker Avance e III (AVIII) 400MHz spectrometer or Bruker Avance Ne The data was recorded using a 600MHz NMR spectrometer. The mass spectrum was manipulated in cation mode. Using electrospray ionization with an Agilent 6210 TOF MS Furthermore, the mass spectrum of metal complexes can be manipulated in cation mode using electrospray ions. Obtained using a Bruker Micro TOF-q LC mass spectrometer with a chemical reaction method. (Serine) Phosphorylated "SAMS" peptide (phosphorylated at residues) HMRSAMS * GLHLV KRR, PeptideSynthetics, Peptide Protein R Obtained from esearch Ltd (purity > 95%).

[0349] Single-crystal X-ray diffraction data, monochromatized by graphite, from a Mo(Kα) source. In a Bruker D8 Venture diffractometer equipped with a low-temperature N2 gas stream, 15 The solution was collected at 0(2)K. The solution was prepared by the conventional heavy atom Patterson method or direct method. Using the SHELXS-97 and SHELXL software respectively, all F 2 De The result was refined using the complete matrix least squares method for the data. 26 Absorption correction is performed using SADABS. This was applied based on multiple and symmetrically equivalent measurements. 27 Almost all structures are solvent molecules Disordered ether due to bi / or counter-anions (generally, substitutional or rotational obstructions) It contains a form that is. In these cases, atoms are PART The model was created using commands and refined for two locations. The anisotropic displacement parameters were used in SIM. The data was processed using U and DELU, and in some cases, ISOR was used if necessary. Electron density ma Due to the diffusivity of the hop, hydrogen atoms were not added to the disordered solvent molecules. [L2Zn3SO 4](BF4) 3.5 The structure contains a wide range of disordered tetrafluoroborate counteranions. And one of them was modeled with almost no refinement, using a 50% occupancy rate.

[0350] (Ligand synthesis) (Synthesis of L) Ligand L was prepared as described above. 28 However, benzoylated thioamide (1) and The procedure for the synthesis of thioamide(2) was slightly modified. [ka]

[0351] (1) Synthesis: Tris(2-aminoethyl)amine (1.0 g, 6) under a dinitrogen atmosphere In a 50 mL solution of 0.84 mmol acetone, the reactants are refluxed at a rate that allows them to flow gently. Benzoyl sothiocyanate (3.7 g, 22.6 mmol) was added. After adding, the reaction product The mixture was stirred overnight, during which time a colorless precipitate formed. The precipitate was isolated by filtration and acetone. Washed with (3 × 5 mL) to obtain (1) as a white solid. Yield = 2.05 g (47%) . 1 1H NMR (400 MHz, DMSO-d 6 ) δ(ppm) 11.20 (s, 3H, -NH), 11.0 (t, 3H, J = 4.8, -C H2NH), 7.81 (d, 6H, J = 7.2, Ph), 7.56 (t, 3H, J = 7.4, Ph), 7.38 (t, 6H, J = 7. 6, Ph), 3.75 (q, 6H, J = 5.7, -CH2CH2NH), 2.89 (t, 6H, J = 6.0 Hz, -CH2CH2NH). 1 3 ¹¹C NMR [100 MHz, DMSO-d6 ]: δ C = 180.5 (C=S), 168.2 (C=O), 133.1 (CH), 132.7 (Q) , 128.9 (CH), 128.6 (CH), 51.9 (CH2), 42.6 (CH2). ESI-MS m / z 636 (M + H + ), HR ES I-MS measured value: 636.1882 C 30 H 33 The calculated N7S3O3 concentration was 636.1880 (error 0.46 ppm).

[0352] Synthesis of (2): Benzoyl urea derivative (1) (1.3 g, 2.05 mmol) is mixed with water The solution was suspended in (20 mL) and NaOH (820 mg, 20.5 mmol) was added. Then, The reaction mixture is heated to 60°C, and after 48 hours, the temperature is gradually lowered, allowing the solution to slowly reach room temperature. It was cooled thoroughly to prevent it from forming on the oil, resulting in the formation of a colorless precipitate. By filtration... After isolation, the sample was washed with ice-cold water (2 × 1 mL) to obtain a colorless solid trithiourea (2). Yield = 503 mg (76%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ(ppm) 7.55 (brs, 3H, - NH), 7.08 (brs, 6H, -NH2), 3.44 (brs, 6H, -CH2CH2NH), 2.58 (brs, 6H, -CH2CH2NH). 13 ¹¹C NMR [100 MHz, DMSO-d 6 ]: δ C = 183.5 (C=S), 52.9 (CH2), 42.3 (CH2). ESI-MS m / z 324 (M + H + ), HR ESI-MS measured value 324.1089 C9H 21 N7S3 calculated value: 324.1093 (error 1.03 ppm) .

[0353] (L 1 (composition of) Ligand L 1 An analogue of ligand L was prepared according to the following protocol.

[0354] Synthesis of α-bromo-2-acetylisoquinoline: 2-acetylisoquinoline at 80°C (1.0 g, 6.28 mmol) carbon tetrachloride (20 mL) solution, carbon tetrachloride (0.6 Slowly add liquid bromine (0.39 mL, 7.55 mmol) in (mL) and TLC (S IO2 (1% MeOH in DCM) was added dropwise until it indicated the absence of starting material. The reaction mixture is cooled and diluted with dichloromethane (100 mL), and saturated sodium carbonate solution (2 Washed thoroughly with 50 mL of water. Removed the organic layer and anhydrous magnesium sulfate. Dehydration was performed with citric acid, and the solvent was removed under reduced pressure, leaving a crude product as a yellow oil. Purified by column chromatography (1% MeOH, SiO2 in DCM), and the solvent was removed. After removal, the pure product remained as a slightly yellowish oil (1.08g, 72%). 1 HN MR (400 MHz, CDCl3) δ (ppm) 9.06 - 9.00 (m, 1H), 8.62 (d, J = 5.5 Hz, 1H), 7.90 - 7.95 (m, 2H), 7.81 - 7.73 (m, 2H), 5.04 (s, 2H). 13 ¹³C NMR [100 MHz, CDCl3]: δ C = 194.1 (Q), 150.1 (Q), 141.1 (CH), 137.1 (Q), 130.7 (CH), 129.7 (CH), 127.1 ( CH), 126.53 (Q), 126.49 (CH), 125.6 (CH), 34.7 (CH2). ESI-MS m / z249.9864 (M + H + ), measured neutral mass 248.9788, C 11 The calculated H8NOBr concentration was 248.9789 ppm (error 0.37 ppm).

[0355] L 1 Synthesis: α-bromo-2-acetylisoquinoline (500 mg, 2.10 mmol) ) in an ethanol (20 mL) solution, 1,1',1"-(nitrilotris(ethane-2, 1-Diyl)Tris(thiourea) (226 mg, 0.70 mmol) was added. The reaction was heated to 80°C for 12 hours, during which time all the solids dissolved and the solution turned yellow. Next, the solution was cooled and the solvent was removed under reduced pressure. The resulting oil was then treated with dichloromethane. Diluted to (50 mL) and washed with saturated sodium bicarbonate aqueous solution (2 × 25 mL). The combined organic layers are dehydrated with anhydrous magnesium sulfate, and the solvent is removed under reduced pressure to obtain a brown / yellow color. Crude oil was obtained. This was then subjected to column chromatography (SiO2, dichlorometh Purified with 10% methanol (from the mixture), an orange solid (277 mg, 51%) was obtained. and L 1 It generated. 1 H NMR (400 MHz, CDCl3) δ (ppm) 8.88 (d, J = 8.5, 3H), 8.56 (d, J = 5.6, 3H), 7.81 (d, J = 8.2, 3H), 7.64-7.57 (m, 6H), 7.48 (ddd, J = 8.3, 7.1, 1.0, 3H), 7.09 (s, 3H), 6.39 (br s, 3H), 3.50 (q, J= 5.3, 6H), 2.90 (t, J (= 5.56 Hz, 6H).13 ¹³C NMR [100 MHz, CDCl3]: δ C = 169.2 (Q), 153.7 (Q), 150.9 (Q), 142.0 (CH), 137.1 (Q), 129.9 (CH), 127.9 (CH), 127.1 (CH), 126.72 (Q), 126.70 ( CH), 120.5 (CH), 108.8 (CH), 53.3 (CH2), 43.4 (CH2). ESI-MS m / z 777.2363 (M + H + ), measured neutral mass 776.2291, C 42 H 36 N 10 S3 calculation value: 776.2287 (error 0.63 ppm). [ka]

[0356] (Synthesis of complexes) (Mononuclear complex) Synthesis of [LZn](ClO4)2. Zn(ClO4)2·6H2O(10mg. 0.0 In a 27 mmol MeCN (1 ml) solution, add ligand L (12 mg, 0.019 mmol) The MeCN suspension was added, and the reactants were sonicated until a clear solution was formed. Add water (approximately 1 ml) to the solution and allow it to evaporate slowly, during which time pale yellow crystals will form. Then, this was isolated by filtration and dried (Yield = 9 mg. 53%). * ) [LMn](Cl The O4)2 complex was prepared using Mn(ClO4)2·6H2O in a similar manner, and a yellow compound was formed. Crystal (Yield = 10 mg, 60%) * ) was obtained. * Percentage yield based on ligand moles .

[0357] (Trinuclear complex) Synthesis of [L2Zn3(SO4)](ClO4)4. Zn(ClO4)2·6H2O(1 0 mg. Ligand L (12 mg, 0.027 mmol) in a 1 ml solution of MeCN. Add a 0.19 mmol MeCN suspension and sow the reactants with ultrasound until a clear solution is formed. Processed. This was then mixed with water containing Bu4NHSO4 (3.1 mg, 0.009 mmol). Add approximately 1 ml of the solution, and slowly evaporate it, during which time a colorless crystal will form. The substance was isolated by filtration and dried (yield = 11 mg, 60%). [L2Mn3(SO4)] The (ClO4)4 complex was prepared using Mn(ClO4)2·6H2O in a similar manner, and yellow Colored crystals (yield = 9 mg, 50%) were obtained.

[0358] Synthesis of [L2Cu3(O3POPh)](ClO4)4. Cu(ClO4)2·6H2 In a solution of O (10 mg, 0.027 mmol) in MeCN (1 ml), add ligand L (12 mg) Add a 0.019 mmol MeCN suspension and stir until a clear solution is formed. It was ultrasonically treated. This contains Na2O3POPh (2.3 mg, 0.009 mmol). Add the water (approximately 1 ml), slowly evaporate the solution to obtain green crystals, and then... Isolated by filtration and dried (yield = 9 mg, 47%).

[0359] Synthesis of [L2Zn3(PO4)](ClO4)3. Zn(ClO4)2·6H2O(1 0 mg. Ligand L (12 mg, 0.027 mmol) in a 1 ml solution of MeCN. Add a 0.19 mmol MeCN suspension and sow the reactants with ultrasound until a clear solution is formed. Processed. This contains Na2O3POPh (2.3 mg, 0.009 mmol). Add water (approximately 1 ml), slowly evaporate the solution to obtain yellow crystals, and filter them. Further isolation and drying (yield = 10 mg, 54%). [L2Mn3(PO4)](ClO 4) The 3 complex was prepared using Mn(ClO4)2·6H2O in a similar manner, producing yellow crystals. (Yield = 9 mg, 50%). [Consideration]

[0360] 1.5 equivalents of L are compared with Zn(ClO4)2 or Mn(ClO4)2. As demonstrated by X-ray crystallography and ESI-MS, mononuclear complexes (for example) ba, [LM] 2+ ) In the solid state, the zinc complex has three pyri from the same ligand. A 6-coordinate Zn molecule coordinated by six nitrogen atoms from a dil-thiazole bidentate unit. 2 Cation Contains Mn 2+ In the analogue, the metal ion is again 6-coordinate, but this is because of the two Four N-donor atoms and two water O-donor atoms from a bidentate pyridylthiazole unit This was due to coordination by the ion (Figure 1). Both complexes have weakly interacting anions. Even in the presence of [L2Cu3], trimetallic capsules (e.g., [L2Cu3] 6+ Cu that can form 2+ Temptation It was different from a conductor. This difference was Cu 2+ (at least pyridyl-thiazole Due to its ability to form 4-coordinate complexes (by Zn), 2+ and Mn 2+ They are both, It prefers a higher coordination geometry, and without the presence of strongly coordinating anions, a single mononucleus is formed. It was done. Mn 2+ Coordination of water in complexes (e.g., [LMn(H2O)2] 2+ ) is this H This is a result of the acidophilicity of the cation, and this behavior is reflected in all structures using this metal. This type of formation has also been observed in the gas phase, and in ESI-MS studies, it has been observed in mononuclear molecules. It was shown that only the corresponding ions exist.

[0361] (In precise stoichiometric proportions) Mn using (Bu4N)HSO4 2+ or Zn 2+ and When L is reacted, a capsule is formed in which a sulfate anion is encapsulated (for example) [L2M3(SO4)] 4+ (Figure 2). In solid form, Zn 2+ This is trinuclear [L2Zn3] 6 + Cu having aggregates 2+ It has an equivalent structure to the derivative and encapsulates within that range. Sulfate anions (e.g., [L3Zn(SO4)]) 4+ ) was 3 Zn 2+ Each atom consists of four N-donor atoms from two bidentate pyridyl-thiazole units. The 5-coordinate was derived from one oxygen donor from the sulfate anion. Zn supplemented by the interaction of two -NH···O hydrogen bonds. 2+ By three coordinate bonds It was held inside the capsule. The remaining uncoordinated oxygen atoms were in three places within the "upper edge" of the cavity. - A hydrogen bond was formed with the NH donor unit. Mn 2+ The very similar aggregates Forming a pipe, Mn 2+ Each of the metal ions is 6-coordinate, which is a characteristic of metal ions. For one of them, four N-donor genes from two bidentate pyridylthiazole units It is produced from two oxygen donors from the child and sulfate anion. The remaining two On is also 6-coordinate, coordinating with two bidentate N-donor ligands, but sulfate an Coordinated by one oxygen atom from one water molecule (e.g., [L2Mn3( H2O)2(SO4)] 4+ This means that weakly interacting anions (for example, halos) Genoxide, ClO4 - , and BF4 - Under ) Zn 2+ and Mn 2+ Both are single They form a nuclear complex, and under the tetrahedral oxoanion, these serve as a template for trimetallic capsule formation. This demonstrated that it would be the case.

[0362] {[L2Zn3(SO4)(ClO4)3} bonded to a divalent ion} + and {[L2M n3(SO4)(ClO4)3} + ESI-MS compatible with m / z1844 and 1 The ions at 812 demonstrated that these species can also be observed in the gas phase.

[0363] Disodium phenyl phosphate [L2Cu3] 6+ When added to the MeCN / H2O solution The color changed from light blue to green. Then, after several days, crystals were deposited, and the fraction was determined by X-ray crystallography. Further analysis forms a trimetallic capsule, but only Ph is retained inside the host. OPO3 2- It was shown to be an anion. The mechanism is very similar to that of other oxoanions. In PhOPO3 2- It is supplemented by a series of -NH····anion interactions. 3 Cu 2+ It was coordinated to the metal ion. However, due to the phenyl substituent ligand, it was slightly They take on different conformations and are formed by two pyridyl-thiazole units in a phenyl unit. It occupied the resulting gap (Figure 3).

[0364] Two equivalents of L, M(ClO4)2 (where M = Zn) 2+ or Mn 2+ ) and PhOP The reaction of three equivalents of O3Na2 yielded very different species. In the solid state, both The structure is maintained within the molecule by a series of interactions between the metal ion and the amine hydrogen atom. Central PO4 3- It contains an anion (Figure 4). [L2Mn3(PO4)] 3+ The complex is, Similar to sulfate analogs, with three 6-coordinate Mn 2+ Metal ions have two bidentate N-donor rings. Coordinated by ligand domains, one metal ion has two oxygen atoms from the anion. The two metal ions are coordinated by one anionic oxygen atom and a water molecule. It was coordinated. [L2Zn3(PO4)] 3+ It differs slightly from the sulfate analog, and contains one The metal ion consists of two bidentate N-donor ligand units and two oxygen atoms of the anion. It was a 6-coordinate system resulting from the position. When the sole oxygen atom from the anion interacts with the metal... The remaining two metal ions were only 5-coordinated.

[0365] This metal-dependent reactivity is also observed in ESI-MS. Observed: PhOPO3Na2 and [L2Cu3](ClO4)6 in water and MeCN. When reacted, {[L2Cu3( PhOPO3)](ClO4)3} + , {[LCu2(PhOPO3)](ClO4)} + , {[LCu](ClO4)} +and {[LCu2(PhOPO3)]} 2+ Compatible The ions obtained were obtained. Even when this sample was heated at 80°C, the ESI-MS spectrum was It was shown that there was no change, and the phenyl phosphate dianion remained unchanged. The similar reaction of PhOPO3Na2 with Zn(ClO4)2 and L was m / z 19 {[L2Zn3(PhOPO3)](ClO4)3} at 20 and 910 respectively + oh [L2Zn3(PhOPO3)](ClO4)2 2+ Using the corresponding ions ESI-MS was performed. {[LZn2(PhO (PO3)(ClO4)} + , {[LZn](ClO4)} + and {[LZn2(Ph OPO3)]} 2+ We also observed corresponding low molecular weight ions. However, at 80°C, the sun When the pull is heated, {[L2Zn3(PO4)](Cl) at m / z 1743 and 822. O4)2} + and {[L2Zn3(PO4)](ClO4)} 2+ The corresponding ions ESI-MS, which now uses simpler spectra, has changed dramatically. First of all, Zn 2+ The contained complex is Cu 2+ Phenyl diphosphate is produced using analogs and a similar method. It reacts with the nion, and this anion (for example, [L2Zn3(PhOPO3)] 4+ ) It was demonstrated that it forms a complex trinuclear complex. However, when heated at room temperature or 80°C for 1 hour... After heating, several days later, the anion is hydrolyzed, and the phosphate is encapsulated within the cryptand. (See Figures 5a to 5d.) L2 equivalent, Zn(ClO4)2 and Ph The reaction with an equivalent amount of OPO3Na23 initially produced a broad complex spectrum, but at 80°C... After 1 hour, a signal corresponding to the phenol hydrolysis product [L2Zn3(PO 4) 3+ When a spectrum containing the corresponding signal is generated, this hydrolysis is 1 This was confirmed by 1H NMR. The reaction with Mn(ClO4)2 was the same as the phosphoric acid observed first. Phenyl bond (e.g., {[LMn2(PhOPO3)](ClO4)}) + ) corresponds to Zn using ions in ESI-MS 2+ Similar to analogs, but hydrolysis (for example) , {[L2Mn3(PO4)](ClO4)2} + and {[L2Mn3(PO4)]( ClO4)} 2+ The ion corresponding to ) was observed after 1 hour of heating. 29

[0366] Zn 2+ The complex exhibits substrate-specific properties in the rate of hydrolysis and its phosphatase activity. The difference was shown. 31 NMR of a 25%:75% mixture of DMSO and buffered H2O solution Zn in the compound (HEPES pH 7.5) 2+ Complexation of phenyldianion phosphate In the hydrolysis analysis, non-hydrolyzable PhOPO3 was observed at t=0. 2- Corresponding to -1.5 ppm A signal was observed at (Figure 6, Spectrum B). After 19 hours at 37°C, the major A signal is currently observed at 8.6 ppm, and this signal is [L2Zn3(PO4)] 3 + This is the same chemical shift, and after 44 hours, PhOPO3 2- The corresponding marker is Qualitatively, no traces were observed (Figure 6, spectra C, D). 4-nitrophenyl phosphate In similar experiments used, 31 The P signal is Zn 2+ After mixing with the complex, the starting material [L2Zn3(PO4 )] 3+ Only was observed, and the rapid yellowing of the solution due to the formation of 4-nitrophenolate was observed. Related

[0367] Considering the importance of protein phosphorylation in intercellular and intracellular signaling, For its common dysregulation in function and cancer, 30、31 Zn 2+ The complex is phosphorus Next, we analyzed whether the oxidized amino acids serine, threonine, and tyrosine could be dephosphorylated. In fact, Zn 2+ Depending on the complex, PhOPO3 2- Serine-P hydrolyzes at a similar rate. O3 2- and tyrosine-OPO3 2- It is dephosphorylated, and the actual hydrolysis takes 24 hours. This occurred over time and ended after 48 hours (Figure 6, spectrum E~H; M~P). Zn 2 + The amino acid threonine-OPO3 complex 2- The dephosphorylation of is slower. However, threonine-OPO3 was found after 48 hours. 2- It remained the dominant species (Figure 6). Spectra (I-L). Differences in reactivity to different substrates are due to steric and electrical effects. This may be due to the difference in reactivity with phenyl phosphate compared to 4-nitro derivatives, which is due to hydrolysis. This may be a result of the electron-withdrawing nitro group that strengthens the serine-PO3. 2- , Chiroshi n-OPO32- and threonine-OPO3 2- They all have similar electrical characteristics. However, threonine has a methyl substituent adjacent to the phosphorylated residue, and the -CHCH3 unit is Because it is deeply housed in the gaps between self-assembled species, [L2Zn3] 6+ After the combination This appeared to potentially lead to undesirable steric interactions (see Figure 3). i. ). This interaction reduces the ability of the cryptand to bind to the anion, and thus Therefore, it is highly likely that the hydrolysis rate was reduced. Both serine and tyrosine are, (Tyrosine-OPO3) 2- PhOPO3 2- It is very similar to , serine-PO3 2- This position does not require a very strict three-dimensional structure -CH2- It has units.), and as a result, it was hydrolyzed more rapidly.

[0368] The rate of substrate hydrolysis also depended on the metal used in the self-assembly process. (Solid state) And ESI-MS data, [L2Cu3] 6+ However, hydrolysis of phenyl phosphate However, aggregates, for example, [L2Cu3(PhOPO3)] 4+ Take this anion inside This suggests that it can be incorporated. The hydrolysis of 4-nitrophenyl phosphate was determined by UV-Vis spectroscopy. By monitoring the decomposition, Mn 2+ Zn (verses) 2+ Comparing the responsiveness of different species And then, 24 hours later, Mn 2+ It has been shown that it is hydrolyzed by more than three times the amount of phosphate, Mn 2 + is, Zn 2+ It was shown to be more active than the complex.

[0369] [Biological research] (Cell lines and cultures) All cell lines used were maintained in antibiotic-free culture medium with a small number of passages, as noted below. Unless otherwise specified, it is ATCC (LGC Standards, Middlesex, UK) or I obtained (Methods). HT29, DLD-1, HCT116 p53 + / + oh HCT116 p53 - / - All of these are colorectal adenocarcinoma cell lines derived from different individuals. Yes, (HCT116 isogeneic cancer cells that are genetically identical except for the p53 state) It harbors different combinations of carcinogenic lesions (excluding N). PSN-1, BxPC-3 and MiaPa Ca2 is a pancreatic cancer cell line, while A549 and H460 are lung cancer cell lines. HT29 DLD-1, PSN-1, BxPC-3, A549 and H460 cell lines were used in a 2mM solution. Contains L-glutamine, 1 mM sodium pyruvate, and 10% fetal bovine serum (FBS). The cells were cultured in RPMI-1640 growth medium (Sigma). HCT116(p5 3 + / + and p53 - / - ) Cell lines and MiaPaCa2 cell lines, Dulbecco modification The cells were cultured in Eagle Medium (Sigma), 2 mM L-glutamine, and 10% FBS. The ARPE-19 retinal epithelial non-cancerous cell line (Dunn et al., 1996) was used in DMEM / F1 Medium 2 (Gibco), 2 mM L-glutamine, 1 mM sodium pyruvate and MCF10A non-cancerous human breast epithelial cell line was cultured in 10% FBS. Medium (Sigma), 2 mM L-glutamine, 1 mM sodium pyruvate, 10 NP1 cells and GBM cells were cultured in %FBS and 1× non-essential amino acids (NEAA). One cell was treated with poly-L-ornithine (5 μg / ml) and laminin (2.4 μg / ml). Cultured in plastic products coated with (Polson et al., 2018; Da Silva et al., 2019). NP1 cells were treated with 5% FBS, hFGF 20 ng / ml, rhEGF 20 ng / ml, 0.5 x B-27 supplement (Gibco), 0.5 x Supplemented with N-2 supplement (Gibco) and 1x GLUTAMAX (Gibco). GBM1 cells were grown in filled DMEM / F12 medium (Gibco). GF 40 ng / ml, rhEGF 40 ng / ml, 0.5 × B-27 supplement (Gi Neuro supplemented with bco (brand) and 0.5×N-2 supplement (Gibco) The cells were cultured in basal medium (Gibco).

[0370] (Studies on chemical sensitivity) [L2M3] 6+ And all other self-assembling complexes, by adding DMSO to the individual components. Next, the cells were newly formed by mixing them together with a pipette. These were added to the cell culture medium so that the final DMSO concentration was 0.2% (vehicle control). Further dilutions were applied. Cisplatin, oxaliplatin, and carboplatin were then buffered with phosphate buffer. Dissolve in saline solution. Dissolve the cell line in 2 × 10⁶ wells. 3 The cells were seeded into a 96-well plate. GBM1 cancer stem-like cells were incubated overnight at 37°C. 3 × 10⁶ cells were incubated per well. 3 cell Seeds were sowed, and NP1 neural progenitor cells were planted at 1.5 × 10⁶ per well. 3 The cells were seeded. The next day, The culture medium was removed and replaced with fresh medium containing the test compound at various concentrations. The cells were then further examined. Incubate with the test compound for 96 hours, then remove the medium and prepare fresh medium (200 The cells were replaced with (μl / well). MTT was added (20 μl at 5 mg / ml), and the cells were further replaced with 4 The medium and MTT were removed, and the formazan crystals were treated with DMSO150. The solution was dissolved in μl, and its absorbance was determined at 540 nm. A dose-response curve was constructed. The concentration required to reduce cell growth by 50% (IC) 50 ) was determined. The selection index was IC in the case of non-cancer cells 50 IC in the case of cancer cell lines 50 Defined as the result of dividing by Furthermore, a value > 1 indicates selectivity for cancer cells compared to non-cancer cells.

[0371] (Immunoblot) Protein lysates and recombinant proteins are dissolved in 15% SDS-polyacrylamide gel. Decomposition was performed on a 35mA buffer overnight at room temperature using 1x trisglycine buffer (Biorad Co., Ltd.). By wet transfer in the nitrocellulose membrane, the protein is transferred to the nitrocellulose membrane. Electroblotting was performed (Allison et al., 2014). After blocking the membrane, these were... After incubation overnight with primary antibody at 4°C, rabbit or mouse secondary antibody (HRP) - The bonded form was added at room temperature and left for 1 hour, and the blot was colored by enhanced chemiluminescence. The primary antibody was anti-Src (whole) (Cell Signalling Technolog Y Company #2123 1:1000), Antiphosphorylated Src (Y527) (Cell Sig Nalling Technology (#21055 1:1000), antiphosphorylation Src(Y416)(Cell Signalling Technology #6 9435 1:1000), anti-AMPKα (overall) (Cell Signaling Technology Inc. #2532 1:1000), Antiphosphorylated AMPKα (T17 2)(Cell Signalling Technology #2532 1:1 000), anti-phospho-Tyr(pan)(Cell Signalling Techn ology #8954 1:2000), anti-p53 (Santa Cruz, DO- 1 clone, 1:1000), anti-β-actin (Merck MAB1501, 1:40) The result was ,000). The digits were obtained by densitometry using ImageJ software. We quantified the value of Naru.

[0372] [Results and Discussion] [L2Cu3] 6+ and [L2Zn3] 6+ This involved the use of three non-cancer cell models and In comparison, it exhibits potent and selective activity against the majority of the cancer cell lines tested (Figure 6). a~c). [L2Zn3] 6+ In this case, IC for cancer cell lines 50 The value is HCT11 6 p53 - / - It is in the range of 70±13nM relative to MiaPaCa2, and 59 The IC50 concentration ranged up to 0.07 ± 5.60 μM. IC50 concentration was obtained for both complexes. 50 The value is IC5 Pancreatic cancer cell lines PSN1 and GBM1 glioblastoma cancer stem cell models with a 0 value of >1 μM Ru 32、33 Except for cancer cells (HT-29, DLD-1, HCT116 (p53 wild) Most of the cells (type and null), BxPC3, A549 and H460 cell lines) were μM untreated. It was full. Cancer stem cells are usually resistant to chemotherapy, 34 Importantly, both In this complex, compared to all three non-cancer cell models, including adult human brain progenitor cells (NP1), In comparison, preferential activity was observed against GBM1 cells. 32、33 However, MiaPa Ca2 pancreatic cancer cell lines are inherently resistant to both complexes, and IC 50 Value > 10 μM This was the case (Figure 7a).

[0373] Characterizing the high selectivity for cancer cells, [L2Cu3] 6+ and [L2Zn3 ] 6+ This is 10 times more effective for most cancer cell lines compared to all three non-cancer cell models. It exceeded (Figures 7b, c). Notably, [L2Zn3] 6+ In this case, exceeding 2000 The selection index was H compared to ARPE-19 non-cancer cells and MCF10A non-cancer cells. CT116 p53 - / - Obtained in the case of cancer cells (Figure 7c). [L2Cu3] 6+ In the case of complexes, the selection index for cancer cell lines is often >100, and [L2Zn3] 6 + The complex's SI value was even higher. However, interestingly, [L2Cu3] 6+ complex The activity of NP1 brain progenitor cells was very similar across three non-cancer cell models, while the activity of NP1 brain progenitor cells was very similar across three non-cancer cell models. 3 2、33 So, Zn 2+ It was shown that the sensitivity to the complex increased.

[0374] Zn 2+ Complex and Cu 2+ The efficacy of the complex (Figure 7a) is similar to that of clinically approved platinum salts. This is preferable compared to the efficacy shown in Figure 7d), and the selectivity of these complexes is the same in v Under the itro experimental conditions, it was significantly superior (Figure 7b, c cf. 6e). On the other hand, Mn 2+ illusion The body exhibited strong cytotoxicity in vitro (Figure 7d), but only moderately against cancer cells. It showed preferential selectivity only (approximately twice as much), comparable to that of platinumate salts (Figure 7e).

[0375] [L2Zn3] at the point of self-assembly before any cell exposure 6+ Complex and [L2Cu3] 6 + The complex contains different specific anions (e.g., PO4) 3- SO4 2- or PhOPO3 2- Encapsulation affected activity and selectivity. The effect was minimal. Includes different anions that have or cause increased or decreased potency depending on the cell line. The results were anion- and cell line-dependent (see Figure 8 and the further results section). For example, [L2Zn3(SO4)] for the PSN1 cell line. 4+ and [L 2Zn3(O3POPh)] 4+ is [L2Zn3(PO4)] 3+ or [L2Zn3 ] 6+ It was significantly more active, compared to the case with the ARPE-19 cell line. This resulted in an improved selection index (Figure 8). A similar but smaller increase in potency was observed in H CT116 p53 + / + It was also observed in (however, it was not observed in the p53 null mutant) (Not done), [L2Zn3(SO4)] 4+ and [L2Zn3(O3POPh)] 4+ in In treated H460 cells, the corresponding relative selectivity increased. In contrast, HT-2 9. [L2Zn3] for DLD-1, BxPC3, and A549 cells 6+ Reduce the activity of The presence of a depressant anion resulted in a corresponding decrease in relative selectivity (Figure 8). Similar results were obtained for PO4 3- SO4 2- or PhOPO3 2- Anion included [L2 Cu3] 6+ The results were also obtained in complexes (see the section on further results). Further investigation is needed to understand the mechanism behind the subsequent effects. However, these results The activity of these complexes provides an inherently flexible platform for drug discovery. By changing the metal and / or anion, it is possible to easily target different cancer cells. It demonstrated that it can be jutoled or potentially "tuned".

[0376] (mechanistic research) Zn 2+ The complex dephosphorylates the amino acids serine, tyrosine, and threonine (Figure 6). Ability and Cu 2+ The complex had the ability to bind to phenyl phosphate (Figure 3). Then, we investigated whether these complexes affect kinase activity. This is because, 33 PA Purified recombinant cells incubated in the presence of TP and a 10 μM complex or solvent control. Using human kinases and substrate peptides, a cell-free screen was created for 140 types of kinases. It was evaluated in this manner. [L2Zn3] 6+ and [L2Cu3] 6+ This involves the activation of multiple kinases. The kinases were inhibited to varying degrees, and the most strongly inhibited kinase was inhibited to nearly 100%. (Figures 9a, b). [L2Cu3] 6+ [L2Zn3] 6+ more kinases It has inhibitory activity against [L2Cu3] 6+ The selection index for [L2Z n3] 6+ This may reflect the fact that the selection index is relatively lower than that for some cases. [L2Zn3] 6+ Or [L2Cu3] 6+ This leads to selective inhibition of specific kinases. (See the further results section.) Across the kinome, [L2Zn3] 6 + Regarding the TK and CAMK families and [L2Cu3] 6+ CA Inhibition of kinases in the MK and AGC families was observed (Figure 10e, f), Further investigation is needed to determine whether this reflects the overall preference of the compound. Regarding the ze, its activity is [L2Cu3] 6+ or [L2Zn3] 6+ This increases (Figure 9c, d) The most notable example is the proto-oncogene Src, a non-receptor tyrosine kinase. That was the case. 35

[0377] i) Direct ATP hydrolysis of complexes (multiple) and kinases for ATP by different Km values Decomposition, and ii) peptide phosphorylation by activated recombinant enzymes and decyclation by their complexes. Zn brings about the oxidation cycle. 2+ Decongestion of peptide substrates by the phosphatase activity of the complex This screen can lead to a "reading" of the kinase inhibition observed, including phosphorylation. There are several potential mechanisms. However, Zn 2+ Complex or Cu 2+ The complex alone is incubable. In the case of β, mass spectrometry showed little to no hydrolysis of ATP (furthermore (See the results section.) Similarly, AMPK is most strongly inhibited by both complexes. Although it is one of the damaged kinases, all complexes are purified phosphorylated AMPK peptide Dephosphorylation was not performed (see the further results section) (Figure 9a, b).

[0378] Alternatives to the observed effects that can be compatible with selective kinase inhibition and activation. The explanation is Zn 2+ Complex and Cu 2+ The complex is the most important regulatory phosphoryl portion of the kinase itself. It modulates the phosphor-site, thereby enhancing or inhibiting kinase activity. It is Zn. 2+ In the case of complexes, specific phosphorylation occurs through their phosphatase activity. Dephosphorylation of regulatory amino acids (Figure 6) can lead to kinase inhibition or activation. Cu 2+ In the case of complexes, the specific ability to bind to phenyl phosphate without hydrolysis is given. It was hypothesized that it could bind to the target phosphorylated amino acids (Figure 3, further results section). See also.) This is related to other proteins (e.g., SH2-domain-containing activation). (or inhibitory protein) 36 By affecting the docking or joining of and It may affect kinase activity through steric or structural effects.

[0379] To further investigate this hypothesis, Zn 2+ Complex or Cu 2+ Recombinant quinine by complex Identification after kinase incubation by kinase screening, AMPK, and Src. We analyzed the regulatory phosphoamino acids of two of the most important kinases. Threonine 172( When AMPKα is phosphorylated with p-T172, AMPK activity 37 [L2Z n3] 6+ Or [L2Cu3] 6+ When AMPK is treated with this method, the molecular weight becomes approximately 63k The p-T172 level detectable by immunoblotting was significantly reduced in Da (Figure 10).

[0380] These results were observed in the kinase screening [L2Zn3] 6+ and [ L2Cu3] 6+ This is consistent with the inhibition of AMPK by (Figures 9a and 9b), but the mechanism is minute. The difference became clear. [L2Cu3] 6+ In this case, the high molecular weight band is >250kDa. However, it was detected by a p-T172-specific Src antibody, and this compound is a phosphoanion molecule (e.g.) For example, consistent with its ability to bind to or encapsulate phenyl phosphate (Figure 3), It was suggested that it binds to the enzyme. On the other hand, [L2Zn3] 6+ This is the p-T172 This results in a clear decrease, and the phosphatase through this phosphorylated amino acid of recombinant AMKPα It did not produce a high molecular weight band consistent with enzyme activity (Figure 6).

[0381] Regarding Src, there are two of the most important regulatory phosphoamino acids, Y527 and Y416. The effect of the complex was tested (Figure 10). Oxidation is known to reduce Src activity, affecting the activation loop of the kinase domain. Autophosphorylation at Y416 increases Src activity. 36、38 Here, [L2Zn3] 6+When recombinant Src is incubated, p -Y527 decreased by approximately 30%, and p-Y416 levels increased by approximately 5 times (Figure 10). When both are combined, as observed in the kinase screen, Src kinase Enhanced activity was expected (Figure 9c, Figure 9d). The decrease in p-Y527 was due to [L2 Zn3] 6+ This was consistent with the selective phosphatase activity of Y527. Dephosphorylation of C Allosteric inhibition of Src kinase activity by the terminal domain is reduced, and S at Y416 Autophosphorylation of rc became possible. 35 Similar to AMPK, [L2C by Src] u3] 6+ When incubated, the control or [L2Zn3] 6+ Not observed during processing As a result, a higher molecular weight band was detected in all Src antibodies, and [L2Cu] was added to Src. 3] 6+ This suggests binding. p-Y416 could not be detected, but this suggests that Sr [L2Cu3] to c 6+ The binding suggested that it could block the detection of this epitope. However, further research has shown how [L2Cu3] to Src 6+ The bond is active It is necessary to elucidate the detailed mechanisms by which this can enhance sexual performance.

[0382] (Selective induction of autophagy and ATP depletion in cancer cells) The kinase screening results were [L2Cu3] 6+ Complex and [L2Zn3] 6+ complex This activates multiple kinases, as well as several others (Figure 9 and further results). See the section. ), and phospho-signaling in cancer. Dysregulation (alling) 31、39 This shows that they can inhibit it, so this means that they It provides a possible mechanism for exhibiting selective activity. Phenotypically, [L2Zn3] 6+ teeth, Autophagy is performed using the established autophagy tracer dye CYTO-ID. This was shown in HCT116 p53 + / + and p53 - / - Appearance of vacuoles in cancer cells This led to it. 40 Mn 2+ The complex also induces autophagy, [L2Cu3] 6+ teeth , it did not induce autophagy (see Figure 11a and the further results section). sea ​​bream.).

[0383] Autophagy is induced in response to metabolic stress, including low ATP levels and starvation. It is a catabolic process that is induced. 37 Zn 2+ Recombination and Mn 2+ Autophagy by complex - Induction leads to cellular ATP depletion caused by the activity of those protein phosphatases, and constitutively active oncogenic kinases 39 Protein phosphorylation by this mechanism and dephosphorylation by complexes. It was hypothesized that this could be due to the repetition of a useless cycle between oxidation and oxidation. Supporting this hypothesis and And, Zn 2+ Recombination and Mn 2+ The complex causes a dose-dependent decrease in ATP levels. (See Figure 11b and ESI.) This is [L2Zn3] 6+ Places to use In total, this is even more evident in HCT116 cancer cells than in ARPE19 non-cancerous cells. Zn 2+ The complex demonstrated cancer-selective ATP depletion that correlated with its superior cancer cell selection index (Figure 7). c) Consistent with the even more moderate selection index, Mn 2+ Complex treatment (further results section) (See the link) AT between HCT116 cancer cells and ARPE19 non-cancer cells The difference in the magnitude of P depletion was smaller (Figure 7d). This is because Mn 2+ The more disordered complex Phosphatase activity or higher hydrolysis rate (see further results section) It may be related to (I want to).

[0384] Immunoblot analysis revealed that autophagy sustains ATP levels as well as [L 2Zn3] 6+ This is a compensatory catabolic response that prevents bioenergy deficiency and death. In HCT116 cancer cells, the "low ATP" sensing kinase AMPK 37 Activation It was suggested that it induces [a certain condition], but not in ARPE19 non-cancer cells (Figure 12). .

[0385] Therefore, the cellular level of AMPKα in p-T172 is [L2Zn3] 6+ by In particular, the total AMPKα level increased in HCT116 cancer cells, but [L2Cu3] 6+ In some cases, it did not increase (Figure 12). T172 AMPKα phosphorylation was associated with low cell A Induced by TP levels, it increases AMP or ADP levels and modulates AMPK gamma This enables competitive binding of AMP / ADP to the subunit, and the AMPK upstream kinase One of these enables AMPKα phosphorylation, and phosphatase access to p-T172. Block the signal. 37 Therefore, paradoxically, [L2Zn3] 6+ is that phosphat Cell-free systems (where ATP is present) (Figures 9a, 10) that correspond to xenzyme activity (Figure 6) This leads to dephosphorylation and kinase inhibition of T172 AMPKα, but also selective ATP depletion. (Figure 11) Increased cellular levels of p-T172 AMPK caused by cancer cells (Figure 12) It was brought about selectively within the group.

[0386] [L2Zn3] in HCT116 cancer cells 6+ After processing, some proteins ( * ) pY There was indeed evidence of an increase (Figure 12), but the overall level of Tyr-phosphorylated proteins A small decrease (approximately 10%) was detected by immunoblotting using panphosphotyrosine antibodies. Detected. Importantly, [L2Cu3] 6+ and [L2Zn3] 6+ Processing The p53 tumor suppressor protein is induced by many different types of cellular stress. The level increases, resulting in appropriate stress that may include cell cycle arrest or induction of cell death. This results in coordinated responses. 41 p53 levels are [L2 Cu3] 6+ The processing increased the amount by approximately 1.7 times, and [L2Zn3] 6+ Depending on the processing The p53 level increased by up to 2.7 times, and in fact, in ARPE19 non-cancer cells treated with the treatment... This further reduced the effect, demonstrating the differential effect of the complex on cancer cells versus non-cancer cells (Figure 12). However, early chemosensibility results indicated that [L2Cu3] 6+ and [L2 Zn3] 6+ The cytotoxicity of p53 is independent, and in fact, both complexes are isogenic p 53 + / + HCT116 p53 from cells - / -It was shown to be more active against cells. (Figure 7a)

[0387] [Further results] Results of chemical sensitivity studies: Figures 13-15 show the efficacy and selection of all evaluated test compounds. This shows the effect of anions on sex. By including an anion, [L2Cu3] 6+ and [L2Zn3] 6+ The effects on efficacy (Figure 13) and selectivity (Figure 14) are enhanced. It decreased, was ineffective, or had no effect. [L2Cu3] 6+ and [L2Zn3] 6+ to The enhancement or reduction of the effect on efficacy and selectivity is strongly cell line-dependent. There was (Figure 15). (For ARPE-19) a particularly significant enhancement of efficacy and selectivity. Cu 2+ and Zn 2+ P treated with ligand plus sulfate and phenyl anion phosphate SN1 and HCT116 p53 + / + We observed the cells. In response to this, BxPC Cu against 3 cells 2+ The efficacy of the ligand plus phenyl anion phosphate was significantly reduced, As a result, this led to decreased selectivity compared to ARPE-19 cells. Different effects were also observed, Cu 2+ Regarding ligands, by including anions... Only a slight effect was observed (against ARPE-19 and MCF10A cells), Z n 2+ In the case of ligands, their activity was significantly reduced in the presence of all the anions tested. This resulted in a relative loss of selectivity (Figure 15). This affected the activity and selection of the complex. Selectivity is likely a factor in the specific kinase inhibitory activity and subsequent effects on quinomes. By modulating cell line-dependent sensitivity, it is possible to create formulations tailored to individual cell lines. This was suggested.

[0388] Inhibition of kinase activity: Figure 16 shows the [L2] inhibition of the activity of 140 human recombinant kinases. Cu3] 6+ and [L2Zn3] 6+ It exhibits the effect of both compounds, which are multitarget kinases. It is an inhibitor, and visually, [L2Cu3] 6+ and [L2Zn3] 6+ Inhibited by There are clear differences among the kinases, [L2Cu3] 6+ However, [L2Zn3] 6+ more It inhibited the kinase more significantly. Depending on the difference present, different spectra of inhibitory activity were observed. Evidence of selectivity has shown its existence. Interestingly, these results suggest that That is, the activity of some kinases increases after drug treatment, and in particular, the stimulation of kinase activity is significant. Enhancement after Src observed in their cell-free assay was demonstrated.

[0389] Autophagy research: Figures 17-19 show HCT116 p53. - / - HCT116 p53 + / + and the induction of cell vacuoles and autophagy in ARPE19 cells 3.125 μM [L2Cu3] 6+ [L2Zn3] 6+ and [L2Mn3] 6+ Osamu Representative cell images are shown to illustrate the effects of the treatment (40 hours). At this concentration, autophagy occurs. The induction is [L2Mn3] 6+ Processed HCT116 p53 - / - The brightest in cells It is white, and it contains [L2Zn3] 6+ This continues, and autophagy is [L2Cu3]6+ by Furthermore, induction was not observed or was barely observed compared to vehicle control-treated cells (Figure) 17). HCT116 p53 + / + In cells, autophagy induction is [L2Mn3 ] 6+ This was also evident in cells treated with HCT116 p53. - / - Compared to the case in cells, at this concentration [L2Zn3] 6+ Processed by It was hardly detectable in cells (Figure 18). This is because [L2Zn3] 6+ However, 96 hours Interchange 50 Based on the values, HCT116 p53 + / + HCT116 p53 from cells - / - This is consistent with approximately 6 times the activity against cells. In ARPE19 cells, autof Azithromycin levels were low in all treatments, and the basal level was lower in cells treated with the control. Similar to Ru (Figure 19).

[0390] Cellular ATP research: Figure 20 shows HCT116 p53 + / + Cells and ARPE19 cells [L2Cu3] relative to the total cellular ATP level within the cell 6+ [L2Zn3] 6+ and [L2 Mn3] 6+ The effects of 20-hour treatment at various different concentrations are shown. Depending on the metal in the complex A differential effect was observed, [L2Mn3] 6+ HCT116 p53 + / + Cancer cells It showed the most significant effect against cysts and ARPE19 non-cancerous cells. 6. (20 hours) 25 μM [L2Mn3] 6+ Through processing, HCT116 p53 + / + A in cancer cells TP levels decreased to <50%, and ATP levels were small and low in ARPE19 non-cancer cells. I took it, but 100 μM [L2Mn3] 6+ The processing reduced it to approximately 40%. [L2Zn 3] 6+ Also, HCT116 p53 + / + It lowers ATP levels in cancer cells, Bell stated ≥25μM[L2Zn3] 6+ At this concentration, the concentration decreased to <50%, and ARPE19 cells The ATP level is 100 μM [L2Zn3] 6 The processing remained at >70%. A [L2Cu3] for TP level 6+ The effect is much less, in HCT116 cells The ATP level decreased to <50% only at the highest concentration of 100 μM. [summary]

[0391] In summary, in this study, three different metal-containing, self-assembled anionic complexes were found to be It is characterized by having unique chemical and biological properties, and possessing these properties It is shown that the reactivity of the complex to different anion species varies depending on the metal, Z n 2+ Recombination and Mn 2+ All of the complexes show significant phosphatase activity, but hydrolysis The speeds differ (Mn 2+ >> Zn 2+ ), on the other hand, Cu 2+ The complex is hydrolyzed. It did not bind to phospho-containing species. Compared to non-cancer cells, it was found to bind to certain cancer cells. Remarkable selective activity is observed when either one of the bindings (Cu 2+ ) via or regulation on kinases Dephosphorylation of the site (Zn 2+ ) modulates multiple kinases through different mechanisms riZn 2+ Complex and Cu2+ This was shown by the complex. Zn 2+ Recombination and Mn 2+ complex This is a result of the futile pathway of rephosphorylation by their phosphatase activity and oncogenic kinases. Cancer cell autophagy is associated with cellular ATP deficiency and lack of bioenergy. This induced different anions (e.g., PO4) before cell exposure. 3- SO4 2- or Ph OPO3 2- Further modulation of the activity and selectivity profile through the uptake of ) is possible for disease Numerical values ​​of metal / anion bonded self-assembly complexes that may differ in efficacy, selectivity, and generation mechanism. This demonstrates the ease of generating numeromodular combinations.

[0392] <Part B> [overview] [L2Cu3] 6+ and [L2Zn3] 6+ chicken embryo chorionic allanic acid (CAM) Three different human cancer cell line models (H460, HT29, HCT116) were used in the study. Regarding in ovo anticancer activity, toxicity, and antimetastatic activity against tumors initiated from The effects were evaluated at three different dosage levels.

[0393] [Methodology] Each compound was stored in a single vial (2 equivalents of ligand, 3 equivalents of metal; and stored at room temperature). The powder, which was pre-weighed inside, was used by a contract research organization (CRO) conducting in ovo research. It was provided to ovotion (La Tronche, France). Then, before use... This is then dissolved in DMSO to 50 mM to produce the stock solution, and further, RPMI1 for administration is added. The solution was freshly diluted in 640 medium or McCoys aqueous cell culture medium.

[0394] Standard of Care (SoC) drugs for a specific tumor type, in vivo efficacy and toxicity The solvent control was tested simultaneously as a comparative measure for evaluation. This was used as a negative control.

[0395] 10 6 Individual tumor cells (H460, HT29, or HCT116) were introduced on embryonic day 9 (E 9) It was transplanted into the chorioalangiocarcinoma (CAM) at the top of developing chicken embryos. White Leghophyll was transplanted into E9. To make a small hole (in the air sac) in the eggshell of a White Leghorn fertilized egg. Therefore, the upper CAM was accessed (15 eggs per experimental group).

[0396] E11, E13, E15, and E17 contain newly prepared experimental compounds and vehicle controls. Alternatively, 100 μl of standard therapeutic (SoC) drugs are pipetteed onto the tumor graft at their effective concentrations. On day E18, the upper CAM (containing the tumor) was removed and washed with PBS buffer. Next, the tumor was directly transferred during PFA (fixed for 48 hours). After that, the tumor was transferred to normal CAM tissue or Then, it was carefully cut and weighed.

[0397] Embryo survival rates were checked daily. The number of dead embryos was counted in E18 and treated accordingly. The induced embryotoxicity was evaluated.

[0398] On day 18 of E, a low CAM of 1 cm 2 The minutes were collected (n=8 per group) and stored at -20°C. The samples were stored and then processed to extract DNA. This was used as a quantitative marker for tumor metastasis to low CAM. The samples were then analyzed for human genomic DNA (qPCR for Alu sequences).

[0399] [result] (1) In vivo efficacy against tumors initiated from human lung cancer cell line H460) (H460 tumor growth reduction) Statistically significant regression of tumor growth (determined by mean tumor weight at E18 at the end of this study) (As is the case) [L2Zn3] 6+ In this case, it was observed at all three test doses, [L2 Cu3] 6+ In this case, it was observed at two different highest test doses (Figure 21). [L2Zn3] 6 + All three test doses and [L2Cu3] 6+ Tumor growth at the highest dose The reduction in performance was comparable to that achieved with the SoC.

[0400] (Analysis of anti-transfer activity) A statistically significant decrease in the H460 metastatic load was observed in [L2Zn3] 6+ of Observed at all three dosage levels, with the decrease at the highest dosage observed by SoC. It was comparable to the result obtained (Figure 22). However, [L2Cu3] in three different test doses ] 6+ There was no statistically significant metastatic regression by [L2Cu 3] 6+ and [L2Zn3] 6+ This demonstrated a differential effect.

[0401] (Embryotoxicity analysis) Regarding toxicity, [L2Cu3] 6+ and [L2Zn3] 6+ all test doses It was well-tolerated, and no statistically significant difference was observed compared to the solvent (negative) control group. Table 1).

[0402] [Table 1]

[0403] (Summary (H460 Tumor)) Overall, these results suggest that [L2Cu3] 6+ and [L2Zn3] 6+ Hasu The test dose showed good tolerability, and [L2Zn3] 6+ This is a primary H460 tumor. In terms of reducing both weight and transfer load, it is comparable to an SoC in ovo. It has been shown to have anti-cancer efficacy. [L2Cu3] 6+ In this case, the highest test dose Therefore, we observed anticancer activity comparable to SoC in the reduction of H460 tumor weight, but statistically, No significant metastatic regression was observed.

[0404] Therefore, validate the anticancer activity and selectivity observed in vitro. The first evidence of the in vivo efficacy of these compounds (at unoptimized dosages) has been shown. The absence of observed embryotoxicity led to the study of higher doses (compared to SoC). This suggests that the potential improvement in in vivo efficacy is justified.

[0405] (2. In vivo efficacy against tumors initiated from the human colon cancer cell line HT29) (Reduced tumor growth in HT29) Statistically significant regression of tumor growth (determined by mean tumor weight at E18 at the end of this study) (As is the case) [L2Zn3] 6+ and [L2Cu3] 6+ In that case, the highest test This was observed at the dose level, and it was comparable to that obtained by SoC (Figure 23).

[0406] (Analysis of anti-transfer activity) Even with SoCs, [L2Cu3] 6+ and [L2Zn3]6+ Even at the test dose, low CA There was no reduction in HT29 tumor cell metastasis to M (data not shown).

[0407] (Embryotoxicity analysis) [L2Cu3] 6+ and [L2Zn3] 6+ It was transplanted using HT29 colon cancer cells. The drug was well-tolerated in chicken embryos and did not show increased embryotoxicity even with dose escalation (Table 2). ).

[0408] [Table 2]

[0409] (Summary (HT29 tumors)) Overall, these results suggest that [L2Cu3] 6+ and [L2Zn3] 6+ Hasu The test dose showed good tolerability, and [L2Cu3] 6+ and [L2Zn3] 6+ At the highest test dose, it reduced tumor weight to a level similar to that shown by SoC. This was shown to be effective against the second tumor type (colorectal cancer). Further evidence of the in vivo efficacy of these compounds (at doses not shown) has been demonstrated, i The anticancer activity and selectivity observed in vitro were further validated. Due to the lack of embryotoxicity, higher dose trials were conducted (compared to SoC and antitransferase activity). This suggests that it justifies the potential improvement in vivo efficacy.

[0410] (3) In vivo efficacy against tumors initiated from the human colon cancer cell line HCT116 sex) (HCT116 tumor growth reduction) The effect was not as clear as that obtained with SoC, but HCT116 tumor growth Statistically significant regression (as determined by the mean tumor weight at E18 at the end of this study) [L2Zn3] 6+ In this case, two different maximum test doses and [L2Cu3] 6+ Case 3 This was observed at all test doses across the street (Figure 24).

[0411] (Analysis of anti-transfer activity) A decrease in HCT116 transition amount comparable to that observed by SoC was observed in [L2Zn3 ] 6+ This was observed at all three dosage levels (Figure 25).

[0412] (Embryotoxicity analysis) Regarding embryotoxicity, L2Zn3 and L2Cu3 were well-tolerated at all test doses. No statistically significant difference was observed compared to the solvent (negative) control group (Table 3).

[0413] [Table 3]

[0414] (Summary (HCT116 tumor)) Based on the results, [L2Cu3] 6+ and [L2Zn3] 6+ It was tolerable at all test doses. It has good capacity, [L2Zn3] 6+ [L2Cu3] was found at two different maximum test doses. 6+ of In this case, all three dosage levels were shown to result in statistically significant regression of tumor growth. Regarding metastatic invasion, none of the conditions induce a significant regression in the amount of metastasis. However, S A strong regression tendency, similar to that obtained by oC, was observed in [L2Zn3]. 6+ (All administrations) This was observed in the case of (amount). This indicates that these compounds (at unoptimized dosages) Further evidence of in vivo efficacy was presented. The absence of observed embryotoxicity suggests a higher level of efficacy. The dosage trials showed (potential in vivo efficacy and anti-transfer activity compared to SoC) It was suggested that the improvements were justified.

[0415] [Conclusion] [L2Cu3] 6+ and [L2Zn3] 6+ chicken embryo chorionic allanic acid (CAM) Three different human cancer cell line models (H460, HT29, HCT116) were used in the study. Regarding the in vivo anticancer activity against tumors initiated from (their in vi tro IC 50 Three unoptimized dosages (based on values) were tested for each tumor model. For [L2Cu3] 6+ and [L2Zn3] 6+ And the tumor growth was statistically significant. Significant regression was observed, and the effect was most evident in the H460 lung cancer model (Figure 21). [L2Zn3] 6+ In this case, the SoC is comparable to that of the H460 and HT29 models. This was achieved (Figures 21 and 23). In the H460 and HCT116 models, the SoC... [L2Zn3] exhibits an antitransition effect comparable to that obtained. 6+ In that case, it was also observed. (Figures 22, 25). These results indicate that (of particular note is the H460 lung cancer variant) In vivo anticancer efficacy in three different models (to varying degrees) relative to seed grafts The first proof of concept of [L2Cu3] was demonstrated. 6+ and [L2Zn3] 6+ The test dose It was very well tolerated at the dose (no statistically significant embryonic lethality), and further dose escalation and the final dose were observed. It is important to note that this indicates room for optimization.

[0416] Specific embodiments of the present invention have been described herein for reference and illustrative purposes, Various modifications may be made without departing from the scope of the present invention as defined by the attached claims. This will be obvious to those skilled in the art.

[0417] [References] 1 Matsumoto, Y. et al. A landmark in dru g discovery based on complex natural pro duct synthesis. Sci Rep. 9, 8656 (2019). 2 Lehn, J. “Supramolecular Chemistry”. Science. 260, 1762-23 (1993). 3 Lehn, J.M. “Perspectives in Supramole cular Chemistry-From Molecular Recogniti on towards Molecular Information Process Angew Chem I nt Ed. 29, 1304-1319 (1990). 4 Lehn, J.-M., Supramolecular Chemistry, VCH, Weinheim (1995). 5 Steed, JW, Atwood, JL, Supramole cular Chemistry, John Wiley and Sons, Ch ichester (2000) 6 Hannon, M. J. & Childs, L. J. Helices and helicates: beautiful supramolecular motifs with emerging applications. Supra mol. Chem. 16, 7 - 22 (2004). 7 Albrecht, M. “Let’s twist again” doubl e-stranded, triple-stranded, and circula r helicates. Chem. Rev. 1...

Claims

1. Formula I below for use as a pharmaceutical: 【Chemistry 1】 [In the formula, R １ N, CR ２ aryl, heteroaryl, carbocykrill and heterocyclyl Selected from the group consisting of R, １ Any aryl, heteroaryl, or carbocykrill inside Alternatively, heterocyclyl may have one or more R ３ It may be replaced in some cases; Each R ３ These are independently hydroxy, cyano, halogen, (1-4C) alkyl, (1- 4C) Haloalkyl, (2-4C) Alkenyl, (2-4C) Alkinyl, Aryl, A Reel(1-3C)alkyl, heteroaryl, heteroaryl(1-3C)alkyl, Carbocyclyl, carbocyclyl(1-3C) alkyl, heterocyclyl, heterocyclyl le (1-3C)alkyl, -OR ３ａ , -NR ３ａ R ３ｂ , -C(O)-R ３ａ , -C( O)-OR ３ａ 、-O-C(O)-R ３ａ 、-C(O)-NR ３ａ R ３ｂ 、-N(R ３ａ ) C(O)-R ３ｂ and -S(O) ０－２ R ３ａ Selected from the group consisting of R ３ Internal position (1-4C) alkyl, (1-4C) haloalkyl, (2-4C) alkenyl, (2 ~4C) Alkynyl, aryl, aryl(1-3C) alkyl, heteroaryl, hetero Roaryl (1-3C) alkyl, carbocyrill, carbocyrill (1-3C) alkyl R, heterocyclyl, or heterocyclyl (1-3C) alkyl is one or more R ３ｃ It may be replaced in some cases; R ３ａ and R ３ｂ These are, independently, hydrogen, (1-3C) alkyl and (1- 3C) Selected from the group consisting of haloalkyl; Each R ３ｃ These are independently hydroxy, halogen, cyano, amino, and (1-3C) alkyl groups. Selected from the group consisting of (1-3C)alkoxy and (1-3C)haloalkyl; R ２ These are hydrogen, hydroxyl, cyano, halogen, (1-4C) alkyl, (1-4C) Haloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, aryl, aryl (1-3C) alkyl, heteroaryl, heteroaryl(1-3C) alkyl, carbo Cyclyl, Carbocyclyl(1-3C) alkyl, Heterocyclyl, Heterocyclyl(1 ~3C) alkyl, -OR ２ａ , -NR ２ａ R ２ｂ , -C(O)-R ２ａ , -C(O)- OR ２ａ 、-O-C(O)-R ２ａ 、-C(O)-NR ２ａ R ２ｂ 、-N(R ２ａ )C( O)-R ２ｂ and -S(O) ０－２ R ９ａ Selected from the group consisting of R ２ Any ( (1-4C) alkyl, (1-4C) haloalkyl, (2-4C) alkenyl, (2-4C ) Alkynyl, aryl, aryl(1-3C)alkyl, heteroaryl, heteroaryl Alkyl (1-3C) alkyl, carbocyrill, carbocyrill (1-3C) alkyl, Telocyryl or heterocyclyl(1-3C)alkyl is one or more R ２ｃ in Substituted depending on the circumstances; R ２ａ and R ２ｂ These are, independently, hydrogen, (1-3C) alkyl and (1- 3C) Selected from the group consisting of haloalkyl; Each R ２ｃ These are independently hydroxy, halogen, cyano, amino, and (1-3C) alkyl groups. Selected from the group consisting of (1-3C)alkoxy and (1-3C)haloalkyl; Each L １ teeth, - (W) ｎ - (X) ｍ - (Y) ｏ - (Z) ｐ - It is a base, n and o are independently 0, 1, or 2, and m and p are independently Independently, o is either 0 or 1, provided that when both m and p are 1, o is 0 Not; Each W is (1-3C) alkylene, (2-3C) alkenylene, (2-3C) alky From nilen, allerene, heteroarrene, carbocyclylene and heterocyclylene Selected from the group, any (1-3C)alkylene and (2-3C)alkene in W. , (2-3C) alkynylene, arylene, heteroarylene, carbocyrylene or Heterocyclylene is one or more W ａ It is replaced depending on the case, and each W ａ Independently hydroxy, cyano, halogen, amino, (1-2)alkoxy and (1-2C)halogen Selected from the group consisting of r-alkyl groups; Xは、-O-、-C(O)-、-C(O)-O-、-O-C(O)-、-S(O) ０ －２ -、-C(O)-N(R ｘ )-、-N(R ｘ )-C(O)-、-NR ｘ -、-N(R ｘ )-C(O)-NR ｘ -, -SO ２ N(R) ｘ )-, and -N(R ｘ ) SO ２ Consists of Selected from the group, each R ｘ These are hydrogen, hydroxyl, cyano, (1-4C) alkyl, (2- Independently selected from the group consisting of 4C) alkenyls and (2-4C) alkinyls; Each Y is (1-3C) alkylene, (2-3C) alkenylene, (2-3C) alky From nilen, allerene, heteroarrene, carbocyclylene and heterocyclylene Selected from the group, any (1-3C)alkylene and (2-3C)alkene in Y , (2-3C) alkynylene, arylene, heteroarylene, carbocyrylene or Heterocyclylene is one or more Y ａ Depending on the case, it may be replaced, and each Y ａ Independently hydroxy, cyano, halogen, amino, (1-2)alkoxy and (1-2C)halogen Selected from the group consisting of r-alkyl groups; Zは、-O-、-C(O)-、-C(O)-O-、-O-C(O)-、-S(O) ０ －２ -、-C(O)-N(R ｚ )-、-N(R ｚ )-C(O)-、-NR ｚ -、-N(R ｚ )-C(O)-NR ｚ -, -SO ２ N(R) ｚ )-, and -N(R ｚ ) SO ２ Consists of Selected from the group, each R ｚ These are independently hydrogen, hydroxyl, cyano, and (1-4C) alkyl groups. Selected from the group consisting of , (2-4C)alkenyl and (2-4C)alkinyl; X ａ is a ring heteroatom located within the A ring, selected from N and O; Each A ring is a monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocyclic, or bicyclic. It is a heterocycle, and any one of them is one or more R ４ It may be replaced in some cases. , each R ４ These are independently hydroxy, cyano, halogen, (1-6C) alkyl, (1- 6C) Haloalkyl, (2-6C) Alkenyl, (2-6C) Alkinyl, Aryl, A Reel(1-3C)alkyl, heteroaryl, heteroaryl(1-3C)alkyl, Carbocyclyl, carbocyclyl(1-3C) alkyl, heterocyclyl, heterocyclyl (1-3C) alkyl, -R ４ａ -OR ４ｂ , -R ４ａ -NR ４ｂ R ４ｃ , -R ４ａ - C(O)-R ４ｂ 、-R ４ａ -C(O)-OR ４ｂ 、-R ４ａ -O-C(O)-R ４ｂ 、 -R ４ａ -C(O)-NR ４ｂ R ４ｃ , -R ４ａ -N(R ４ｂ )C(O)-R ４ｃ and -R ４ａ -S(O) ０－２ R ４ｂ is selected from the group consisting of, R ４ any (1-6C) in Alkyl, (1-6C)haloalkyl, (2-6C)alkenyl, (2-6C)alkini aryl, aryl(1-3C)alkyl, heteroaryl, heteroaryl(1- 3C) alkyl, carbocyrill, carbocyrill (1-3C) alkyl, heterocyclyl R or heterocyclyl(1-3C) alkyl is one or more R ４ｄ Depending on the circumstances Replaced; R ４ａ It is either absent or selected from the group consisting of hydroxy, halo, and amino. It is a (1-3C) alkylene which is substituted with one or optionally with a substituent; R ４ｂ and R ４ｃ These are, independently, hydrogen, (1-3C) alkyl and (1- 3C) Selected from the group consisting of haloalkyl; Each R ４ｄ These are independently hydroxy, halogen, cyano, amino, and (1-3C) alkyl groups. Selected from the group consisting of (1-3C)alkoxy and (1-3C)haloalkyl; X ｂ It is a ring heteroatom located within the B ring, selected from N and O. Each B ring is a monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocyclic, or bicyclic. It is a heterocycle, and any one of them is one or more R ５ It may be replaced in some cases. , each R ５ These are independently hydroxy, cyano, halogen, (1-6C) alkyl, (1- 6C) Haloalkyl, (2-6C) Alkenyl, (2-6C) Alkinyl, Aryl, A Reel(1-3C)alkyl, heteroaryl, heteroaryl(1-3C)alkyl, Carbocyclyl, carbocyclyl(1-3C) alkyl, heterocyclyl, heterocyclyl (1-3C) alkyl, -R ５ａ -OR ５ｂ , -R ５ａ -NR ５ｂ R ５ｃ , -R ５ａ - C(O)-R ５ｂ 、-R ５ａ -C(O)-OR ５ｂ 、-R ５ａ -O-C(O)-R ５ｂ 、 -R ５ａ -C(O)-NR ５ｂ R ５ｃ , -R ５ａ -N(R) ５ｂ ) C(O)-R ５ｃ and -R ５ａ -S(O) ０－２ R ５ｂ Selected from the group consisting of R ５ Any of the (1-6C) inside Alkyl, (1-6C)haloalkyl, (2-6C)alkenyl, (2-6C)alkini aryl, aryl(1-3C)alkyl, heteroaryl, heteroaryl(1- 3C) alkyl, carbocyrill, carbocyrill (1-3C) alkyl, heterocyclyl R or heterocyclyl(1-3C) alkyl is one or more R ５ｄ Depending on the circumstances Replaced; R ５ａ It is either absent or selected from the group consisting of hydroxy, halo, and amino. It is a (1-3C) alkylene which is substituted with one or optionally with a substituent; R ５ｂ and R ５ｃ Each is independently hydrogen, (1-5C) alkyl (for example, ( Selected from the group consisting of (1-3C)alkyl and (1-3C)haloalkyl; Each R ５ｄ These are independently hydroxy, halogen, cyano, amino, and (1-3C) alkyl groups. Selected from the group consisting of (1-3C)alkoxy and (1-3C)haloalkyl; Each L ２ is non-existent (in this case, ring A is directly bonded to ring B), (1-2C) alkyl Selected from the group consisting of , ethenylene and ethinylene, L ２ Any (1-2C) inside Alkylene, ethenylene, and ethynylene are hydroxy, halogen, cyano, amino, (1-3C)alkyl, (1-3C)alkoxy, and (1-3C)haloalkyl It may be substituted with one or more substituents selected from the group. Compounds having the structure of, or pharmaceutically acceptable salts, hydrates, or solvates thereof And, The compound of formula I, or the pharmaceutically acceptable salt, hydrate, or solvate thereof It is intended for use in combination with a source of M, where M is Zn ２＋ Mn ２＋ , C u ２＋ Fe ２＋ Co ２＋ and Ni ２＋ A compound selected from the group consisting of, A pharmaceutically acceptable salt, hydrate, or solvate thereof.

2. Each A ring independently has a total of 1, 2, or 3 ring heterogeneities selected from N, O, and S. A 5-6 member monocyclic heteroaryl containing an O atom, or independently composed of N, O, and S Selected monocyclic heterocycles containing a total of 1, 2, or 3 ring heteroatoms, comprising 5-6 membered rings. Each A ring is one or more R ４ It may be replaced in some cases. X ａ However, L １ The use of the carbon atom bonded to the carbon atom as described in claim 1 Compounds, pharmaceutically acceptable salts, hydrates, or solvates for this purpose.

3. Each B ring, i) A total of one, two, or three ring heterogenities independently selected from N, O, and S. A monocyclic heterocycle with 5-6 members containing a child; ii) A total of one, two, or three ring heterozygotes independently selected from N, O, and S. A monocyclic heteroaryl with 5-6 members containing an atom; iii) A total of 1, 2, or 3 ring hetes independently selected from N, O, and S A 9-10 member bicyclic heterocycle containing a 10-member atom; or iv) One, two, or three ring heterozygotes, independently selected from N, O, and S. 9-10 membered bicyclic heteroaryls containing atoms And, Any ring in B is one or more R ５ It may be replaced in some cases. X ｂ However, L ２ The carbon atom bonded to the carbon atom is located directly adjacent to it, as described in claim 1 or 2. Compounds, pharmaceutically acceptable salts, hydrates, or solvates for use.

4. Each A ring is based on the following: 【Chemistry 2】 [wherein a is 0 or 1.] The use according to any one of claims 1 to 3 Compounds, pharmaceutically acceptable salts, hydrates, or solvates for use in the field.

5. Each B ring is based on the following: 【Transformation 3】 [In the formula, b １ is 0, 1, or 2, b ２ is 0, 1, 2, or 3. ] one of claims 1 to 4 Compounds, pharmaceutically acceptable salts, hydrates, or solvates for use as described in any one of the items. thing.

6. Each W is selected from the group consisting of (1-3C)alkylene or phenylene, and the unit in W The (1-3C) alkylene or phenylene is one or more W ａ Depending on the situation, place Replaced; X is -C(O)-N(R ｘ )-,-N(R ｘ )-C(O)- and -NR ｘ - from Selected from the group; Each Y is selected from the group consisting of (1-3C) alkylenes or phenylenes, and one of the Y The (1-3C) alkylene or phenylene is one or more Y ａ Depending on the situation, place Replaced; Z is -C(O)-N(R ｚ )-,-N(R ｚ )-C(O)- and -NR ｚ - from A compound for use according to any one of claims 1 to 5, selected from the group, pharmaceutical A salt, hydrate, or solvate that is permissible.

7. n is 0 or 1, and W is a group consisting of (1-3C)alkylene or phenylene. Selected from, any (1-3C) alkylene or phenylene in W, one or more The number W ａ It is replaced depending on the case, and each W ａ However, independently, hydroxyl, halogen, (1-2 Selected from the group consisting of alkoxys and (1-2C)haloalkyls; m is 0; The group in which o is 0 or 1 and Y consists of (1-3C) alkylene or phenylene. Selected from, any (1-3C) alkylene or phenylene in Y, one or more The number Y ａ Depending on the case, it may be replaced, and each Y ａ However, independently, hydroxyl, halogen, (1-2 Selected from the group consisting of alkoxys and (1-2C)haloalkyls; p is 1, and Z is -NR ｚ - and R ｚ However, it is hydrogen, any of claims 1 to 6 A compound, pharmaceutically acceptable salt, hydrate, or solvate for use as described in any one of the items.

8. n is 0 or 1, and W is a group consisting of (1-3C)alkylene or phenylene. Selected from, any (1-3C) alkylene or phenylene in W, one or more The number W ａ It is replaced depending on the case, and each W ａ However, independently, hydroxyl, halogen, (1-2 Selected from the group consisting of alkoxys and (1-2C)haloalkyls; m is 0; The group in which o is 0 or 1 and Y consists of (1-3C) alkylene or phenylene. Selected from, any (1-3C) alkylene or phenylene in Y, one or more The number Y ａ Depending on the case, it may be replaced, and each Y ａ However, independently, hydroxyl, halogen, (1-2 Selected from the group consisting of alkoxys and (1-2C)haloalkyls; p is 1, and Z is -NR ｚ - and R ｚ However, it is hydrogen, any of claims 1 to 7 A compound, pharmaceutically acceptable salt, hydrate, or solvate for use as described in any one of the items.

9. L １ However, the following: 【Chemistry 4】 Having any one of the structures described in any one of claims 1 to 8, for use according to any one of claims 1 to 8 Compounds, pharmaceutically acceptable salts, hydrates, or solvates thereof.

10. L ２ However, selected from the group consisting of non-existent and (1-2C)alkylenes, L ２ any The (1-2C)alkylene is hydroxy, halogen, and (1-2C) haloalkyl. Claim 1, optionally substituted with one or more substituents selected from the group. Compounds, pharmaceutically acceptable salts, hydrates or Solvate.

11. R １ However, N, CR ２ Selected from the group consisting of phenyl and cyclohexyl, R １ Medium Any phenyl or cyclohexyl is one or more R ３ It may be replaced in some cases. ； Each R ３ However, independently, hydroxy, halogen, (1-4C)alkyl, (1-4C) Roalkyl and -OR ３ａ Selected from the group consisting of R ３ Any (1-4C) inside Kill or (1-4C) haloalkyl, one or more R ３ｃ It may be replaced in some cases. ； R ２ However, R is selected from the group consisting of hydrogen and (1-3C)alkyl. ２ any inside (1-4C) alkyl groups, one or more R ２ｃ Claims which are replaced in some cases Compounds for use as described in any one of items 1 to 10, pharmaceutically acceptable salts, hydrates, etc. or solvates.

12. R １ However, the following: 【Transformation 5】 Having one of the structures described in any one of claims 1 to 11, for use according to any one of claims 1 to 11 Compounds, pharmaceutically acceptable salts, hydrates, or solvates.

13. R ５ｂ and R ５ｃ However, each is independent of hydrogen, (1-3C)alkyl and (1- 3C) Selected from the group consisting of haloalkyls, according to any one of claims 1 to 12 Compounds for use, pharmaceutically acceptable salts, hydrates, or solvates.

14. M is Zn ２＋ ,Cd ２＋ Mn ２＋ and Fe ２＋ A request selected from the group consisting of Compounds, pharmaceutically acceptable salts, or hydrates for use as described in any one of items 1 to 13. Or a solvate.

15. The compound of formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, Q Further combined with the source of Q, Q is a spherical monoanionic anion, a planar triangular anion dianionic tetrahedron anion, trianionic tetrahedron anion, dianionic octahedron An anion selected from the group consisting of anions and trianionic octahedral anions. , compounds for use according to any one of claims 1 to 14, pharmaceutically acceptable salts, Hydrate or solvate.

16. Q is a dianionic tetrahedral oxoanion and a trianionic tetrahedral oxoanion. A compound for use according to claim 15, which is an anion selected from the group consisting of the following: A pharmaceutically acceptable salt, hydrate, or solvate.

17. Q is sulfate (SO ４ ２－ ), phosphate (PO ４ ３－ ) or organophosphates (for example, A compound, drug, for use according to claim 15 or 16, which is monophenyl phosphate. A scientifically acceptable salt, hydrate, or solvate.

18. The compound of formula I is as follows: 【Transformation 6】 【change】 Any one of these structures, or a pharmaceutically acceptable salt, hydrate, and / or A compound for use according to any one of claims 1 to 17, having a solvate, pharmaceutically A salt, hydrate, or solvate that is permissible.

19. The compound of formula I has the following structure: 【Transformation 7】 Claim 1, or having a pharmaceutically acceptable salt, hydrate and / or solvate thereof. Compounds for use as described in any one of items ~18, pharmaceutically acceptable salts, hydrates or It is a solvate.

20. Formula II below for use as a pharmaceutical: 【Transformation 8】 [In the formula, M, R １ , L １ A, X ａ , L ２ , B, X ｂ And any related subgroups, please A compound having the structure defined in any one of the requirements 1 to 19, and This refers to its pharmaceutically acceptable salt, hydrate, or solvate.

21. The compound of formula II, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, Further combined with a source of Q as defined in any one of claims 15 to 17 The compounds, pharmaceutically acceptable salts, hydrates or Solvate.

22. The compound of formula II is as follows: 【Chemistry 9】 Any one of the structures, or a pharmaceutically acceptable salt, hydrate, and / or The compound, pharmaceutically acceptable, has a solvate, for use according to claim 20 or 21. A salt, hydrate, or solvate that is accepted.

23. For use as a pharmaceutical product, the following formula III 【Chemistry 10】 [In the formula, M, Q, R １ , L １ A, X ａ , L ２ , B, X ｂ and any related subgroups , as defined in any one of claims 1 to 19. A compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

24. The compound of formula III is as follows: 【Chemistry 11】 Any one of the structures, or a pharmaceutically acceptable salt, hydrate, and / or A compound, pharmaceutically acceptable salt, having a solvate, for use according to claim 23. , hydrate or solvate.

25. Claims 1-2, wherein the pharmaceutical product is for the treatment of proliferative disorders (e.g., cancer). Compounds, pharmaceutically acceptable salts, hydrates, or solutions for use as described in any one of paragraphs 4. medium.

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