Radiopharmaceutical composition targeting carbonic anhydrase IX and its use

Abstract

Conjugates and compositions targeting carbonic anhydrase IX, as well as their uses, are described herein. The conjugates and compositions of the present invention are useful in the treatment of cancer.

Description

[Technical Field]

[0001] cross reference This application claims the interests of U.S. Provisional Patent Application No. 63 / 499,666, filed on 2 May 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] The expression of characteristic proteins on the surface of tumor cells provides an opportunity to diagnose or characterize the disease by exploring the phenotypic identity of the tumor, as well as its biochemical composition and activity. Radiomolecules that selectively bind to specific tumor cell surface proteins enable the use of non-invasive imaging techniques such as molecular imaging or nuclear medicine to detect the presence and quantity of tumor-associated proteins, thereby providing crucial information regarding the diagnosis and extent of the disease, prognosis, and treatment management options. Furthermore, it is possible to prepare radiopharmaceuticals that can not only image the disease but also deliver therapeutic radionuclides to affected tissues, thereby enabling treatment, particularly cancer treatment. Selective expression of CA-IX on tumors in response to hypoxia makes it an attractive target for use in non-invasive imaging and targeted radiotherapy.

[0003] To grow to a diameter of several millimeters or more, tumor micrometastases need an oxygen supply to maintain the high metabolic rate characteristic of rapid growth, and they do so by inducing the formation of new blood vessels. The distance between tumor cells and blood vessels is inversely proportional to the oxygen pressure of the tumor. Even if angiogenesis occurs and blood supply is established, the internal regions of the growing tumor mass with fewer blood vessels remain hypoxic and eventually lead to necrosis.

[0004] Hypoxia is associated with poor response to radiotherapy and leads to tumor resistance. Since oxygen is necessary for the cytotoxic effects of free radicals generated by radiation, higher, often inappropriate, levels of radiation are required to promote damage to tumors. Therefore, non-invasive techniques are needed to stratify patients based on cancer hypoxia, including those who are not expected to respond to radiotherapy due to hypoxia, as well as those who may be candidates for the increasingly available alternative hypoxia-activated chemotherapy. Because hypoxia constitutes a significant difference between tumors and normal tissues, it can be used in the development of tumor-specific probes.

[0005] Hypoxia is a potent stimulus to the expression of certain genes, some of which trigger vasculogenesis to supply oxygen to tumors, increase metabolism and oxygen extractive factors, and promote an environment favorable to tumor growth. Activation of hypoxia-inducible genes is partly mediated by the transcription factor HIF-1α. Under normal oxygen conditions, HIF-1α is hydroxylated by proline hydroxylase at a proline residue located within the protein's oxygen-inducible degradation domain. Hydroxyproline promotes the binding of von Hippel-Lindau factor (VHL), a tumor suppressor that promotes the ubiquitination and degradation of HIF-1α upon binding. During hypoxic conditions, proline hydroxylase is inhibited, and VHL no longer binds to HIF-1α. Stabilized HIF-1α translocates to the nucleus and binds to HIF-1α. The heterodimeric transcription factor then binds to the carbonic anhydrase isoform CA-IX, as well as to the HIF-1 response DNA sequence in the promoter region of target genes, including VEGF, erythropoietin, and glucose transporters.

[0006] Carbonic anhydrase reacts: [ka] Carbonic anhydrase II is a family of enzymes composed of 16 isozymes that catalyze pH regulation and therefore play a crucial role in pH adjustment. Specific isozymes are found either in the cytosol, bound to the membrane, in the mitochondria, or secreted from the cell. The well-studied constitutively expressed isozyme of carbonic anhydrase II is found in the cytosol of most cell types and is the major isoform involved in regulating intracellular pH.

[0007] CA-IX is a membrane-bound isoform of the enzyme in which its catalytic domain is located in the extracellular space. It has a limited tissue distribution and is mainly found at low levels in the gastrointestinal tract. CA-IX expression is regulated by HIF-1α, and this isozyme is highly expressed both in vitro and in vivo in tumor cells exposed to hypoxia. Increased CA-IX expression has been detected in cervical, ovarian, renal, esophageal, lung, breast, and brain cancers. CA-IX has been reported to promote extracellular acidification. Low extracellular pH as a result of CA-IX activity leads to tumorigenesis, chromosome rearrangement, extracellular matrix degradation, migration and invasion, growth factor induction, protease activation, and chemotherapy resistance.

[0008] Currently, many small molecule inhibitors of CA-IX exhibit undesirable side effects due to inhibition of other CA isozymes present in the target organ. There is a need for a CA-IX selective inhibitor that can mitigate these undesirable side effects, which may arise from the inhibition of other CA isozymes, including non-membrane-related ones. [Overview of the Initiative]

[0009] Formula (A): [ka] [In the formula, TL1 represents the first targeting site that binds to carbonic anhydrase IX; TL2 represents the second targeting site that binds to carbonic anhydrase IX; L A This represents the linker; s is either 0 or 1; Ring A is a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, or a heteroaryl group, which may be optionally substituted; CL stands for metal chelating agent. Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are disclosed herein.

[0010] Formula (A'): [ka] [In the formula, Each TL1 independently represents the first targeting site that binds to carbonic anhydrase IX; Each TL2 independently represents a second targeting site that binds to carbonic anhydrase IX; L B This represents the linker; Each ring A is independently a optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; CL stands for metal chelating agent. Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are also disclosed herein.

[0011] Formula (B): [ka] [In the formula, L A This represents the linker; s is either 0 or 1; CL stands for metal chelating agent; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1 is given by equation (IB): [ka] It is represented by; TL2 is given by equation (IIB): [ka] [represented by] Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are also disclosed herein.

[0012] Formula (C): [ka] [In the formula, L A This represents the linker; s is either 0 or 1; CL stands for metal chelating agent; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1 is given by equation (IC): [ka] It is represented by; TL2 is given by equation (IIC): [ka] [represented by] Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are also provided herein.

[0013] Also disclosed herein are radiopharmaceutical conjugates and pharmaceutical compositions comprising pharmaceutically acceptable excipients or carriers.

[0014] In some embodiments, the pharmaceutical composition is formulated for intravenous administration to a subject.

[0015] Also disclosed herein is a method for diagnosing or imaging a disease or disorder in an object requiring diagnosis or imaging, characterized by administering to the object a radiopharmaceutical conjugate or pharmaceutical composition disclosed herein.

[0016] Also disclosed herein is a method for treating a disease or disorder in a subject requiring treatment, characterized by administering to the subject a radiopharmaceutical conjugate or a pharmaceutical composition disclosed herein.

[0017] In some embodiments, the disease or disorder is cancer.

[0018] In some embodiments, cancer is a solid tumor cancer.

[0019] In some embodiments, cancer is hypoxic.

[0020] In some embodiments, the cancer is clear cell renal cell carcinoma (ccRCC), endometrial cancer, basal cell carcinoma, liver cancer, colon cancer, gastric cancer, cervical squamous cell carcinoma, oral squamous cell carcinoma, pancreatic cancer, breast cancer, ovarian cancer, glioblastoma, head and neck cancer, or lung cancer.

[0021] In some embodiments, the cancer is cellular renal cell carcinoma (ccRCC).

[0022] Built-in by reference All publications, patents, and patent applications described herein are incorporated herein by reference to the same extent as each publication, patent, and patent application is specifically and individually incorporated by reference. [Brief explanation of the drawing]

[0023] Novel features of this disclosure are specifically described in the appended claims. A deeper understanding of the features and advantages of this disclosure can be obtained by referring to the following detailed description of illustrative embodiments in which the principles of this disclosure are utilized, and to the accompanying drawings (also referred to herein as "figure" and "FIG."). [Figure 1] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 2] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 3] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 4] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 5] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 6] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 7] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 8] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 9] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 10] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 11] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 12] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 13] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 14] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 15] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 16]Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 17] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 18] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Figure 19] Figures 1 to 19 illustrate the structures of typical metal chelating agents. [Modes for carrying out the invention]

[0024] definition In the following description, certain specific details are provided to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the invention can be carried out without these details. In other examples, well-known structures are not shown or described in detail to avoid unnecessarily complicating the description of the embodiments. Unless the context requires otherwise, the word “comprise” and its variations (such as “comprises” and “comprising”) throughout this specification and the appended claims should be interpreted in an open, comprehensive sense, i.e., “including, but not limited to.” Furthermore, the headings provided herein are for convenience only and do not construe as to the scope or meaning of the invention described in the claims.

[0025] Throughout this specification, any reference to “several embodiments” or “embodiments” means that the specific features, structures, or characteristics described in relation to that embodiment are included in at least one embodiment. Therefore, the appearance of the phrase “in one embodiment” or “embodiments” in various places throughout this specification does not necessarily all refer to the same embodiment. Furthermore, specific features, structures, or characteristics may be combined in appropriate ways in one or more embodiments. Also, where used in this specification and the appended claims, the singular forms “a,” “an,” and “the” refer to multiple subjects unless otherwise explicitly stated in the text. Note that the term “or” is generally used to mean “and / or” unless otherwise explicitly stated in the text.

[0026] The following terms, as used herein, have the meanings set forth below unless otherwise specified.

[0027] "Oxo" refers to =O.

[0028] "Carboxyl" refers to the -COOH group.

[0029] "Cyano" refers to -CN.

[0030] "Alkyl" refers to a linear or branched saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer-chain alkyl groups such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" means that the alkyl group may consist of one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms; however, this definition also includes appearances of the term "alkyl" without specifying a numerical range. In some embodiments, alkyl is C1- 10It is alkyl. In some embodiments, the alkyl is C1-6 alkyl. In some embodiments, the alkyl is C1-5 alkyl. In some embodiments, the alkyl is C1-4 alkyl. In some embodiments, the alkyl is C1-3 alkyl. Unless otherwise specifically described herein, the alkyl may be appropriately substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl may be appropriately substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl may be appropriately substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl may be appropriately substituted with halogen.

[0031] "Alkenyl" refers to a linear or branched hydrocarbon monoradical having one or more carbon-carbon double bonds and containing 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group may be in either a cis or trans configuration with respect to the double bond, and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and similar groups. Whenever it appears herein, numerical ranges such as "C2-C6 alkenyl" or "C2-6 alkenyl" mean that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also includes appearances of the term "alkenyl" without a specified numerical range. Unless otherwise specifically described herein, the alkenyl group may be appropriately substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl may be appropriately substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl may be appropriately substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl may be appropriately substituted with halogen.

[0032] "Alkynyl" refers to a linear or branched hydrocarbon monoradical having one or more carbon-carbon triple bonds and containing 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiinyl, and the like. Whenever it appears herein, a numerical range such as "C2-C6 alkynyl" or "C2-6 alkynyl" means that the alkynyl group may consist of 2, 3, 4, 5, or 6 carbon atoms; however, this definition also includes instances of the term "alkynyl" without a specified numerical range. Unless otherwise specifically described herein, the alkynyl group may be appropriately substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl may be appropriately substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl may be appropriately substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl may be appropriately substituted with halogen.

[0033] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically described herein, alkylene groups may be appropriately substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkylene may be appropriately substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene may be appropriately substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene may be appropriately substituted with halogen.

[0034] "Alkoxy" refers to a radical of the formula -Oalkyl (wherein alkyl is as defined above). Unless otherwise specifically described herein, the alkoxy group may be appropriately substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy may be appropriately substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy may be appropriately substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy may be appropriately substituted with halogen.

[0035] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and may include condensed (when condensed with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded via an aromatic ring atom) or bridging ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Examples of aryl radicals derived from the hydrocarbon ring systems of anthreene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthreene, naphthylene, phenanthrene, anthracene, azulene, benzene, chrysene, fluorantene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically described herein, aryls may be appropriately substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, and the like. In some embodiments, aryls may be appropriately substituted with halogens, methyls, ethyls, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryls may be appropriately substituted with halogens, methyls, ethyls, -CN, -CF3, -OH, or -OMe. In some embodiments, aryls may be appropriately substituted with halogens.

[0036] "Cycloalkyl" refers to a partially or completely saturated monocyclic or polycyclic carbocyclic ring, which may include condensed (when condensed with an aryl or heteroaryl ring, the cycloalkyl is bonded via a non-aromatic ring atom), spiro, or bridging ring systems. In some embodiments, the cycloalkyl is completely saturated. Typical cycloalkyls have 3 to 15 carbon atoms (e.g., C3-C3). 15 Fully saturated cycloalkyl or C3-C 15(cycloalkenyl), 3 to 10 carbon atoms (e.g., C3-C 10 fully saturated cycloalkyl or C3-C 10Examples of cycloalkyls include, but are not limited to, cycloalkenyls having 3 to 8 carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 to 10-membered fully saturated cycloalkyl or a 3 to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 to 6-membered fully saturated cycloalkyl or a 3 to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 to 6-membered fully saturated cycloalkyl or a 5 to 6-membered cycloalkenyl. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, dekalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cisdecalin, transdecalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethylbicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically described herein, cycloalkyls may be appropriately substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, cycloalkyls may be appropriately substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the cycloalkyl group may be appropriately substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group may be appropriately substituted with halogen.

[0037] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodine. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0038] "Haloalkyl" refers to alkyl radicals as defined above, which are substituted by one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0039] "Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Examples of hydroxyalkyls include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0040] "Aminoalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Examples of aminoalkyls include aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0041] A "heteroalkyl" refers to an alkyl group in which one or more of the alkyl backbone atoms are atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. In a heteroalkyl group, the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. In one embodiment, a heteroalkyl group is a C1-C6 heteroalkyl group in which the heteroalkyl group consists of 1-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, and the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specifically described herein, heteroalkyls may be appropriately substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroalkyls may be appropriately substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyls may be appropriately substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyls may be appropriately substituted with halogens.

[0042] "Heterocycloalkyl" refers to a 3-24 member partially or fully saturated ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1-3 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom and 1 oxygen atom. Unless otherwise specifically described herein, heterocycloalkyl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may include condensed (when condensed with an aryl or heteroaryl ring, the heterocycloalkyl is bonded via a non-aromatic ring atom), spiro, or bridging ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be oxidized as appropriate, and the nitrogen atom may be quaternized as appropriate. Typical heterocycloalkyls have 2 to 15 carbon atoms (e.g., C2-C 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyl), 2 to 10 carbon atoms (e.g., C2-C 10 Fully saturated heterocycloalkyl or C2-C 10Examples of heterocycloalkyls include, but are not limited to, heterocycloalkenyls having 2 to 8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl), 2 to 5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include azilidinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperadinyl, 4-piperidonyl, pyrrolidinyl Examples include, but are not limited to, yl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all cyclic carbohydrates, including monosaccharides, disaccharides, and oligosaccharides, but is not limited to these. In some embodiments, heterocycloalkyls have 2 to 10 carbon atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl group, it should be understood that the number of carbon atoms in a heterocycloalkyl group is not the same as the total number of atoms that make up the heterocycloalkyl group (including heteroatoms) (i.e., the skeletal atoms of the heterocycloalkyl ring).In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specifically described herein, heterocycloalkyls may be appropriately substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like, as described below. In some embodiments, heterocycloalkyls may be appropriately substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyls may be appropriately substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyls may be appropriately substituted with halogen.

[0043] A "heteroaryl" refers to a 5-14 membered ring radical comprising 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogen atoms. In some embodiments, the heteroaryl contains 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1 nitrogen atom. Heteroaryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and may include condensed (when condensed with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded via aromatic ring atoms) or bridging ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be oxidized as appropriate, and the nitrogen atoms may be quaternized as appropriate. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl Examples include, but are not limited to, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthylidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically described herein, heteroaryls may be appropriately substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, and the like. In some embodiments, heteroaryls may be appropriately substituted with halogens, methyls, ethyls, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryls may be appropriately substituted with halogens, methyls, ethyls, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl may be appropriately substituted with a halogen.

[0044] The terms “optional” or “optionally” mean that the events or situations described thereafter may or may not occur, and that such descriptions include examples in which such events or situations occur and examples in which they do not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Furthermore, optional groups may be unsubstituted (e.g., -CH2CH3), totally substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between totally and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). With respect to any group containing one or more substituents, it will be understood by those skilled in the art that such groups are not intended to introduce sterically unrealistic and / or synthetically unrealistic substitutions or substitution patterns. Therefore, it should be understood that any substituents described generally have a maximum molecular weight of about 1,000 daltons, and more generally, a maximum of about 500 daltons.

[0045] The term "one or more" means that, when referring to optional substituents, the group in question may be appropriately substituted with one, two, three, four, or more substituents. In some embodiments, the group in question may be appropriately substituted with one, two, three, or four substituents. In some embodiments, the group in question may be appropriately substituted with one, two, or three substituents. In some embodiments, the group in question may be appropriately substituted with one or two substituents. In some embodiments, the group in question may be appropriately substituted with one substituent. In some embodiments, the group in question may be appropriately substituted with two substituents.

[0046] An "effective dose" or "therapeutic dose" refers to the amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, that is effective in producing the desired therapeutic effect.

[0047] The “treatment” of an individual (e.g., a mammal such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of that individual or cell. In some embodiments, treatment includes the administration of a pharmaceutical composition after the onset of a pathological event or contact with a pathogen, and includes stabilization of the condition (e.g., preventing the condition from worsening) or alleviation of the condition.

[0048] compound Conjugates and pharmaceutical compositions targeting the CA-IX receptor are disclosed herein. In some embodiments, the conjugates disclosed herein are selective for CA-IX rather than CA-XII.

[0049] The conjugates and compositions may be useful in the treatment of cancer. The conjugates and compositions may also be useful in imaging and disease diagnosis.

[0050] In one embodiment, a conjugate comprising a target ligand that binds to the CA-IX protein is described herein. In some embodiments, the conjugate described herein comprises a target ligand that binds to the CA-IX protein and a metal chelating agent configured to bind to a radionuclide. In some embodiments, the conjugate described herein comprises a radionuclide.

[0051] Formula (A): [ka] [In the formula, TL1 represents the first targeting site that binds to carbonic anhydrase IX; TL2 represents the second targeting site that binds to carbonic anhydrase IX; L A This represents the linker; s is either 0 or 1; Ring A is a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, or a heteroaryl group, which may be optionally substituted; CL stands for metal chelating agent. Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are disclosed herein.

[0052] Formula (AC): [ka] [In the formula, TL1 represents the first targeting site that binds to carbonic anhydrase IX; TL2 represents the second targeting site that binds to carbonic anhydrase IX; L A This represents the linker; s is either 0 or 1; Ring A is a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, or a heteroaryl group, which may be optionally substituted; R 30 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2Ra -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted as appropriate (e.g., with one or more R); or R 30 This is the albumin-binding portion or the payload portion; R a , R b , R c , R d , and R have the meanings defined in formula (IA). Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are disclosed herein.

[0053] In some embodiments, the conjugate compound of formula (AC) comprises a covalently bonded radioactive isotope.

[0054] Formula (A'): [ka] [In the formula, Each TL1 independently represents the first targeting site that binds to carbonic anhydrase IX; Each TL2 independently represents a second targeting site that binds to carbonic anhydrase IX; L B This represents the linker; Each ring A is independently a optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; CL stands for metal chelating agent. Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are disclosed herein.

[0055] Formula (AC'): [ka] [In the formula, Each TL1 independently represents the first targeting site that binds to carbonic anhydrase IX; Each TL2 independently represents a second targeting site that binds to carbonic anhydrase IX; L B This represents the linker; Each ring A is independently a optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 30 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted as appropriate (e.g., with one or more R); or R 30 This is the albumin-binding portion or the payload portion; R a , R b , R c , R d , and R have the meanings defined in formula (IA). Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are disclosed herein.

[0056] In some embodiments, the conjugate compound of formula (AC') comprises a covalently bonded radioactive isotope.

[0057] In some embodiments of the compound of formula (A') or (AC'), TL1 is identical. In some embodiments of the compound of formula (A') or (AC'), TL1 is different. In some embodiments of the compound of formula (A') or (AC'), TL2 is identical. In some embodiments of the compound of formula (A') or (AC'), TL2 is different. In some embodiments of the compound of formula (A') or (AC'), ring A is identical. In some embodiments of the compound of formula (A') or (AC'), ring A is different. In some embodiments of the compound of formula (A') or (AC'), TL1 is independently the target moiety of formula (IA). In some embodiments of the compound of formula (A') or (AC'), TL2 is independently the target moiety of formula (IIA).

[0058] In some embodiments of compounds of formula (A), (AC), (A'), or (AC'), Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl rings may be appropriately substituted with one or more R rings; R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O )OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alternatively, two R atoms on the same atom can form an oxo molecule.

[0059] In some embodiments of the compounds of formula (A), (AC), (A'), or (AC'), ring A is a heterocycloalkyl which may be appropriately substituted with one or more Rs.

[0060] In some embodiments of the compounds of formula (A), (AC), (A'), or (AC'), ring A is a monocyclic heterocycloalkyl, which may be appropriately substituted with one or more Rs.

[0061] In some embodiments of the compounds of formula (A), (AC), (A'), or (AC'), ring A is a bicyclic heterocycloalkyl, which may be appropriately substituted with one or more Rs.

[0062] In some embodiments of the compounds of formula (A), (AC), (A'), or (AC'), ring A is a 4- to 6-membered heterocycloalkyl, which may be appropriately substituted with one or more R groups. In some embodiments of the compounds of formula (A), (AC), (A'), or (AC'), ring A is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which may be appropriately substituted with one or more R groups. In some embodiments of the compounds of formula (A), (AC), (A'), or (AC'), ring A is piperidinyl or piperazinyl, each of which may be appropriately substituted with one or more R groups. In some embodiments of the compounds of formula (A), (AC), (A'), or (AC'), ring A is piperidinyl, which may be appropriately substituted with one or more R groups. In some embodiments of the compounds of formula (A), (AC), (A'), or (AC'), ring A is piperazinyl, which may be appropriately substituted with one or more R groups.

[0063] In some embodiments of compounds of formula (A), (AC), (A'), or (AC'), [ka] teeth, [ka] In some embodiments of compounds of formula (A), (AC), (A'), or (AC'), [ka] teeth, [ka] In some embodiments of compounds of formula (A), (AC), (A'), or (AC'), [ka] teeth, [ka] In some embodiments of compounds of formula (A), (AC), (A'), or (AC'), [ka] teeth, [ka] In some embodiments of compounds of formula (A), (AC), (A'), or (AC'), [ka] teeth, [ka] In some embodiments of compounds of formula (A), (AC), (A'), or (AC'), [ka] teeth, [ka] In some embodiments of formula (A) or formula (AC), *** is the linker L of ring A. A Represents the bonding point to the metal chelating agent (CL) of ring A. In some embodiments of formula (A), when s is 0, *** represents the bonding point of ring A to the metal chelating agent (CL). In some embodiments of formula (AC), when s is 0, *** represents the bonding point of ring A to the metal chelating agent (CL). 30Represents a bonding point to. In some embodiments of formula (A) or formula (AC), ** represents a bonding point of ring A to TL1, and * represents a bonding point of ring A to TL2. In some embodiments of formula (A) or formula (AC), * represents a bonding point of ring A to TL1, and ** represents a bonding point of ring A to TL2. In some embodiments of formula (A’) or formula (AC’), *** represents a linker L of ring A B Represents a bonding point to. In some embodiments of formula (A’) or formula (AC’), ** represents a bonding point of ring A to TL1, and * represents a bonding point of ring A to TL2. In some embodiments of formula (A’) or formula (AC’), * represents a bonding point of ring A to TL1, and ** represents a bonding point of ring A to TL2.

[0064] In some embodiments of the compound of formula (A), (AC), (A’), or (AC’), TL1 is of formula (IA):

Chemical formula

[0065] In some embodiments of compounds of formula (A), (AC), (A'), or (AC'), TL1 is of formula (IA): [ka] [In the formula, W 1 -C(=O)- or -C(=O)NR does not exist. 11 -and; X 1 C1-C 10 It is alkylene; A 1 is a heteroaryl that does not exist or may be appropriately substituted with one or more R; T 1 It does not exist; B 1 C1-C 10 It is alkylene or cycloalkyl; S 1 It does not exist; Y 1 -O-, -S-, -S(=O)2-, -C(=O)NR do not exist. 11 -, or -NR 11 C(=O)- and; R 11 is hydrogen; Ring C 1 It is a heteroaryl; R 12 These are, independently, halogen and -S(=O)2NR c R d , or -NR c R d and; n is 0, 1, 2, or 3; R c and R d Each of these is independently hydrogen, a C1-C6 alkyl group, a -L-cycloalkyl group, or a -L-aryl group, where each alkyl group, cycloalkyl group, and aryl group may be independently substituted with one or more R groups as appropriate; L is either nonexistent or a C1-C3 alkylene; R is independently either a C1-C3 alkyl group or a C1-C3 alkoxy group. It is represented as follows.

[0066] In some embodiments of the compound of formula (IA), W 1 -O-, -S-, -NR do not exist. 11 -, -C(=O)-, -C(=O)NR 11 -, or -NR 11 C(=O)-

[0067] In some embodiments of the compound of formula (IA), W 1 -C(=O)- or -C(=O)NR does not exist. 11 - is

[0068] In some embodiments of the compound of formula (IA), W 1 It does not exist.

[0069] In some embodiments of the compound of formula (IA), W 1 This is -C(=O)-.

[0070] In some embodiments of the compound of formula (IA), W 1 is -C(=O)NR 11 - is

[0071] In some embodiments of the compound of formula (IA), X 1 is a C1-C6 alkylene which may be appropriately substituted with one or more R, where one or two carbon atoms of the C1-C6 alkylene are -S-, -S(=O)-, -S(=O)2-, -O-, or -NR 11 - may be substituted as appropriate.

[0072] In some embodiments of the compound of formula (IA), X 1 These are C1-C6 alkylenes.

[0073] In some embodiments of the compound of formula (IA), X 1 It is a C1-C4 alkylene.

[0074] In some embodiments of the compound of formula (IA), X 1 It is -CH2-.

[0075] In some embodiments of the compound of formula (IA), X 1 It is -CH2CH2-.

[0076] In some embodiments of the compound of formula (IA), X 1 It is -CH2CH2CH2-.

[0077] In some embodiments of the compound of formula (IA), X 1 It is -CH2CH2CH2CH2-.

[0078] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] That is the case.

[0079] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] That is the case.

[0080] In some embodiments of the compound of formula (IA), A 1 It does not exist.

[0081] In some embodiments of the compound of formula (IA), A 1 is a heteroaryl compound that may be appropriately substituted with one or more R compounds.

[0082] In some embodiments of the compound of formula (IA), A 1 is a triazolyl which may be appropriately substituted with one or more R. In some embodiments of the compound of formula (IA), A 1 It is an unsubstituted triazolyl compound.

[0083] In some embodiments of the compound of formula (IA), A 1 teeth, [ka] Here, R' is hydrogen or R. In some embodiments of the compound of formula (IA), A 1 teeth, [ka] Here, R' is hydrogen or R. In some embodiments, R' is hydrogen.

[0084] In some embodiments of the compound of formula (IA), A 1 This is a heterocycloalkyl that may be appropriately substituted with one or more Rs.

[0085] In some embodiments of the compound of formula (IA), A 1 This is a monocyclic heterocycloalkyl compound that may be appropriately substituted with one or more R atoms.

[0086] In some embodiments of the compound of formula (IA), A 1 This is a bicyclic heterocycloalkyl compound that may be appropriately substituted with one or more R atoms.

[0087] In some embodiments of the compound of formula (IA), A 1 teeth, [ka] That is the case.

[0088] In some embodiments of the compound of formula (IA), T 1 It is either non-existent or a C1-C3 alkylene.

[0089] In some embodiments of the compound of formula (IA), T 1 It does not exist.

[0090] In some embodiments of the compound of formula (IA), B 1 C1-C 10 Alkylene or cycloalkyl, where the alkylene and cycloalkyl may be appropriately substituted with one or more R, and the C1-C 10 The one, two, three, or four carbon atoms of an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR. 11 - may be substituted as appropriate.

[0091] In some embodiments of the compound of formula (IA), B 1C1-C may be appropriately substituted with one or more Rs. 10 It is an alkylene, where the C1-C 10 The one, two, three, or four carbon atoms of an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR. 11 - may be substituted as appropriate.

[0092] In some embodiments of the compound of formula (IA), B 1 C1-C may be appropriately substituted with one or more Rs. 10 It is alkylene.

[0093] In some embodiments of the compound of formula (IA), B 1 These are C1-C6 alkylenes.

[0094] In some embodiments of the compound of formula (IA), B 1 It is -CH2CH2CH2-.

[0095] In some embodiments of the compound of formula (IA), B 1 It is -CH2CH2CH2CH2-.

[0096] In some embodiments of the compound of formula (IA), B 1 This is a cycloalkyl group which may be appropriately substituted with one or more R groups.

[0097] In some embodiments of the compound of formula (IA), B 1 This is a monocyclic cycloalkyl compound that may be appropriately substituted with one or more R atoms.

[0098] In some embodiments of the compound of formula (IA), B 1 This is a bicyclic cycloalkyl compound that may be appropriately substituted with one or more R atoms.

[0099] In some embodiments of the compound of formula (IA), B 1These are bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.1.1]hexanyl.

[0100] In some embodiments of the compound of formula (IA), B 1 This is bicyclo[1.1.1]pentanyl.

[0101] In some embodiments of the compound of formula (IA), S 1 It does not exist.

[0102] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] That is the case.

[0103] In some embodiments of the compound of formula (IA), Y 1 -O-, -S-, -S(=O)2-, -C(=O)NR do not exist. 11 -, or -NR 11 C(=O)-

[0104] In some embodiments of the compound of formula (IA), Y 1 This is -S(=O)2-.

[0105] In some embodiments of the compound of formula (IA), Y 1 is -C(=O)NR 11 - is

[0106] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] That is the case.

[0107] In some embodiments of the compound of formula (IA), the ring C 1 is aryl or heteroaryl. In some embodiments of the compound of formula (IA), the ring C 1 is phenyl or heteroaryl. In some embodiments of the compound of formula (IA), the ring C 1 It is a heteroaryl compound. In some embodiments of the compound of formula (IA), the ring C 1 It is a 5-12 member heteroaryl compound. In some embodiments of the compound of formula (IA), the ring C 1 It is a 5-10 membered heteroaryl. In some embodiments of the compound of formula (IA), the ring C 1 It is a 5-6 member heteroaryl compound. In some embodiments of the compound of formula (IA), the ring C 1 It is a 7-10 membered heteroaryl compound. In some embodiments of the compound of formula (IA), the ring C 1It is a monocyclic heteroaryl compound. In some embodiments of the compound of formula (IA), the ring C 1 is thiadiazolyl or phenyl. In some embodiments of the compound of formula (IA), the ring C 1 It is thiadiazolyl. In some embodiments of the compound of formula (IA), the ring C 1 It is phenyl.

[0108] In some embodiments of the compound of formula (IA), the ring C 1 It is a bicyclic heteroaryl compound.

[0109] In some embodiments of the compound of formula (IA), the ring C 1 These are benzothiazolyl or imidazothiadiazolyl.

[0110] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] And here, Z 1 These are, independently, -N- or -CR. 12’ -and; Z 2 -O-, -S-, or -NR 12’’ -and; R 12’ These are, independently, hydrogen, halogen, -CN, -OH, and -OR. a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; R 12’’ This is hydrogen, -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -C(=O)R a , -C(=O)ORb -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl groups.

[0111] In some embodiments, Z 2 is -O- or -S-. In some embodiments, Z 2 is -S-. In some embodiments, Z 1 These are -N-, respectively.

[0112] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] That is the case.

[0113] In some embodiments of the compound of formula (IA), R 12 These are, independently, halogen, -CN, -OH, and -OR. a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (IA), R 12One of them is -S(=O)2NR c R d That is the case.

[0114] In some embodiments of the compound of formula (IA), R 12 These are, independently, halogen, -CN, -OH, and -OR. a -S(=O)R a -S(=O)2R a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d It is either a C1-C6 alkyl group or a C1-C6 haloalkyl group.

[0115] In some embodiments of the compound of formula (IA), R 12 These are, independently, halogen and -S(=O)2NR c R d , or -NR c R d That is the case.

[0116] In some embodiments of the compound of formula (IA), R 12 These are, independently, halogen or -NR c R d That is the case.

[0117] In some embodiments of the compound of formula (IA), n is 0, 1, 2, 3, 4, or 5. In some embodiments of the compound of formula (IA), n is 0, 1, 2, 3, or 4. In some embodiments of the compound of formula (IA), n is 0, 1, 2, or 3. In some embodiments of the compound of formula (IA), n is 0, 1, or 2. In some embodiments of the compound of formula (IA), n is 0 or 1.

[0118] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] That is the case.

[0119] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] That is the case.

[0120] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] In some embodiments of the compound of formula (IA), [ka] teeth, [ka] That is the case.

[0121] In some embodiments of the compound of formula (IA), R 11 R is hydrogen or a C1-C6 alkyl group. In some embodiments of the compound of formula (IIA), 11 It is hydrogen.

[0122] In some embodiments of the compound of formula (IA), R a Each of these is independently a C1-C6 alkyl group.

[0123] In some embodiments of the compound of formula (IA), R bEach of these is independently either hydrogen or a C1-C6 alkyl group.

[0124] In some embodiments of the compound of formula (IA), R c and R d Each of these is independently hydrogen, a C1-C6 alkyl group, a -L-cycloalkyl group, or a -L-aryl group, where each alkyl group, cycloalkyl group, and aryl group may be independently substituted with one or more R groups as appropriate.

[0125] In some embodiments of the compound of formula (IA), L is absent or is a C1-C3 alkylene.

[0126] In some embodiments of the compound of formula (IA), R is independently a C1-C3 alkyl or a C1-C3 alkoxy.

[0127] In some embodiments of compounds of formula (A), (AC), (A'), or (AC'), TL1 is of formula (IA): [ka] [In the formula, [ka] teeth, [ka] and; [ka] Together, they form a linking group containing 3 to 30 atoms in a linear chain (optionally, 5 to 25 atoms, 8 to 20 atoms, 8 to 15 atoms, or 10 to 14 atoms, or 8, 9, 10, 11, 12, 13, 14, or 15 atoms). It is represented as follows.

[0128] In some embodiments, [ka] Together, they form linking groups containing 3 to 30 atoms in a linear chain, which are selected from C, N, and O.

[0129] In some embodiments, the linking group contains 3 to 30 atoms in the linear chain, including carbon, 1 to 5 nitrogen atoms, and 0 to 1 oxygen atom. In some embodiments, the linking group contains 3 to 30 atoms selected from N and C in the linear chain, including 2, 3, or 4 nitrogen atoms. In some embodiments, the linking group contains one or more ring groups, and the atoms in the linear chain include part of the ring groups. In some embodiments, A 1 and B 1 These are all ring groups. In some embodiments, the linking groups are -O-, -S-, -S(=O)-, -S(=O)2-, -NR 21 -, -C(=O)-, -C(=O)NR 21 -, -NR 21 C(=O)-, -S(=O)2NR 21 -, or -NR 21 S(=O)2, C1-C which may be substituted as appropriate. 10 Alkylene, C1-C may be substituted as appropriate. 10 The group comprises one or more groups selected from heteroalkylene, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or a combination thereof.

[0130] In some embodiments of compounds of formula (A), (AC), (A'), or (AC'), TL2 is of formula (IIA): [ka] [In the formula, W 2 -O-, -S-, -S(=O)-, -S(=O)2-, -NR do not exist.21 -, -C(=O)-, -C(=O)NR 21 -, -NR 21 C(=O)-, -S(=O)2NR 21 -, or -NR 21 S(=O)² is; X 2 C1-C may not exist or may be appropriately replaced with one or more R's. 10 It is an alkylene, where the C1-C 10 The one, two, three, or four carbon atoms of an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR. 21 - may be substituted as appropriate; Y 2 -O-, -S-, -S(=O)-, -S(=O)2-, -NR do not exist. 21 -, -C(=O)-, -C(=O)NR 21 -, -NR 21 C(=O)-, -S(=O)2NR 21 -, or -NR 21 S(=O)² is; A 2 C1-C does not exist. 10 Alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 22 This may be substituted as appropriate; R 22 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c Rd , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; S 2 -O-, -S-, -S(=O)-, -S(=O)2-, -NR do not exist. 21 -, -C(=O)-, -C(=O)NR 21 -, -NR 21 C(=O)-, -S(=O)2NR 21 -, or -NR 21 S(=O)² is; T 2 C1-C may not exist or may be appropriately replaced with one or more R's. 10 It is an alkylene, where the C1-C 10 The one, two, three, or four carbon atoms of an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR. 21 - may be substituted as appropriate; R 21 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; (i)B 2 It does not exist; or (ii)B 2 is -N(R 23 )2; R 23 Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; or (iii)B 2 is -CF3; or (iv)B 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 24 This may be substituted as appropriate; R 24 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; or (v)B 2 teeth, [ka] and; Ring C 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 25 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; m is 0, 1, 2, 3, or 4; R 26 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Ring D 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 27 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; p is 0, 1, 2, 3, or 4; R a Each of these is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; R b Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; R c and R dEach of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; Alternatively, R c and R d These, together with the atoms to which they are bonded, form a heterocycloalkyl group which may be appropriately substituted with one or more R groups; L is a C1-C3 alkylene that is absent or may be appropriately substituted with one or more R; R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O )OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alternatively, two R atoms on the same atom may form an oxo; Alternatively, two R atoms on the same or different atoms together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group. It is represented as follows.

[0131] In some embodiments of compounds of formula (A), (AC), (A'), or (AC'), TL2 is of formula (IIA): [ka] [In the formula, W 2 It does not exist, -C(=O)-, or -NR 21 C(=O)- and; X 2 C1-C may be appropriately substituted with one or more Rs. 10 It is alkylene; Y 2 -NR does not exist. 21 -, or -NR 21 C(=O)- and; A 2 C1-C 10 Alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 22 This may be substituted as appropriate; R 22 These are, independently, halogen, -CN, and -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 aminoalkyl; S 2 -NR does not exist. 21 -, -C(=O)-, or -NR 21 C(=O)- and; T 2 It does not exist, or C1-C 10 It is alkylene; R 21 is hydrogen; B 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 24 This may be substituted as appropriate; R 24These are, independently, halogen, -OH, -SF5, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; Or, B 2 teeth, [ka] and; Ring C 2 is an allele; R 25 These are, independently, a halogen, -OH, or C1-C6 alkyl; m is 0, 1, or 2; R 26 is hydrogen or a C1-C6 alkyl group; Ring D 2 is an allele; R 27 These are, independently, a halogen, -OH, or C1-C6 alkyl; p is 0, 1, or 2; R b Each of these is independently either hydrogen or a C1-C6 alkyl group; R c and R d Each of these is independently either hydrogen or a C1-C6 alkyl group; R is either -C(=O)OH or -C(=O)NH2, independently of each other. It is represented as follows.

[0132] In some embodiments of the compound of formula (IIA), W 2 It does not exist, -C(=O)-, or -NR 21 C(=O)-

[0133] In some embodiments of the compound of formula (IIA), W 2 is -C(=O)-. In some embodiments of the compound of formula (IIA), W 2 It does not exist. In some embodiments of the compound of formula (IIA), W 2is -C(=O)-. In some embodiments of the compound of formula (IIA), W 2 -NR 21 C(=O)-

[0134] In some embodiments of the compound of formula (IIA), X 2 This is a C1-C6 alkylene which may be appropriately substituted with one or more R groups.

[0135] In some embodiments of the compound of formula (IIA), X 2 This is a C1-C4 alkylene which may be appropriately substituted with one or more R groups.

[0136] In some embodiments of the compound of formula (IIA), X 2 It is -CH2-.

[0137] In some embodiments of the compound of formula (IIA), X 2 This is -CH2CH[C(=O)OH]- or -CH2CH[C(=O)NH2]-.

[0138] In some embodiments of the compound of formula (IIA), X 2 This is -CH2CH2CH[(C=O)OH]- or -CH2CH2CH[C(=O)NH2]-.

[0139] In some embodiments of the compound of formula (IIA), X 2 This may be appropriately substituted with one or more R, where C1-C 10 One or two carbon atoms in an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR 21 It will be replaced with -.

[0140] In some embodiments of the compound of formula (IIA), Y 2 -O-, -S-, -NR do not exist. 21 -, -C(=O)-, -C(=O)NR 21 -, or -NR 21 C(=O)-

[0141] In some embodiments of the compound of formula (IIA), Y 2 -NR does not exist. 21 -, or -NR 21 C(=O)-

[0142] In some embodiments of the compound of formula (IIA), Y 2 -NR 21 C(=O)-

[0143] In some embodiments of the compound of formula (IIA), [ka] teeth, [ka] That is the case.

[0144] In some embodiments of the compound of formula (IIA), [ka] teeth, [ka] That is the case.

[0145] In some embodiments of the compound of formula (IIA), A 2 C1-C 10 Alkylene, heterocycloalkyl, aryl, or heteroaryl, where the alkylene, heterocycloalkyl, aryl, and heteroaryl are one or more R 22 This may be substituted as appropriate.

[0146] In some embodiments of the compound of formula (IIA), A 2 is one or more R 22 These are C1-C6 alkylenes that may be substituted as appropriate.

[0147] In some embodiments of the compound of formula (IIA), A 2 This is -CH2CH[C(=O)OH]-.

[0148] In some embodiments of the compound of formula (IIA), A 2 is one or more R 22 It is a heterocycloalkyl that may be appropriately substituted.

[0149] In some embodiments of the compound of formula (IIA), A 2 is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinil, each containing one or more R 22 This may be substituted as appropriate.

[0150] In some embodiments of the compound of formula (IIA), A 2 is one or more R 22 This is piperidinyl which may be substituted as appropriate.

[0151] In some embodiments of the compound of formula (IIA), A 2 teeth, [ka] Each of these is one or more R 22 This may be substituted as appropriate.

[0152] In some embodiments of the compound of formula (IIA), A 2 is one or more R 22 It may be replaced as appropriate. [ka] That is the case.

[0153] In some embodiments of the compound of formula (IIA), A 2 is an aryl or heteroaryl, where the aryl and heteroaryl are one or more R 22 This may be substituted as appropriate.

[0154] In some embodiments of the compound of formula (IIA), A 2 is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl, each containing one or more R 22 This may be substituted as appropriate.

[0155] In some embodiments of the compound of formula (IIA), A 2 teeth, [ka] Each of these is one or more R 22 This may be substituted as appropriate.

[0156] In some embodiments of the compound of formula (IIA), A 2 teeth, [ka] That is the case.

[0157] In some embodiments of the compound of formula (IIA), R 22 These are, independently, halogen, -CN, -OH, and -OR. a , -NR c R d , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0158] In some embodiments of the compound of formula (IIA), R 22 These are -CN and -C(=O)OR, respectively, independently. b -C(=O)NR c R d It is either a C1-C6 alkyl group or a C1-C6 aminoalkyl group.

[0159] In some embodiments of the compound of formula (IIA), R22 These are, independently, -C(=O)OR b Or -C(=O)NR c R d That is the case.

[0160] In some embodiments of the compound of formula (IIA), R 22 These are, independently, -C(=O)NR c R d That is the case.

[0161] In some embodiments of the compound of formula (IIA), A 2 teeth, [ka] And R 22 These are halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0162] In some embodiments of the compound of formula (IIA), A 2 teeth, [ka] And R 22 -CN, -C(=O)OR b -C(=O)NR c R d It is either a C1-C6 alkyl group or a C1-C6 aminoalkyl group.

[0163] In some embodiments of the compound of formula (IIA), A 2 teeth, [ka] And R 22is -C(=O)OR b Or -C(=O)NR c R d That is the case.

[0164] In some embodiments of the compound of formula (IIA), A 2 teeth, [ka] And R 22 is -C(=O)NR c R d That is the case.

[0165] In some embodiments of the compound of formula (IIA), A 2 teeth, [ka] In some embodiments of the compound of formula (IIA), A 2 teeth, [ka] That is the case.

[0166] In some embodiments of the compound of formula (IIA), S 2 -O-, -S-, -NR do not exist. 21 -, -C(=O)-, -C(=O)NR 21 -, or -NR 21 C(=O)-

[0167] In some embodiments of the compound of formula (IIA), S 2 -NR does not exist. 21 -, -C(=O)-, or -NR 21 C(=O)-

[0168] In some embodiments of the compound of formula (IIA), S 2 This is -C(=O)- or -NR 21 C(=O)-

[0169] In some embodiments of the compound of formula (IIA), T 2 is a C1-C6 alkylene that does not exist or may be appropriately substituted with one or more Rs.

[0170] In some embodiments of the compound of formula (IIA), T 2 This is a C1-C6 alkylene which may be appropriately substituted with one or more R groups.

[0171] In some embodiments of the compound of formula (IIA), T 2 It is -CH2CH2-.

[0172] In some embodiments of the compound of formula (IIA), T 2 It is -CH2CH2CH2-.

[0173] In some embodiments of the compound of formula (IIA), [ka] teeth, [ka] In some embodiments of the compound of formula (IIA), [ka] teeth, [ka] That is the case.

[0174] In some embodiments of the compound of formula (IIA), B 2 It does not exist.

[0175] In some embodiments of the compound of formula (IIA), B 2 is -N(R 23 )2.

[0176] In some embodiments of the compound of formula (IIA), B 2 It is -CF3.

[0177] In some embodiments of the compound of formula (IIA), B 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 24 This may be substituted as appropriate.

[0178] In some embodiments of the compound of formula (IIA), B 2 is one or more R 24 It is a cycloalkyl that may be appropriately substituted.

[0179] In some embodiments of the compound of formula (IIA), B 2 is one or more R 24 It is a monocyclic cycloalkyl that may be appropriately substituted.

[0180] In some embodiments of the compound of formula (IIA), B 2 is one or more R 24 It is a bicyclic cycloalkyl that may be appropriately substituted with other compounds.

[0181] In some embodiments of the compound of formula (IIA), B 2 is one or more R 24 This is a phenyl compound that may be appropriately substituted.

[0182] In some embodiments of the compound of formula (IIA), B 2 is one or more R 24 It is a heteroaryl that may be substituted as appropriate.

[0183] In some embodiments of the compound of formula (IIA), B 2 is one or more R 24 It is a 5-10 member heteroaryl (e.g., monocyclic or bicyclic heteroaryl) which may be substituted as appropriate.

[0184] In some embodiments of the compound of formula (IIA), B 2 is one or more R 24 It is a 5-6 member heteroaryl that may be substituted as appropriate.

[0185] In some embodiments of the compound of formula (IIA), B 2 These are indazolyl, phenyl, pyridyl, pyridininyl, pyrazinyl, pyridadinyl, cyclopropyl, cyclohexyl, cyclobutyl, cycloheptyl, pyrazolyl, oxazolyl, triazolyl, spiroheptanil, or bicycloheptanil.

[0186] In some embodiments of the compound of formula (IIA), R 24 These are, independently, halogen, -CN, -OH, and -OR. a , -NR c R d The elements are -SF5, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate.

[0187] In some embodiments of the compound of formula (IIA), R 24 These are, independently, a halogen, -OH, C1-C6 alkyl, or C1-C6 haloalkyl.

[0188] In some embodiments of the compound of formula (IIA), B 2 teeth, [ka] and; Ring C 2is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 25 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; m is 0, 1, 2, 3, or 4; R 26 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Ring D 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R27 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; p is 0, 1, 2, 3, or 4.

[0189] In some embodiments of the compound of formula (IIA), the ring C 2 It is phenyl.

[0190] In some embodiments of the compound of formula (IIA), R 25 These are, independently, halogen, -CN, -OH, and -OR. a -SF5, -SH, -SR a , -NRc R d These are C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments of the compound of formula (IIA), R 25 These are, independently, halogen, -CN, -OH, and -OR. a , -NR c R d , or C1-C6 alkyl. In some embodiments of the compound of formula (IIA), R 25 Each of these is independently -OH.

[0191] In some embodiments of the compound of formula (IIA), m is 0 or 1. In some embodiments of the compound of formula (IIA), m is 0, 1, or 2. In some embodiments of the compound of formula (IIA), m is 0. In some embodiments of the compound of formula (IIA), m is 1. In some embodiments of the compound of formula (IIA), m is 2. In some embodiments of the compound of formula (IIA), m is 3.

[0192] In some embodiments of the compound of formula (IIA), ring D 2 It is phenyl.

[0193] In some embodiments of the compound of formula (IIA), R 27 These are, independently, halogen, -CN, -OH, and -OR. a -SF5, -SH, -SR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments of the compound of formula (IIA), R 27 These are, independently, halogen, -CN, -OH, and -OR. a , -NR c R d , or C1-C6 alkyl. In some embodiments of the compound of formula (IIA), R 27 Each of these is independently -OH.

[0194] In some embodiments of the compound of formula (IIA), p is 0 or 1. In some embodiments of the compound of formula (IIA), p is 0, 1, or 2. In some embodiments of the compound of formula (IIA), p is 0. In some embodiments of the compound of formula (IIA), p is 1. In some embodiments of the compound of formula (IIA), p is 2. In some embodiments of the compound of formula (IIA), p is 3.

[0195] In some embodiments of the compound of formula (IIA), R 26 R is hydrogen or a C1-C6 alkyl group. In some embodiments of the compound of formula (IIA), 26 It is a C1-C6 alkyl group.

[0196] In some embodiments of the compound of formula (IIA), B 2 teeth, [ka] That is the case.

[0197] In some embodiments of the compound of formula (IIA), R 21 R is hydrogen or a C1-C6 alkyl group. In some embodiments of the compound of formula (IIA), 21 It is hydrogen.

[0198] In some embodiments of the compound of formula (IIA), R a Each of these is independently a C1-C6 alkyl group.

[0199] In some embodiments of the compound of formula (IIA), R b Each of these is independently either hydrogen or a C1-C6 alkyl group.

[0200] In some embodiments of the compound of formula (IIA), R c and R dEach of these is independently either hydrogen or a C1-C6 alkyl group.

[0201] In some embodiments of the compound of formula (IIA), R is independently either -C(=O)OH or -C(=O)NH2.

[0202] In some embodiments of compounds of formula (A), (AC), (A'), or (AC'), TL2 is of formula (IIA): [ka] [In the formula, B 2 teeth, [ka] and; [ka] Together, they form a linking group containing 3 to 30 atoms in a linear chain (optionally, 5 to 25 atoms, 8 to 20 atoms, 8 to 15 atoms, or 10 to 14 atoms, or 8, 9, 10, 11, 12, 13, 14, or 15 atoms). It is represented as follows.

[0203] In some embodiments, [ka] Together, they form a linking group containing 3 to 30 atoms in the linear chain, which are selected from C, N, and O. In some embodiments, the linking group contains 3 to 30 atoms in the linear chain, including carbon, 1 to 5 N, and 0 to 1 O. In some embodiments, the linking group contains 3 to 30 atoms selected from N and C in the linear chain, including 2, 3, or 4 N. In some embodiments, the linking group includes one or more ring groups, and the atoms in the linear chain include part of the ring group. In some embodiments, A 2The linking group is a ring group. In some embodiments, the linking groups are -O-, -S-, -S(=O)-, -S(=O)2-, -NR 21 -, -C(=O)-, -C(=O)NR 21 -, -NR 21 C(=O)-, -S(=O)2NR 21 -, or -NR 21 S(=O)2, C1-C which may be substituted as appropriate. 10 Alkylene, C1-C may be substituted as appropriate. 10 The group comprises one or more groups selected from heteroalkylene, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or a combination thereof.

[0204] In some embodiments, (i) radionuclides selected from Table 3 (for example, 225 Ac, 177 Lu, 64 Cu, and 68 (ii) and (ii) a radiopharmaceutical conjugate comprising a compound of formula (A) or a salt thereof is disclosed herein, where CL is selected from the chelating agents of Figures 1-19 (e.g., DOTA, DOTA-GA); s is 0; ring A is piperidinyl or piperazinyl, each of which may be substituted as appropriate; TL1 is given by equation (IA): [ka] [In formula (IA), W 1 -C(=O)- or -C(=O)NR does not exist. 11 -and; X 1 C1-C 10 It is alkylene; A 1 is a heteroaryl (e.g., triazolyl) that does not exist or may be appropriately substituted with one or more R; T 1 It does not exist; B 1 C1-C 10 Alkylene or cycloalkyl (e.g., bicyclo[1.1.1]pentanyl); S1 It does not exist; Y 1 -O-, -S-, -S(=O)2-, -C(=O)NR do not exist. 11 -, or -NR 11 C(=O)- and R 11 is hydrogen; ring C 1 It is a heteroaryl; R 12 These are, independently, halogen and -S(=O)2NR c R d , or -NR c R d [and n is 0, 1, 2, or 3] It is represented by; TL2 is given by equation (IIA): [ka] [In formula (IIA), W 2 It does not exist, -C(=O)-, or -NR 21 C(=O)- and X 2 C1-C may be appropriately substituted with one or more Rs. 10 It is alkylene; Y 2 -NR does not exist. 21 -, or -NR 21 C(=O)- and A 2 C1-C 10 Alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 22 It may be replaced as appropriate; R 22 These are, independently, halogen, -CN, and -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl; S 2 -NR does not exist. 21 -, -C(=O)-, or -NR 21 C(=O)- and; T 2 C1-C may not exist or may be appropriately replaced with one or more R's.10 It is an alkylene, where the C1-C 10 The one, two, three, or four carbon atoms of an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR. 21 - may be substituted as appropriate; R 21 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; B 2 teeth, [ka] It is; ring C 2 is an aryl; R 25 These are, independently, halogen, -CN, -OH, and -OR. a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl; m is 0, 1, or 2; R 26 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; ring D 2 is an aryl; R 27 These are, independently, halogen, -CN, -OH, and -OR. a , -NR c R d [It is a C1-C6 alkyl or C1-C6 haloalkyl; p is 0, 1, or 2] It is represented as follows.

[0205] Formula (B): [ka] [In the formula, L A This represents the linker; s is either 0 or 1; CL stands for metal chelating agent; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1 is given by equation (IB): [ka] [In formula (IB), W 1 -O-, -S-, -S(=O)-, -S(=O)2-, -NR do not exist. 11 -, -C(=O)-, -C(=O)NR 11 -, -NR 11 C(=O)-, -S(=O)2NR 11 -, or -NR 11 S(=O)² is; X 1 C1-C may be appropriately substituted with one or more Rs. 10 It is an alkylene, where the C1-C 10 The one, two, three, or four carbon atoms of an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR. 11 - may be substituted as appropriate; A 1 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl that does not exist, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be appropriately substituted with one or more R; T 1 R is a C1-C3 alkylene that does not exist or may be appropriately substituted with one or more R, where one carbon atom of the C1-C3 alkylene is -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -O-, -NR 11 - may be substituted as appropriate; B 1 is a cycloalkyl, heterocycloalkyl, or aryl, where the cycloalkyl, heterocycloalkyl, and aryl may be appropriately substituted with one or more Rs; or B 1 is a heteroaryl compound substituted with one or more Rs; S 1is a C1-C3 alkylene that does not exist or may be appropriately substituted with one or more R, where one or two carbon atoms of the C1-C3 alkylene are -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -O-, or -NR 11 - may be substituted as appropriate; Y 1 -O-, -S-, -S(=O)-, -S(=O)2-, -NR do not exist. 11 -, -C(=O)-, -C(=O)NR 11 -, -NR 11 C(=O)-, -S(=O)2NR 11 -, or -NR 11 S(=O)² is; R 11 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Ring C 1 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 12 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NRc R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; n is 0, 1, 2, 3, 4, 5, or 6. It is represented by; TL2 is given by equation (IIB): [ka] [In formula (IIB), W 2 -O-, -S-, -S(=O)-, -S(=O)2-, -NR do not exist. 21 -, -C(=O)-, -C(=O)NR 21 -, -NR 21 C(=O)-, -S(=O)2NR 21 -, or -NR 21 S(=O)² is; X 2 C1-C may not exist or may be appropriately replaced with one or more R's. 10 It is an alkylene, where the C1-C 10 The one, two, three, or four carbon atoms of an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR. 21 - may be substituted as appropriate; Y 2 -O-, -S-, -S(=O)-, -S(=O)2-, -NR do not exist. 21 -, -C(=O)-, -C(=O)NR 21 -, -NR 21 C(=O)-, -S(=O)2NR 21 -, or -NR 21 S(=O)² is; A 2 C1-C does not exist. 10Alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 22 This may be substituted as appropriate; R 22 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; S 2 -O-, -S-, -S(=O)-, -S(=O)2-, -NR do not exist. 21 -, -C(=O)-, -C(=O)NR 21 -, -NR 21C(=O)-, -S(=O)2NR 21 -, or -NR 21 S(=O)² is; T 2 C1-C may not exist or may be appropriately replaced with one or more R's. 10 It is an alkylene, where the C1-C 10 The one, two, three, or four carbon atoms of an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR. 21 - may be substituted as appropriate; R 21 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; (i)B 2 It does not exist; or (ii)B 2 is -N(R 23 )2; R 23 Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; or (iii)B 2 is -CF3; or (iv)B 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 24 This may be substituted as appropriate; R 24 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a、 -OC(=O)R a 、 -OC(=O)OR b 、 -OC(=O)NR c R d 、 -SF5, -SH, -SR a 、 -S(=O)R a 、 -S(=O)2R a 、 -S(=O)2NR c R d 、 -NR c R d 、 -NR b 、 -NR c C(=O)NR d 、 -NR b C(=O)R a 、 -NR b C(=O)OR b 、 -NR b S(=O)2R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each independently be optionally substituted with one or more R; or (v) B 2 is

Chemical formula

[0206] Formula (B): [ka] [In the formula, L A This represents the linker; s is either 0 or 1; CL stands for metal chelating agent; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1 is given by equation (IB): [ka] [In formula (IB), W 1is absent, -C(=O)-, or -C(=O)NR 11 -; X 1 is C1-C 10 alkylene; A 1 is absent or heteroaryl optionally substituted with one or more R; T 1 is absent; B 1 is cycloalkyl; S 1 is absent; Y 1 is absent, -O-, -S-, -S(=O)2-, -C(=O)NR 11 -, or -NR 11 C(=O)-; R 11 is hydrogen; Ring C 1 is heteroaryl; R 12 are each independently halogen, -S(=O)2NR c R d , or -NR c R d ; n is 0, 1, 2, or 3] represented by; TL2 is of formula (IIB):

Chemical formula

[0207] Formula (BC): [ka] [In the formula, R 30 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NRb C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted as appropriate (e.g., with one or more R); or R 30 This is the albumin-binding portion or the payload portion; The remaining elements have the meanings defined in formula (B). Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are also disclosed herein.

[0208] In some embodiments, the conjugate compound of formula (BC) comprises a covalently bonded radioactive isotope.

[0209] Formula (B'): [ka] [In the formula, L B This represents the linker; CL stands for metal chelating agent; Each X is independently N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1 represents the first targeting site that binds to carbonic anhydrase IX; TL2 represents the second targeting region that binds to carbonic anhydrase IX. Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are also disclosed herein.

[0210] Formula (BC'): [ka] [In the formula, L B This represents the linker; Each X is independently N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1 represents the first targeting site that binds to carbonic anhydrase IX; TL2 represents the second targeting site that binds to carbonic anhydrase IX; R 30 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted as appropriate (e.g., with one or more R); or R 30 This is the albumin-binding portion or the payload portion; The remaining elements have the meanings defined in formula (B). Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are also disclosed herein.

[0211] In some embodiments, the conjugate compound of formula (BC') comprises a covalently bonded radioactive isotope.

[0212] In some embodiments of the compound of formula (B') or (BC'), TL1 is identical. In some embodiments of the compound of formula (B') or (BC'), TL1 is different. In some embodiments of the compound of formula (B') or (BC'), TL2 is identical. In some embodiments of the compound of formula (B') or (BC'), TL2 is different. In some embodiments of the compound of formula (B') or (BC'), X is identical. In some embodiments of the compound of formula (B') or (BC'), X is different. In some embodiments of the compound of formula (B') or (BC'), TL1 is independently the target portion of formula (IB). In some embodiments of the compound of formula (B') or (BC'), TL2 is independently the target portion of formula (IIB).

[0213] In some embodiments of the compounds of formula (B') or (BC'), TL1 is defined by formula (B), respectively. In some embodiments of the compounds of formula (B') or (BC'), TL2 is defined by formula (B), respectively.

[0214] In some embodiments of compounds of formula (B), (BC), (B'), (BC'), or (IB), T 1 It is either non-existent or a C1-C3 alkylene.

[0215] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IB), T 1 It does not exist.

[0216] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IB), B 1 This is a cycloalkyl group which may be appropriately substituted with one or more R groups.

[0217] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IB), B 1 This is a monocyclic cycloalkyl compound that may be appropriately substituted with one or more R atoms.

[0218] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IB), B 1 This is a bicyclic cycloalkyl compound that may be appropriately substituted with one or more R atoms.

[0219] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IB), B 1 These are bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.1.1]hexanyl.

[0220] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IB), B1 This is bicyclo[1.1.1]pentanyl.

[0221] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IB), B 1 is a heterocycloalkyl which may be appropriately substituted with one or more R. In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IB), B 1 is an aryl which may be appropriately substituted with one or more R. In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IB), B 1 This is a heteroaryl compound that is substituted with one or more R compounds.

[0222] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IB), S 1 It does not exist.

[0223] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IB), [ka] teeth, [ka] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IB), [ka] teeth, [ka] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IB), [ka] teeth, [ka] That is the case.

[0224] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 C1-C 10 Alkylene, heterocycloalkyl, aryl, or heteroaryl, where the alkylene, heterocycloalkyl, aryl, and heteroaryl are one or more R 22 This may be substituted as appropriate.

[0225] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 is one or more R 22 These are C1-C6 alkylenes that may be substituted as appropriate.

[0226] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 This is -CH2CH[C(=O)OH]-.

[0227] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 is one or more R 22 It is a heterocycloalkyl that may be appropriately substituted.

[0228] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinil, each containing one or more R 22 This may be substituted as appropriate.

[0229] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 is one or more R 22This is piperidinyl which may be substituted as appropriate.

[0230] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 teeth, [ka] Each of these is one or more R 22 This may be substituted as appropriate.

[0231] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 is one or more R 22 It may be replaced as appropriate. [ka] That is the case.

[0232] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 is an aryl or heteroaryl, where the aryl and heteroaryl are one or more R 22 This may be substituted as appropriate.

[0233] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl, each containing one or more R 22 This may be substituted as appropriate.

[0234] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 teeth, [ka] Each of these is one or more R 22 This may be substituted as appropriate.

[0235] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 teeth, [ka] That is the case.

[0236] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), R 22 These are, independently, halogen, -CN, -OH, and -OR. a , -NR c R d , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0237] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), R 22 These are -CN and -C(=O)OR, respectively, independently. b -C(=O)NR c R d It is either a C1-C6 alkyl group or a C1-C6 aminoalkyl group.

[0238] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), R 22 These are, independently, -C(=O)OR b Or -C(=O)NR c R d That is the case.

[0239] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), R 22 These are, independently, -C(=O)NR c R d That is the case.

[0240] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 teeth, [ka] And R 22 These are halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0241] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 teeth, [ka] And R 22 -CN, -C(=O)OR b -C(=O)NR c R d It is either a C1-C6 alkyl group or a C1-C6 aminoalkyl group.

[0242] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 teeth, [ka] And R 22 is -C(=O)OR b Or -C(=O)NR c R d That is the case.

[0243] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2teeth, [ka] And R 22 is -C(=O)NR c R d That is the case.

[0244] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 teeth, [ka] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), A 2 teeth, [ka] That is the case.

[0245] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), R a Each of these is independently a C1-C6 alkyl group.

[0246] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), R b Each of these is independently either hydrogen or a C1-C6 alkyl group.

[0247] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), or (IIB), R c and R d Each of these is independently hydrogen, a C1-C6 alkyl group, a -L-cycloalkyl group, or a -L-aryl group, where each alkyl group, cycloalkyl group, and aryl group may be independently substituted with one or more R groups as appropriate.

[0248] In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), or (IIB), L is absent or a C1-C3 alkylene.

[0249] In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), or (IIB), R is independently a C1-C3 alkyl, a C1-C3 alkoxy, a -C(=O)OH, or a -C(=O)NH2.

[0250] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), (IIB), (C), (C'), (CC), (CC'), or (IC), TL1 is, [ka] It has the structure, and in the formula, [ka] teeth, [ka] and; [ka] Together, they form a linking group containing 3 to 30 atoms in the linear chain (optionally, 5 to 25 atoms, 8 to 20 atoms, 8 to 15 atoms, or 10 to 14 atoms, or 8, 9, 10, 11, 12, 13, 14, or 15 atoms). In some embodiments, [ka] Together, they form a linking group containing 3 to 30 atoms in the linear chain, which are selected from C, N, and O. In some embodiments, the linking group contains 3 to 30 atoms in the linear chain, including carbon, 1 to 5 N, and 0 to 1 O. In some embodiments, the linking group contains 3 to 30 atoms selected from N and C in the linear chain, including 2, 3, or 4 N. In some embodiments, the linking group includes one or more ring groups, and the atoms in the linear chain include part of the ring group. In some embodiments, A 1 and B 1 These are all ring groups. In some embodiments, the linking groups are -O-, -S-, -S(=O)-, -S(=O)2-, -NR 21 -, -C(=O)-, -C(=O)NR 21 -, -NR 21 C(=O)-, -S(=O)2NR 21 -, or -NR 21 S(=O)2, C1-C which may be substituted as appropriate. 10 Alkylene, C1-C may be substituted as appropriate. 10 The group comprises one or more groups selected from heteroalkylene, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or a combination thereof.

[0251] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), (IIB), (C), (C'), (CC), (CC'), or (IC), TL2 is, [ka] It has the structure, and in the formula, B 2 teeth, [ka] and; [ka] Together, they form a linking group containing 3 to 30 atoms in the linear chain (optionally, 5 to 25 atoms, 8 to 20 atoms, 8 to 15 atoms, or 10 to 14 atoms, or 8, 9, 10, 11, 12, 13, 14, or 15 atoms). In some embodiments, [ka] Together, they form a linking group containing 3 to 30 atoms in the linear chain, which are selected from C, N, and O. In some embodiments, the linking group contains 3 to 30 atoms in the linear chain, including carbon, 1 to 5 N, and 0 to 1 O. In some embodiments, the linking group contains 3 to 30 atoms selected from N and C in the linear chain, including 2, 3, or 4 N. In some embodiments, the linking group includes one or more ring groups, and the atoms in the linear chain include part of the ring group. In some embodiments, A 2 The linking group is a ring group. In some embodiments, the linking groups are -O-, -S-, -S(=O)-, -S(=O)2-, -NR 21 -, -C(=O)-, -C(=O)NR 21 -, -NR 21 C(=O)-, -S(=O)2NR 21 -, or -NR 21 S(=O)2, C1-C which may be substituted as appropriate. 10 Alkylene, C1-C may be substituted as appropriate. 10 The group comprises one or more groups selected from heteroalkylene, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or a combination thereof.

[0252] Formula (C): [ka] [In the formula, L A This represents the linker; s is either 0 or 1; CL stands for metal chelating agent; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1 is given by equation (IC): [ka] [In formula (IC), W 1 -O-, -S-, -S(=O)-, -S(=O)2-, -NR do not exist. 11 -, -C(=O)-, -C(=O)NR 11 -, -NR 11 C(=O)-, -S(=O)2NR 11 -, or -NR 11 S(=O)² is; X 1 C1-C may be appropriately substituted with one or more Rs. 10 It is an alkylene, where the C1-C 10 The one, two, three, or four carbon atoms of an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR. 11 - may be substituted as appropriate; A 1 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl that does not exist, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be appropriately substituted with one or more R; T 1 R is a C1-C3 alkylene that does not exist or may be appropriately substituted with one or more R, where one carbon atom of the C1-C3 alkylene is -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -O-, -NR 11 - may be substituted as appropriate; B 1 C1-C does not exist. 10Alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be appropriately substituted with one or more R, and the C1-C 10 The 1, 2, 3, or 4 carbon atoms of alkylene are -S-, -S(=O)-, -S(=O)2-, -O-, -NR 11 - may be substituted as appropriate; S 1 is a C1-C3 alkylene that is absent or may be appropriately substituted with one or more R, where one or two carbon atoms of the C1-C3 alkylene are -S-, -S(=O)-, -S(=O)2-, -O-, or -NR 11 - may be substituted as appropriate; Y 1 -O-, -S-, -S(=O)-, -S(=O)2-, -NR do not exist. 11 -, -C(=O)-, -C(=O)NR 11 -, -NR 11 C(=O)-, -S(=O)2NR 11 -, or -NR 11 S(=O)² is; R 11 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Ring C 1 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 12 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c Rd , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; n is 0, 1, 2, 3, 4, 5, or 6. It is represented by; TL2 is given by equation (IIC): [ka] [In formula (IIC), W 2 -O-, -S-, -S(=O)-, -S(=O)2-, -NR do not exist. 21 -, -C(=O)-, -C(=O)NR 21 -, -NR 21 C(=O)-, -S(=O)2NR 21 -, or -NR 21 S(=O)² is; X 2 C1-C may not exist or may be appropriately replaced with one or more R's. 10 It is an alkylene, where the C1-C 10 The one, two, three, or four carbon atoms of an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR. 21 - may be substituted as appropriate; Y2 -O-, -S-, -S(=O)-, -S(=O)2-, -NR do not exist. 21 -, -C(=O)-, -C(=O)NR 21 -, -NR 21 C(=O)-, -S(=O)2NR 21 -, or -NR 21 S(=O)² is; A 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 22 This may be substituted as appropriate; R 22 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; S 2 -O-, -S-, -S(=O)-, -S(=O)2-, -NR do not exist. 21 -, -C(=O)-, -C(=O)NR 21 -, -NR 21 C(=O)-, -S(=O)2NR 21 -, or -NR 21 S(=O)² is; T 2 C1-C may not exist or may be appropriately replaced with one or more R's. 10 It is an alkylene, where the C1-C 10 The one, two, three, or four carbon atoms of an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR. 21 - may be substituted as appropriate; R 21 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; (i)B 2 It does not exist; or (ii)B 2 is -N(R 23 )2; R 23Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; or (iii)B 2 is -CF3; or (iv)B 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 24 This may be substituted as appropriate; R 24 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; or (v)B 2 teeth, [ka] and; Ring C 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 25 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; m is 0, 1, 2, 3, or 4; R 26 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Ring D 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 27 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; p is 0, 1, 2, 3, or 4; R a Each of these is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; R b Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; R c and R dEach of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; Alternatively, R c and R d These, together with the atoms to which they are bonded, form a heterocycloalkyl group which may be appropriately substituted with one or more R groups; L is a C1-C3 alkylene that is absent or may be appropriately substituted with one or more R; R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O )OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alternatively, two R atoms on the same atom may form an oxo; Alternatively, two R atoms on the same or different atoms together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group. [represented by] Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are also disclosed herein.

[0253] Formula (C): [ka] [In the formula, L A This represents the linker; s is either 0 or 1; CL stands for metal chelating agent; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1 is given by equation (IC): [ka] [In formula (IC), W 1 -C(=O)- or -C(=O)NR does not exist. 11 -and; X 1 C1-C 10 It is alkylene; A 1 is a heteroaryl that does not exist or may be appropriately substituted with one or more R; T 1 It does not exist; B 1 C1-C 10 It is alkylene or cycloalkyl; S 1 It does not exist; Y 1 -O-, -S-, -S(=O)2-, -C(=O)NR do not exist. 11 -, or -NR 11 C(=O)- and; R 11 is hydrogen; Ring C 1 It is a heteroaryl; R 12 These are, independently, halogen and -S(=O)2NR c R d , or -NR c R d and; n is 0, 1, 2, or 3. It is represented by; TL2 is given by equation (IIC): [ka] [In formula (IIC), W 2 It does not exist, -C(=O)-, or -NR 21 C(=O)- and; X 2 C1-C may be appropriately substituted with one or more Rs. 10 It is alkylene; Y 2 -NR does not exist. 21 -, or -NR 21 C(=O)- and; A 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 22 This may be substituted as appropriate; R 22 These are, independently, halogen, -CN, and -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 aminoalkyl; S 2 -NR does not exist. 21 -, -C(=O)-, or -NR 21 C(=O)- and; T 2 It does not exist, or C1-C 10 It is alkylene; R 21 is hydrogen; B 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 24 This may be substituted as appropriate; R 24 These are, independently, halogen, -OH, -SF5, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; Or, B 2 teeth, [ka] and; Ring C 2 is an allele; R 25 These are, independently, a halogen, -OH, or C1-C6 alkyl; m is 0, 1, or 2; R 26 is hydrogen or a C1-C6 alkyl group; Ring D 2 is an allele; R 27 These are, independently, a halogen, -OH, or C1-C6 alkyl; p is 0, 1, or 2; R b Each of these is independently either hydrogen or a C1-C6 alkyl group; R c and R d Each of these is independently hydrogen, a C1-C6 alkyl group, a -L-cycloalkyl group, or a -L-aryl group, where each alkyl group, cycloalkyl group, and aryl group may be independently substituted with one or more R groups as appropriate; L is either nonexistent or a C1-C3 alkylene; R is independently a C1-C3 alkyl, a C1-C3 alkoxy, a -C(=O)OH, or a -C(=O)NH2. [represented by] Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are also disclosed herein.

[0254] Formula (CC): [ka] [In the formula, R 30 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted as appropriate (e.g., with one or more R); or R 30 This is the albumin-binding portion or the payload portion; The remaining elements have the meanings defined in formula (C). Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are also disclosed herein.

[0255] In some embodiments, the conjugate compound of formula (CC) comprises a covalently bonded radioactive isotope.

[0256] Formula (C'): [ka] [In the formula, L B This represents the linker; CL stands for metal chelating agent; Each X is independently N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1 represents the first targeting site that binds to carbonic anhydrase IX; TL2 represents the second targeting region that binds to carbonic anhydrase IX. Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are also disclosed herein.

[0257] Formula (CC'): [ka] [In the formula, L B This represents the linker; Each X is independently N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1 represents the first targeting site that binds to carbonic anhydrase IX; TL2 represents the second targeting site that binds to carbonic anhydrase IX; R 30 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)Ra -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted as appropriate (e.g., with one or more R); or R 30 This is the albumin-binding portion or the payload portion. Conjugates thereof, or pharmaceutically acceptable salts or stereoisomers thereof, are also disclosed herein.

[0258] In some embodiments, the conjugate compound of formula (CC') comprises a covalently bonded radioactive isotope.

[0259] In some embodiments of the compound of formula (C') or (CC'), TL1 is identical. In some embodiments of the compound of formula (C') or (CC'), TL1 is different. In some embodiments of the compound of formula (C') or (CC'), TL2 is identical. In some embodiments of the compound of formula (C') or (CC'), TL2 is different. In some embodiments of the compound of formula (C') or (CC'), X is identical. In some embodiments of the compound of formula (C') or (CC'), X is different. In some embodiments of the compound of formula (C') or (CC'), TL1 is independently the target moiety of formula (IC). In some embodiments of the compound of formula (C') or (CC'), TL2 is independently the target moiety of formula (IIC).

[0260] In some embodiments of the compounds of formula (C') or (CC'), TL1 is defined by formula (C), respectively. In some embodiments of the compounds of formula (C') or (CC'), TL2 is defined by formula (C), respectively.

[0261] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), T 1 It is either non-existent or a C1-C3 alkylene.

[0262] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), T 1 It does not exist.

[0263] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), B 1 C1-C 10 Alkylene or cycloalkyl, where the alkylene and cycloalkyl may be appropriately substituted with one or more R, and the C1-C 10The one, two, three, or four carbon atoms of an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR. 11 - may be substituted as appropriate.

[0264] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), B 1 C1-C may be appropriately substituted with one or more Rs. 10 It is an alkylene, where the C1-C 10 The one, two, three, or four carbon atoms of an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR. 11 - may be substituted as appropriate.

[0265] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), B 1 C1-C may be appropriately substituted with one or more Rs. 10 It is alkylene.

[0266] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), B 1 These are C1-C6 alkylenes.

[0267] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), B 1 It is -CH2CH2CH2-.

[0268] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), B 1 It is -CH2CH2CH2CH2-.

[0269] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), B 1 This is a cycloalkyl group which may be appropriately substituted with one or more R groups.

[0270] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), B 1 This is a monocyclic cycloalkyl compound that may be appropriately substituted with one or more R atoms.

[0271] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), B 1 This is a bicyclic cycloalkyl compound that may be appropriately substituted with one or more R atoms.

[0272] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), B 1 These are bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.1.1]hexanyl.

[0273] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), B 1 This is bicyclo[1.1.1]pentanyl.

[0274] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), S 1 It does not exist.

[0275] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), [ka] teeth, [ka] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), [ka] teeth, [ka] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IC), [ka] teeth, [ka] That is the case.

[0276] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 is a heterocycloalkyl, aryl, or heteroaryl, where the heterocycloalkyl, aryl, and heteroaryl are one or more R 22 This may be substituted as appropriate.

[0277] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 is one or more R 22 It is a heterocycloalkyl that may be appropriately substituted.

[0278] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinil, each containing one or more R 22 This may be substituted as appropriate.

[0279] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 is one or more R 22 This is piperidinyl which may be substituted as appropriate.

[0280] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A2 teeth, [ka] Each of these is one or more R 22 This may be substituted as appropriate.

[0281] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 is one or more R 22 It may be replaced as appropriate. [ka] That is the case.

[0282] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 is an aryl or heteroaryl, where the aryl and heteroaryl are one or more R 22 This may be substituted as appropriate.

[0283] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl, each containing one or more R 22 This may be substituted as appropriate.

[0284] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 teeth, [ka] Each of these is one or more R 22 This may be substituted as appropriate.

[0285] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 teeth, [ka] That is the case.

[0286] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), R 22 These are, independently, halogen, -CN, -OH, and -OR. a , -NR c R d , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0287] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), R 22 These are -CN and -C(=O)OR, respectively, independently. b -C(=O)NR c R d It is either a C1-C6 alkyl group or a C1-C6 aminoalkyl group.

[0288] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), R 22 These are, independently, -C(=O)OR b Or -C(=O)NR c R d That is the case.

[0289] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), R 22 These are, independently, -C(=O)NR c R d That is the case.

[0290] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 teeth, [ka] And R 22 These are halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0291] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 teeth, [ka] And R 22 -CN, -C(=O)OR b -C(=O)NR c R d It is either a C1-C6 alkyl group or a C1-C6 aminoalkyl group.

[0292] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 teeth, [ka] And R 22 is -C(=O)OR b Or -C(=O)NR c R d That is the case.

[0293] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 teeth, [ka] And R 22 is -C(=O)NRc R d That is the case.

[0294] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 teeth, [ka] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), A 2 teeth, [ka] That is the case.

[0295] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), R a Each of these is independently or a C1-C6 alkyl group.

[0296] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), R b Each of these is independently either hydrogen or a C1-C6 alkyl group.

[0297] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), R c and R d Each of these is independently hydrogen, a C1-C6 alkyl group, a -L-cycloalkyl group, or a -L-aryl group, where each alkyl group, cycloalkyl group, and aryl group may be independently substituted with one or more R groups as appropriate.

[0298] In some embodiments of compounds of formula (C), (C'), (CC), (CC'), or (IIC), L is either absent or a C1-C3 alkylene.

[0299] In some embodiments of the compounds of formula (C), (C'), (CC), (CC'), or (IIC), R is independently a C1-C3 alkyl, a C1-C3 alkoxy, a -C(=O)OH, or a -C(=O)NH2.

[0300] In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), X is CH. In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), X is CH which may be appropriately substituted with a halogen or C1-C6 alkyl. In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), X is N.

[0301] In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), X is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be appropriately substituted with one or more R; R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O )OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alternatively, two R atoms on the same atom can form an oxo molecule.

[0302] In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), X is a heterocycloalkyl which may be optionally substituted.

[0303] In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), X is a heterocycloalkyl which may be appropriately substituted with one or more R.

[0304] In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), X is a monocyclic heterocycloalkyl which may be appropriately substituted with one or more R.

[0305] In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), X is a bicyclic heterocycloalkyl which may be appropriately substituted with one or more R. In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), X is a spiro-dicyclic heterocycloalkyl which may be appropriately substituted with one or more.

[0306] In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), X is a 4- to 6-membered heterocycloalkyl, which may be appropriately substituted with one or more Rs. In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), X is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which may be appropriately substituted with one or more Rs. In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), X is piperidinyl or piperazinyl, each of which may be appropriately substituted with one or more Rs. In some embodiments of the compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), X is piperidinyl which may be appropriately substituted with one or more R.

[0307] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), [ka] teeth, [ka] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), [ka] teeth, [ka] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), [ka] teeth, [ka] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), [ka] teeth, [ka] In some embodiments of compounds of formula (B), (B'), (BC), (BC'), (C), (C'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0308] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), W 1 -O-, -S-, -NR do not exist. 11 -, -C(=O)-, -C(=O)NR 11 -, or -NR 11 C(=O)-

[0309] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), W 1 -C(=O)- or -C(=O)NR does not exist. 11- is

[0310] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), W 1 It does not exist.

[0311] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), W 1 This is -C(=O)-.

[0312] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), W 1 is -C(=O)NR 11 - is

[0313] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), X 1 is a C1-C6 alkylene which may be appropriately substituted with one or more R, where one or two carbon atoms of the C1-C6 alkylene are -S-, -S(=O)-, -S(=O)2-, -O-, or -NR 11 - may be substituted as appropriate.

[0314] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), X 1 These are C1-C6 alkylenes.

[0315] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), X 1 It is a C1-C4 alkylene.

[0316] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), X 1 It is -CH2-.

[0317] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), X 1 It is -CH2CH2-.

[0318] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), X 1 It is -CH2CH2CH2-.

[0319] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), X 1 It is -CH2CH2CH2CH2-.

[0320] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0321] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0322] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), A 1 It does not exist.

[0323] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), A 1 is a heteroaryl compound that may be appropriately substituted with one or more R compounds.

[0324] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), A 1 This is a triazolyl compound that may be appropriately substituted with one or more R compounds.

[0325] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), A 1 teeth, [ka] Here, R' is hydrogen or R. In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), A 1 teeth, [ka] Here, R' is hydrogen or R. In some embodiments, R' is hydrogen.

[0326] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), A1 This is a heterocycloalkyl that may be appropriately substituted with one or more Rs.

[0327] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), A 1 This is a monocyclic heterocycloalkyl compound that may be appropriately substituted with one or more R atoms.

[0328] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), A 1 This is a bicyclic heterocycloalkyl compound that may be appropriately substituted with one or more R atoms.

[0329] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), A 1 teeth, [ka] That is the case.

[0330] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), T 1 It is either non-existent or a C1-C3 alkylene.

[0331] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), T 1 It does not exist.

[0332] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), B 1This is a cycloalkyl group which may be appropriately substituted with one or more R groups.

[0333] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), B 1 This is a monocyclic cycloalkyl compound that may be appropriately substituted with one or more R atoms.

[0334] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), B 1 This is a bicyclic cycloalkyl compound that may be appropriately substituted with one or more R atoms.

[0335] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), B 1 These are bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.1.1]hexanyl.

[0336] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), B 1 This is bicyclo[1.1.1]pentanyl.

[0337] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), S 1 It does not exist.

[0338] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0339] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0340] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0341] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), Y 1 -O-, -S-, -S(=O)2-, -C(=O)NR do not exist. 11 -, or -NR 11 C(=O)-

[0342] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), Y 1 This is -S(=O)2-.

[0343] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), Y 1 is -C(=O)NR 11 - is

[0344] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0345] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), the ring C 1 is an aryl or heteroaryl compound. In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), the ring C 1 is a phenyl or heteroaryl compound. In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), the ring C 1is a heteroaryl compound. In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), the ring C 1 It is a 5-12 member heteroaryl. In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), the ring C 1 It is a 5-10 member heteroaryl. In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), the ring C 1 It is a 5-6 member heteroaryl. In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), the ring C 1 It is a 7-10 member heteroaryl. In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), the ring C 1 is a monocyclic heteroaryl compound. In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), the ring C 1 is thiadiazolyl or phenyl. In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), the ring C 1 is thiadiazolyl. In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), the ring C 1 It is phenyl.

[0346] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), the ring C 1 It is a bicyclic heteroaryl compound.

[0347] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), the ring C 1 These are benzothiazolyl or imidazothiadiazolyl.

[0348] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] And here, Z 1 These are, independently, -N- or -CR. 12’ -and; Z 2 -O-, -S-, or -NR 12’’ -and; R 12’ These are, independently, hydrogen, halogen, -CN, -OH, and -OR. a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; R 12’’ This is hydrogen, -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl groups.

[0349] In some embodiments, Z 2is -O- or -S-. In some embodiments, Z 2 is -S-. In some embodiments, Z 1 These are -N-, respectively.

[0350] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0351] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0352] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), R 12 These are, independently, halogen, -CN, -OH, and -OR. a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d It is either a C1-C6 alkyl group or a C1-C6 haloalkyl group.

[0353] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), R 12 These are, independently, halogen, -CN, -OH, and -OR. a -S(=O)R a -S(=O)2R a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d It is either a C1-C6 alkyl group or a C1-C6 haloalkyl group.

[0354] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), R 12 These are, independently, halogen and -S(=O)2NR c R d , or -NR c R d That is the case.

[0355] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), R 12 These are, independently, halogen or -NR c R d In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), R 12 One of them is -S(=O)2NR c R d That is the case.

[0356] In some embodiments of the compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), n is 0, 1, 2, 3, 4, or 5. In some embodiments of the compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), n is 0, 1, 2, 3, or 4. In some embodiments of the compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), n is 0, 1, 2, or 3. In some embodiments of the compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), n is 0, 1, or 2.

[0357] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0358] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0359] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] In some embodiments of compounds of formula (B), (B'), (IB), (C), (C'), (IC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0360] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), W 2 It does not exist, -C(=O)-, or -NR 21 C(=O)-

[0361] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), W 2 This is -C(=O)-.

[0362] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), W 2 It does not exist. In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), W 2 This is -C(=O)-.

[0363] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), X 2 This is a C1-C6 alkylene which may be appropriately substituted with one or more R groups.

[0364] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), X 2 This is a C1-C4 alkylene which may be appropriately substituted with one or more R groups.

[0365] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), X 2 It is -CH2-.

[0366] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), X 2 This is -CH2CH[C(=O)OH]- or -CH2CH[C(=O)NH2]-.

[0367] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), X 2 This is -CH2CH2CH[(C=O)OH]- or -CH2CH2CH[C(=O)NH2]-.

[0368] In embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), X 2 This may be appropriately substituted with one or more R, where C1-C 10 One or two carbon atoms in an alkylene can be -S-, -S(=O)-, -S(=O)2-, -O-, or -NR 21It will be replaced with -.

[0369] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), Y 2 -O-, -S-, -NR do not exist. 21 -, -C(=O)-, -C(=O)NR 21 -, or -NR 21 C(=O)-

[0370] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), Y 2 -NR does not exist. 21 -, or -NR 21 C(=O)-

[0371] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), Y 2 -NR 21 C(=O)-

[0372] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0373] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0374] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), S 2 -O-, -S-, -NR do not exist. 21 -, -C(=O)-, -C(=O)NR 21 -, or -NR 21 C(=O)-

[0375] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), S 2 -NR does not exist. 21 -, -C(=O)-, or -NR 21 C(=O)-

[0376] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), S 2 This is -C(=O)- or -NR 21 C(=O)-

[0377] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), T 2 is a C1-C6 alkylene that does not exist or may be appropriately substituted with one or more Rs.

[0378] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), T 2 This is a C1-C6 alkylene which may be appropriately substituted with one or more R groups.

[0379] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), T 2 It is -CH2CH2-.

[0380] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), T 2 It is -CH2CH2CH2-.

[0381] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), [ka] teeth, [ka] That is the case.

[0382] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2 It does not exist.

[0383] In embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2is -N(R 23 )2. In embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2 It is -CF3.

[0384] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R 24 This may be substituted as appropriate.

[0385] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2 is one or more R 24 It is a cycloalkyl that may be appropriately substituted.

[0386] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2 is one or more R 24 It is a monocyclic cycloalkyl that may be appropriately substituted.

[0387] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2 is one or more R 24 It is a bicyclic cycloalkyl that may be appropriately substituted with other compounds.

[0388] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2is one or more R 24 This is a phenyl compound that may be appropriately substituted.

[0389] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2 is one or more R 24 It is a heteroaryl that may be substituted as appropriate.

[0390] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2 is one or more R 24 It is a 5-10 member heteroaryl (e.g., monocyclic or bicyclic heteroaryl) which may be substituted as appropriate.

[0391] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2 is one or more R 24 It is a 5-6 member heteroaryl that may be substituted as appropriate.

[0392] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2 These are indazolyl, phenyl, pyridyl, pyridinyl, pyrazinyl, pyridadinyl, cyclopropyl, cyclohexyl, cyclobutyl, cycloheptyl, pyrazolyl, oxazolyl, triazolyl, spiroheptanil, or bicycloheptanil.

[0393] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), R 24 These are, independently, halogen, -CN, -OH, and -OR. a , -NRc R d The elements are -SF5, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate.

[0394] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), R 24 These are, independently, a halogen, -OH, C1-C6 alkyl, or C1-C6 haloalkyl.

[0395] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2 teeth, [ka] And in the formula, Ring C 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 25 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NRb C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; m is 0, 1, 2, 3, or 4; R 26 These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Ring D 2 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 27 These are, independently, halogen, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)ORb , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; p is 0, 1, 2, 3, or 4.

[0396] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), the ring C 2 It is phenyl.

[0397] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), R 25 These are, independently, halogen, -CN, -OH, and -OR. a -SF5, -SH, -SR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), R 25 These are, independently, halogen, -CN, -OH, and -OR. a , -NR c R d, or C1-C6 alkyl. In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), R 25 Each of these is independently -OH.

[0398] In some embodiments of the compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), m is 0 or 1. In some embodiments of the compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), m is 0, 1, or 2. In some embodiments of the compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), m is 0. In some embodiments of the compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), m is 1. In some embodiments of the compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), m is 2. In some embodiments of the compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), m is 3.

[0399] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), ring D 2 It is phenyl.

[0400] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), R 27 These are, independently, halogen, -CN, -OH, and -OR. a -SF5, -SH, -SR a , -NRc R d These are C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), R 27 These are, independently, halogen, -CN, -OH, and -OR. a , -NR c R d , or C1-C6 alkyl. In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), R 27 Each of these is independently -OH.

[0401] In some embodiments of the compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), p is 0 or 1. In some embodiments of the compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), p is 0, 1, or 2. In some embodiments of the compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), p is 0. In some embodiments of the compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), p is 1. In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), p is 2. In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), p is 3.

[0402] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), R 26 R is hydrogen or a C1-C6 alkyl group. In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), R 26 It is a C1-C6 alkyl group.

[0403] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), B 2 teeth, [ka] That is the case.

[0404] In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), R 11 R is hydrogen or a C1-C6 alkyl group. In some embodiments of compounds of formula (B), (B'), (IIB), (C), (C'), (IIC), (BC), (BC'), (CC), or (CC'), R 11 It is hydrogen.

[0405] In some embodiments of the compounds of formula (A'), (A), (B), (B'), (C), (C'), (AC), (AC'), (BC), (BC'), (CC), or (CC'), TL1 and TL2 bind to different sites on the same carbonic anhydrase IX protein. In some embodiments of the compounds of formula (A'), (A), (B), (B'), (C), (C'), (AC), (AC'), (BC), (BC'), (CC), or (CC'), TL1 is a target portion that binds to the carbonic anhydrase IX protein at a first binding site. In some embodiments of the compounds of formula (A'), (A), (B), (B'), (C), (C'), (AC), (AC'), (BC), (BC'), (CC), or (CC'), TL1 is a target moiety that binds to carbonic anhydrase IX protein at a site different from the binding site of TL2. In some embodiments of the compounds of formula (A'), (A), (B), (B'), (C), (C'), (AC), (AC'), (BC), (BC'), (CC), or (CC'), TL2 is a target moiety that binds to carbonic anhydrase IX protein at a second binding site. In some embodiments of compounds of formula (A'), (A), (B), (B'), (C), (C'), (AC), (AC'), (BC), (BC'), (CC), or (CC'), TL2 is a target portion that binds to carbonic anhydrase IX protein at a site different from the binding site of TL1.

[0406] In some embodiments of the compounds of formula (A), (B), (C), (AC), (BC), or (CC), s is 0.

[0407] In some embodiments of the compounds of formula (A), (B), (C), (AC), (BC), or (CC), s is 1.

[0408] In some embodiments of compounds of formula (A), (B), (C), (AC), (BC), or (CC), the linker contains 1 to 30 interposing atoms selected from C, N, O, S, and Si between the metal chelating agent (CL) and the target ligand (TL).

[0409] In some embodiments of compounds of formula (A), (B), (C), (AC), (BC), or (CC), the linker contains 1 to 20 interposing atoms selected from C, N, O, S, and Si between the metal chelating agent (CL) and the target ligand (TL).

[0410] In some embodiments of compounds of formula (A), (B), (C), (AC), (BC), or (CC), the linker contains 1 to 10 interposing atoms selected from C, N, O, S, and Si between the metal chelating agent (CL) and the target ligand (TL).

[0411] In some embodiments of the compounds of formula (A), (B), (C), (AC), (BC), or (CC), the intervening atoms include C, N, or O. In some embodiments of the compounds of formula (A), (B), (C), (AC), (BC), or (CC), the intervening atoms include at least one N atom.

[0412] In some embodiments of the compounds of formula (A), (B), (C), (AC), (BC), or (CC), the intervening atom contains at least one oxygen atom.

[0413] In some embodiments of the compounds of formula (A), (B), (C), (AC), (BC), or (CC), the linker comprises one or more amino acid residues.

[0414] In some embodiments of the compounds of formula (A), (B), (C), (AC), (BC), or (CC), the linker contains one or more PEG moieties. In some embodiments of the compounds of formula (A), (B), (C), (AC), (BC), or (CC), the linker contains two to eight PEG moieties. In some embodiments of the compounds of formula (A), (B), (C), (AC), (BC), or (CC), the linker contains two PEG moieties. In some embodiments of the compounds of formula (A), (B), (C), (AC), (BC), or (CC), the linker contains eight PEG moieties.

[0415] In some embodiments of compounds of formula (A), (B), (C), (AC), (BC), or (CC), linker L A Equation (L-1): [ka] [In the formula, L 0 These are -O- and -NR, respectively, independently. L -, -N(R L )2 + -, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L C(=S)NR L -, -CR L =N-, -N=CR L , -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, -S(=O)2NR L C(=O)-, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, C1-C 30 Alkylene, C2-C 30 Alkenylene, C2-C 30 Alkynylene, C1-C 30 Heteroalkylene, -(C1-C 30 Alkylene)-O-,-O-(C1-C 30 Alkylene)-,-(C1-C 30 Alkylene)-NR L -, -NR L -(C1-C 30 Alkylene)-,-(C1-C 30 Alkylene)-N(R L )2+ -, or -N(R L )2 + -(C1-C 30 Alkylene)-, where each cycloalkylene, heterocycloalkylene, arylene, heteroarylene, alkylene, alkenylene, alkynylene, and heteroalkylene may be independently substituted with one or more R as appropriate; R L Each of these is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; k is between 1 and 20; R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O )OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alternatively, two R atoms on the same atom may form an oxo molecule. It has the structure of [the object].

[0416] In some embodiments of compounds of formula (A), (B), (C), (AC), (BC), or (CC), linker L A Equation (L-1): [ka] [In the formula, L 0These are -O- and -NR, respectively, independently. L -, -C(=O)-, -OC(=O)-, -C(=O)NR L -, -NR L C(=O)-, cycloalkylene, heterocycloalkylene, C1-C 30 Alkylene, -(C1-C 30 Alkylene)-O-, or -O-(C1-C 30 Alkylene)-, where each cycloalkylene, heterocycloalkylene, and alkylene may be independently substituted with one or more R as appropriate; R L Each of these is independently either hydrogen or a C1-C4 alkyl group; k is between 1 and 20; R is independently -C(=O)OH. It has the structure of [the object].

[0417] In some embodiments of the compound of formula (L-1), L 0 These are -O- and -NR, respectively, independently. L -, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR L -, -NR L C(=O)-, cycloalkylene, heterocycloalkylene, C1-C 30 Alkylene, C1-C 30 Heteroalkylene, -(C1-C 30 Alkylene)-O-,-O-(C1-C 30 Alkylene)-,-(C1-C 30 Alkylene)-NR L -, or -NR L -(C1-C 30 Alkylene)-, where each cycloalkylene, heterocycloalkylene, alkylene, and heteroalkylene may be independently substituted with one or more R as appropriate.

[0418] In some embodiments of the compound of formula (L-1), L 0 These are -O- and -NR, respectively, independently. L-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR L -, -NR L C(=O)-, heterocycloalkylene, C1-C 30 Alkylene, C1-C 30 Heteroalkylene, -(C1-C 30 Alkylene)-O-, or -O-(C1-C 30 Alkylene)-, where heterocycloalkylene, alkylene, and heteroalkylene may each be independently substituted with one or more R as appropriate.

[0419] In some embodiments of the compound of formula (L-1), L 0 These are -O- and -NR, respectively, independently. L -, -C(=O)-, -OC(=O)-, -NR L C(=O)-, heterocycloalkylene, C1-C 30 Alkylene, C1-C 30 Heteroalkylene, or -O-(C1-C 30 Alkylene)-, where heterocycloalkylene, alkylene, and heteroalkylene may each be independently substituted with one or more R as appropriate.

[0420] In some embodiments of the compound of formula (L-1), L 0 These are -O- and -NR, respectively, independently. L -, -C(=O)-, -OC(=O)-, -NR L C(=O)-, heterocycloalkylene, C1-C6alkylene, C1-C6 heteroalkylene, or -O-(C1-C6alkylene)-, where heterocycloalkylene, alkylene, and heteroalkylene may each be independently substituted with one or more R as appropriate.

[0421] In some embodiments of the compound of formula (L-1), L 0 These are -O- and -NR, respectively, independently. L -, -C(=O)-, -OC(=O)-, -NR LC(=O)-, heterocycloalkylene, C1-C4 alkylene, C1-C4 heteroalkylene, or -O-(C1-C4 alkylene)-, where heterocycloalkylene, alkylene, and heteroalkylene may each be independently substituted with one or more R as appropriate.

[0422] In some embodiments of the compound of formula (L-1), R L Each is independently hydrogen or a C1-C4 alkyl group. In some embodiments of the compound of formula (L-1), R L These are hydrogen atoms, respectively.

[0423] In some embodiments of the compound of formula (L-1), k is 1 to 15. In some embodiments of the compound of formula (L-1), k is 1 to 14. In some embodiments of the compound of formula (L-1), k is 1 to 13. In some embodiments of the compound of formula (L-1), k is 1 to 12. In some embodiments of the compound of formula (L-1), k is 1 to 11. In some embodiments of the compound of formula (L-1), k is 1 to 10. In some embodiments of the compound of formula (L-1), k is 1 to 9. In some embodiments of the compound of formula (L-1), k is 1 to 8. In some embodiments of the compound of formula (L-1), k is 1 to 7. In some embodiments of the compound of formula (L-1), k is 1 to 6. In some embodiments of the compound of formula (L-1), k is 1 to 5. In some embodiments of the compound of formula (L-1), k is 1 to 4. In some embodiments of the compound of formula (L-1), k is 1 to 3. In some embodiments of the compound of formula (L-1), k is 1 or 2.

[0424] In some embodiments of compounds of formula (A), (B), (C), (AC), (BC), or (CC), linker L A Equation (L-1a): [ka] [In the formula, L 1 It does not exist, -O-, -NR L -, -N(R L )2 + -, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, or -S(=O)2NR L C(=O)- and; L 2 teeth, [ka] , C1-C 10 An alkylene, or a heterocycloalkylene which may be appropriately substituted with one or more R; L 3 It does not exist, or C1-C 10 It is alkylene; L 4 It does not exist, -O-, -NR L -, -N(R L )2 + -, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, or -S(=O)2NRL C(=O)- It has the structure of [the object].

[0425] In some embodiments of compounds of formula (A), (B), (C), (AC), (BC), or (CC), linker L A Equation (L-1a): [ka] [In the formula, L 1 is nonexistent, -O-, or -NR L -and; L 2 teeth, [ka] , C1-C 10 An alkylene, or a heterocycloalkylene which may be appropriately substituted with one or more R; L 3 It does not exist, or C1-C 10 It is alkylene; L 4 It does not exist, -O-, -NR L -, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR L -, or -NR L C(=O)- It has the structure of [the object].

[0426] In some embodiments of the compound of formula (L-1a), L 1 It does not exist, -O-, -NR L -, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR L -, or -NR L It is C(=O)-. In some embodiments of the compound of formula (L-1a), L 1 is nonexistent, -O-, or -NR L - is the case. In some embodiments of the compound of formula (L-1a), L 1 It does not exist, or -NR L- is the case. In some embodiments of the compound of formula (L-1a), L 1 It does not exist, or it is -NH-.

[0427] In some embodiments of the compound of formula (L-1a), L 2 teeth, [ka] , C1-C6 alkylene, or heterocycloalkylene which may be appropriately substituted with one or more R. In some embodiments of the compound of formula (L-1a), L 2 teeth, [ka] , C1-C4 alkylene, or heterocycloalkylene which may be appropriately substituted with one or more R. In some embodiments of the compound of formula (L-1a), L 2 teeth, [ka] Alternatively, it is a heterocycloalkylene that may be appropriately substituted with one or more Rs.

[0428] In some embodiments of the compound of formula (L-1a), L 2 teeth, [ka] In some embodiments of the compound of formula (L-1a), L 2 teeth, [ka] In some embodiments of the compound of formula (L-1a), L 2 teeth, [ka] In some embodiments of the compound of formula (L-1a), L 2 teeth, [ka] That is the case.

[0429] In some embodiments of the compound of formula (L-1a), L 2 C1-C 10 It is an alkylene. In some embodiments of the compound of formula (L-1a), L 2 L is a C1-C6 alkylene. In some embodiments of the compound of formula (L-1a), L 2 It is a C1-C4 alkylene.

[0430] In some embodiments of the compound of formula (L-1a), L 2 is a heterocycloalkylene which may be appropriately substituted with one or more R. In some embodiments of the compound of formula (L-1a), L 2 is a monocyclic heterocycloalkylene which may be appropriately substituted with one or more R. In some embodiments of the compound of formula (L-1a), L 2 is a bicyclic heterocycloalkylene which may be appropriately substituted with one or more R. In some embodiments of the compound of formula (L-1a), L 2 is piperidinylene, azetidinylene, or diazaspiroheptanylene, each of which may be appropriately substituted with one or more Rs.

[0431] In some embodiments of the compound of formula (L-1a), L 3 It does not exist. In some embodiments of the compound of formula (L-1a), L 3 It is -CH2-.

[0432] In some embodiments of the compound of formula (L-1a), L 4 It does not exist, -O-, -NR L -, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR L -, or -NR L It is C(=O)-. In some embodiments of the compound of formula (L-1a), L4 -C(=O)-, -OC(=O)-, or -NR does not exist. L It is C(=O)-. In some embodiments of the compound of formula (L-1a), L 4 It does not exist; it is -C(=O)-, -OC(=O)-, or -NHC(=O)-.

[0433] In some embodiments of compounds of formula (A), (B), (C), (AC), (BC), or (CC), linker L A teeth, [ka] That is the case.

[0434] In some embodiments of compounds of formula (A), (B), (C), (AC), (BC), or (CC), linker L A Equation (L-2): [ka] [In the formula, L 1 , L 2 , and L 3 These are -O- and -NR, respectively, independently. L -, -N(R L )2 + -, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L C(=S)NR L -, -CR L =N-, -N=CR L , -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NRL S(=O)2-, -S(=O)2NR L C(=O)-, C3-C 15 Cycloalkylene, C1-C 12 Heterocycloalkylene, arylene, heteroarylene, C1-C 30 Alkylene, C2-C 30 Alkenylene, C2-C 30 Alkynylene, C1-C 30 Heteroalkylene, -(C1-C 30 Alkylene)-O-,-O-(C1-C 30 Alkylene)-,-(C1-C 30 Alkylene)-NR L -, -NR L -(C1-C 30 Alkylene)-,-(C1-C 30 Alkylene)-N(R L )2 + -, or -N(R L )2 + -(C1-C 30 Alkylene)-, where each cycloalkylene, heterocycloalkylene, arylene, heteroarylene, alkylene, alkenylene, alkynylene, and heteroalkylene may be independently substituted with one or more R as appropriate; R H This is the hydrophobic part; Y is N or CR L and; R L Each of these is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; k1 is between 0 and 20; k2 is between 0 and 15; k3 is between 0 and 15; R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O )OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alternatively, two R atoms on the same atom may form an oxo molecule. It has the structure of [the object].

[0435] In some embodiments of compounds of formula (A), (B), (C), (AC), (BC), or (CC), linker L A Equation (L-2): [ka] [In the formula, L 1 , L 2 , and L 3 These are -O- and -NR, respectively, independently. L -, or -C(=O)-; R H This is the hydrophobic part; Y is N or CR L and; R L Each of these is independently either hydrogen or a C1-C4 alkyl group; k1 is between 0 and 20; k2 is between 0 and 15; k3 is between 0 and 15. It has the structure of [the object].

[0436] In some embodiments of the compound of formula (L-2), L 2 and L 3 These are -O- and -NR, respectively, independently. L -, -N(R L )2 + -, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -O-(CH2CH2)-O-(CH2CH2), or a C1-C6 alkylene which may be appropriately substituted with one or more R groups independently; R L is hydrogen or a C1-C4 alkyl group; k2 is between 1 and 5; k3 is between 1 and 5.

[0437] In some embodiments of the compound of formula (L-2), L 1 These are -O- and -NR, respectively, independently. L -, -N(R L )2 + -, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -O-(CH2CH2), or a C1-C6 alkylene which may be appropriately substituted with one or more R groups independently; R L is hydrogen or a C1-C4 alkyl group; k1 is between 1 and 15; k2 is between 1 and 15.

[0438] In some embodiments of the compound of formula (L-2), L2 and L 3 These are -O- and -NR, respectively, independently. L -, -N(R L )2 + -, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L It is a C1-C6 alkylene that may be appropriately substituted with -, -O-(CH2CH2), or one or more R groups independently.

[0439] In some embodiments of the compound of formula (L-2), L 2 and L 3 These are -O- and -NR, respectively, independently. L -, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR L -, -NR L It is a C1-C6 alkylene that may be C(=O)-, -O-(CH2CH2), or independently substituted with one or more R as appropriate.

[0440] In some embodiments of the compound of formula (L-2), L 2 and L 3 These are -O- and -NR, respectively, independently. L It is a C1-C6 alkylene which may be appropriately substituted with -, -C(=O)-, -O-(CH2CH2), or one or more R groups independently.

[0441] In some embodiments of the compound of formula (L-2), L 2 and L 3 These are -O- and -NR, respectively, independently. L -, or -C(=O)-.

[0442] In some embodiments of the compound of formula (L-2), L 2 and L 3These are, independently, -NH- or -C(=O)-.

[0443] In some embodiments of the compound of formula (L-2), L 1 These are -O- and -NR, respectively, independently. L -, -N(R L )2 + -, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L It is a C1-C6 alkylene that may be appropriately substituted with -, -O-(CH2CH2), or one or more R groups independently.

[0444] In some embodiments of the compound of formula (L-2), L 1 These are -O- and -NR, respectively, independently. L -, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR L -, -NR L It is a C1-C6 alkylene that may be C(=O)-, -O-(CH2CH2), or independently substituted with one or more R as appropriate.

[0445] In some embodiments of the compound of formula (L-2), L 1 These are, independently, -C(=O)NR L -, -NR L It is a C1-C6 alkylene that may be C(=O)-, -O-(CH2CH2), or independently substituted with one or more R as appropriate.

[0446] In some embodiments of the compound of formula (L-2), L 1 These are C1-C6 alkylenes that may be independently substituted with -C(=O)NH-, -NHC(=O)-, -O-(CH2CH2), or one or more R groups as appropriate.

[0447] In some embodiments of the compound of formula (L-2), R L R is hydrogen or a C1-C4 alkyl group. In some embodiments of the compound of formula (L-2), L It is hydrogen.

[0448] In some embodiments of the compound of formula (L-2), k1 is 1 to 19. In some embodiments of the compound of formula (L-2), k1 is 1 to 18. In some embodiments of the compound of formula (L-2), k1 is 1 to 17. In some embodiments of the compound of formula (L-2), k1 is 1 to 16. In some embodiments of the compound of formula (L-2), k1 is 1 to 15. In some embodiments of the compound of formula (L-2), k1 is 1 to 14. In some embodiments of the compound of formula (L-2), k1 is 1 to 13. In some embodiments of the compound of formula (L-2), k1 is 1 to 12. In some embodiments of the compound of formula (L-2), k1 is 1 to 11. In some embodiments of the compound of formula (L-2), k1 is 1 to 10. In some embodiments of the compound of formula (L-2), k1 is 1 to 9. In some embodiments of the compound of formula (L-2), k1 is 1 to 8. In some embodiments of the compound of formula (L-2), k1 is 1 to 7. In some embodiments of the compound of formula (L-2), k1 is 1 to 6. In some embodiments of the compound of formula (L-2), k1 is 1 to 5. In some embodiments of the compound of formula (L-2), k1 is 1 to 4. In some embodiments of the compound of formula (L-2), k1 is 1 to 3. In some embodiments of the compound of formula (L-2), k1 is 1 or 2.

[0449] In some embodiments of the compound of formula (L-2), k2 is 1 to 14. In some embodiments of the compound of formula (L-2), k2 is 1 to 13. In some embodiments of the compound of formula (L-2), k2 is 1 to 12. In some embodiments of the compound of formula (L-2), k2 is 1 to 11. In some embodiments of the compound of formula (L-2), k2 is 1 to 10. In some embodiments of the compound of formula (L-2), k2 is 1 to 9. In some embodiments of the compound of formula (L-2), k2 is 1 to 8. In some embodiments of the compound of formula (L-2), k2 is 1 to 7. In some embodiments of the compound of formula (L-2), k2 is 1 to 6. In some embodiments of the compound of formula (L-2), k2 is 1 to 5. In some embodiments of the compound of formula (L-2), k2 is 1 to 4. In some embodiments of the compound of formula (L-2), k2 is 1 to 3. In some embodiments of the compound of formula (L-2), k2 is 1 or 2.

[0450] In some embodiments of the compound of formula (L-2), k3 is 1 to 14. In some embodiments of the compound of formula (L-2), k3 is 1 to 13. In some embodiments of the compound of formula (L-2), k3 is 1 to 12. In some embodiments of the compound of formula (L-2), k3 is 1 to 11. In some embodiments of the compound of formula (L-2), k3 is 1 to 10. In some embodiments of the compound of formula (L-2), k3 is 1 to 9. In some embodiments of the compound of formula (L-2), k3 is 1 to 8. In some embodiments of the compound of formula (L-2), k3 is 1 to 7. In some embodiments of the compound of formula (L-2), k3 is 1 to 6. In some embodiments of the compound of formula (L-2), k3 is 1 to 5. In some embodiments of the compound of formula (L-2), k3 is 1 to 4. In some embodiments of the compound of formula (L-2), k3 is 1 to 3. In some embodiments of the compound of formula (L-2), k3 is 1 or 2.

[0451] In some embodiments of the compound of formula (L-2), R H This is a fatty acid chain, C6-C 10 The alkyl chain, sterol, aryl, or heteroaryl, where the aryl and heteroaryl may be appropriately substituted with one or more R; R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O These are OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl.

[0452] In some embodiments of the compound of formula (L-2), R H This is a phenyl compound substituted with a halogen or a C1-C3 alkyl group.

[0453] In some embodiments of compounds of formula (A), (B), (C), (AC), (BC), or (CC), linker L A teeth, [ka] That is the case.

[0454] In some embodiments of compounds of formula (A), (B), (C), (AC), (BC), or (CC), linker L A teeth, [ka] That is the case.

[0455] In some embodiments of compounds of formula (A'), (B'), (C'), (AC'), (BC'), or (CC'), linker L B Equation (L-3): [ka] [In the formula, L 1 , L 2 , and L 3 These are -O- and -NR, respectively, independently. L -, -N(R L )2 + -, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L C(=S)NR L -, -CR L =N-, -N=CR L , -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, -S(=O)2NR L C(=O)-, C3-C 15 Cycloalkylene, C1-C 12 Heterocycloalkylene, arylene, heteroarylene, C1-C 30 Alkylene, C2-C 30 Alkenylene, C2-C 30 Alkynylene, C1-C 30 Heteroalkylene, -(C1-C 30 Alkylene)-O-,-O-(C1-C 30 Alkylene)-,-(C1-C 30 Alkylene)-NRL -, -NR L -(C1-C 30 Alkylene)-,-(C1-C 30 Alkylene)-N(R L )2 + -, or -N(R L )2 + -(C1-C 30 Alkylene)-, where each cycloalkylene, heterocycloalkylene, arylene, heteroarylene, alkylene, alkenylene, alkynylene, and heteroalkylene may be independently substituted with one or more R as appropriate; Y is N or CR L and; R L Each of these is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; k1 is between 0 and 15; k2 is between 0 and 15; k3 is between 0 and 15; R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O )OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alternatively, two R atoms on the same atom may form an oxo molecule. It has the structure of [the object].

[0456] In some embodiments of compounds of formula (A'), (B'), (C'), (AC'), (BC'), or (CC'), linker L B Equation (L-3): [ka] [In the formula, L 1 , L 2 , and L 3 These are -O- and -NR, respectively, independently. L -, -C(=O)-, C1-C 30 Alkylene, -(C1-C 30 Alkylene)-O-, or -O-(C1-C 30 Alkylene)- and; Y is N or CR L and; R L Each of these is independently either hydrogen or a C1-C4 alkyl group; k1 is between 0 and 15; k2 is between 0 and 15; k3 is between 0 and 15. It has the structure of [the object].

[0457] In some embodiments of the compound of formula (L-3), L 2 and L 3 These are -O- and -NR, respectively, independently. L -, -N(R L )2 + -, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L It is a C1-C6 alkylene that may be appropriately substituted with -, -O-(CH2CH2), or one or more R groups independently.

[0458] In some embodiments of the compound of formula (L-3), L 2and L 3 These are -O- and -NR, respectively, independently. L -, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR L -, -NR L It is a C1-C6 alkylene that may be C(=O)-, -O-(CH2CH2), or independently substituted with one or more R as appropriate.

[0459] In some embodiments of the compound of formula (L-3), L 2 and L 3 These are -O- and -NR, respectively, independently. L It is a C1-C6 alkylene which may be appropriately substituted with -, -C(=O)-, -O-(CH2CH2), or one or more R groups independently.

[0460] In some embodiments of the compound of formula (L-3), L 2 and L 3 These are C1-C6 alkylenes, each independently substituted with -C(=O)-, -O-(CH2CH2), or one or more R groups as appropriate.

[0461] In some embodiments of the compound of formula (L-3), L 2 and L 3 These are, independently, -C(=O)-, -O-(CH2CH2), or C1-C6 alkylene.

[0462] In some embodiments of the compound of formula (L-3), L 2 and L 3 These are, independently, -C(=O)- or C1-C6 alkylenes.

[0463] In some embodiments of the compound of formula (L-3), L 1 These are -O- and -NR, respectively, independently. L -, -N(R L )2 + -, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L-, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L It is a C1-C6 alkylene that may be appropriately substituted with -, -O-(CH2CH2), or one or more R groups independently.

[0464] In some embodiments of the compound of formula (L-3), L 1 These are -O- and -NR, respectively, independently. L -, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR L It is a C1-C6 alkylene that may be appropriately substituted with -, -O-(CH2CH2), or one or more R groups independently.

[0465] In some embodiments of the compound of formula (L-3), L 1 These are -O- and -NR, respectively, independently. L It is a C1-C6 alkylene which may be appropriately substituted with -, -C(=O)-, -O-(CH2CH2), or one or more R groups independently.

[0466] In some embodiments of the compound of formula (L-3), L 1 These are, independently, -NR L It is a C1-C6 alkylene which may be appropriately substituted with -, -C(=O)-, or one or more R groups independently.

[0467] In some embodiments of the compound of formula (L-3), L 1 These are, independently, -NR L - is

[0468] In some embodiments of the compound of formula (L-3), Y is N or CR. L In some embodiments of the compound of formula (L-3), Y is N. In some embodiments of the compound of formula (L-3), Y is CR. LIn some embodiments of the compound of formula (L-3), Y is CH.

[0469] In some embodiments of the compound of formula (L-3), k1 is 1 to 15. In some embodiments of the compound of formula (L-3), k1 is 1 to 14. In some embodiments of the compound of formula (L-3), k1 is 1 to 13. In some embodiments of the compound of formula (L-3), k1 is 1 to 12. In some embodiments of the compound of formula (L-3), k1 is 1 to 11. In some embodiments of the compound of formula (L-3), k1 is 1 to 10. In some embodiments of the compound of formula (L-3), k1 is 1 to 9. In some embodiments of the compound of formula (L-3), k1 is 1 to 8. In some embodiments of the compound of formula (L-3), k1 is 1 to 7. In some embodiments of the compound of formula (L-3), k1 is 1 to 6. In some embodiments of the compound of formula (L-3), k1 is 1 to 5. In some embodiments of the compound of formula (L-3), k1 is 1 to 4. In some embodiments of the compound of formula (L-3), k1 is 1 to 3. In some embodiments of the compound of formula (L-3), k1 is 1 or 2. In some embodiments of the compound of formula (L-3), k1 is 0 to 2. In some embodiments of the compound of formula (L-3), k1 is 0 or 1. In some embodiments of the compound of formula (L-3), k1 is 0. In some embodiments of the compound of formula (L-3), k1 is 1. In some embodiments of the compound of formula (L-3), k1 is 2. In some embodiments of the compound of formula (L-3), k1 is 3. In some embodiments of the compound of formula (L-3), k1 is 4.

[0470] In some embodiments of the compound of formula (L-3), k2 is 1 to 14. In some embodiments of the compound of formula (L-3), k2 is 1 to 13. In some embodiments of the compound of formula (L-3), k2 is 1 to 12. In some embodiments of the compound of formula (L-3), k2 is 1 to 11. In some embodiments of the compound of formula (L-3), k2 is 1 to 10. In some embodiments of the compound of formula (L-3), k2 is 1 to 9. In some embodiments of the compound of formula (L-3), k2 is 1 to 8. In some embodiments of the compound of formula (L-3), k2 is 1 to 7. In some embodiments of the compound of formula (L-3), k2 is 1 to 6. In some embodiments of the compound of formula (L-3), k2 is 1 to 5. In some embodiments of the compound of formula (L-3), k2 is 1 to 4. In some embodiments of the compound of formula (L-3), k2 is 1 to 3. In some embodiments of the compound of formula (L-3), k2 is 1 or 2.

[0471] In some embodiments of the compound of formula (L-3), k3 is 1 to 14. In some embodiments of the compound of formula (L-3), k3 is 1 to 13. In some embodiments of the compound of formula (L-3), k3 is 1 to 12. In some embodiments of the compound of formula (L-3), k3 is 1 to 11. In some embodiments of the compound of formula (L-3), k3 is 1 to 10. In some embodiments of the compound of formula (L-3), k3 is 1 to 9. In some embodiments of the compound of formula (L-3), k3 is 1 to 8. In some embodiments of the compound of formula (L-3), k3 is 1 to 7. In some embodiments of the compound of formula (L-3), k3 is 1 to 6. In some embodiments of the compound of formula (L-3), k3 is 1 to 5. In some embodiments of the compound of formula (L-3), k3 is 1 to 4. In some embodiments of the compound of formula (L-3), k3 is 1 to 3. In some embodiments of the compound of formula (L-3), k3 is 1 or 2.

[0472] In some embodiments of compounds of formula (A'), (B'), (C'), (AC'), (BC'), or (CC'), linker L B teeth, [ka] That is the case.

[0473] In some embodiments of compounds of formula (A'), (B'), (C'), (AC'), (BC'), or (CC'), linker L B teeth, [ka] That is the case.

[0474] In some embodiments of the compounds disclosed herein, R a Each of these is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl may each be independently substituted with one or more R as appropriate. In some embodiments of the compounds disclosed herein, R a Each of these is independently a C1-C6 alkyl, a C1-C6 haloalkyl, an -L-cycloalkyl, or an -L-heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl may be independently substituted with one or more R as appropriate. In some embodiments of the compounds disclosed herein, R a Each of these is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, where each alkyl may be independently substituted with one or more R as appropriate. In some embodiments of the compounds disclosed herein, R aEach is independently a C1-C6 alkyl or a C1-C6 haloalkyl, where each alkyl may be independently substituted with one or more R as appropriate. In some embodiments of the compounds disclosed herein, R a Each is independently a C1-C6 alkyl or a C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R a Each of these is independently a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, R a Each of these is independently a C1-C6 haloalkyl group.

[0475] In some embodiments of the compounds disclosed herein, R b Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl may each be independently substituted with one or more R as appropriate. In some embodiments of the compounds disclosed herein, R b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, an -L-cycloalkyl, or an -L-heterocycloalkyl, where the alkyl, cycloalkyl, and heterocycloalkyl may each be independently substituted with one or more R as appropriate. In some embodiments of the compounds disclosed herein, R b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 hydroxyalkyl, a C1-C6 aminoalkyl, or a C1-C6 heteroalkyl, where each alkyl may be independently substituted with one or more R as appropriate. In some embodiments of the compounds disclosed herein, R bEach is independently hydrogen, a C1-C6 alkyl, or a C1-C6 haloalkyl, where each alkyl may be independently substituted with one or more R as appropriate. In some embodiments of the compounds disclosed herein, R b R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, R b Each is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, R b Each is independently hydrogen or a C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R b R is hydrogen, respectively. In some embodiments of the compounds disclosed herein, R b Each of these is independently a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, R b Each of these is independently a C1-C6 haloalkyl group.

[0476] In some embodiments of the compounds disclosed herein, R b Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl may each be independently substituted with one or more R as appropriate. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, an -L-cycloalkyl, or an -L-heterocycloalkyl, where the alkyl, cycloalkyl, and heterocycloalkyl may each be independently substituted with one or more R as appropriate. In some embodiments of the compounds disclosed herein, R c and R dEach of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 hydroxyalkyl, a C1-C6 aminoalkyl, or a C1-C6 heteroalkyl, where each alkyl may be independently substituted with one or more R as appropriate. In some embodiments of the compounds disclosed herein, R c and R d Each is independently hydrogen, a C1-C6 alkyl, or a C1-C6 haloalkyl, where each alkyl may be independently substituted with one or more R as appropriate. In some embodiments of the compounds disclosed herein, R c and R d R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, R c and R d Each is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, R c and R d Each is independently hydrogen or a C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R c and R d R is hydrogen, respectively. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently a C1-C6 haloalkyl group.

[0477] In some embodiments of the compounds disclosed herein, R c and R d These, together with the atoms to which they are bonded, form a heterocycloalkyl group which may be appropriately substituted with one or more R atoms.

[0478] In some embodiments of the compounds disclosed herein, L is absent or a C1-C3 alkylene. In some embodiments of the compounds disclosed herein, L is absent. In some embodiments of the compounds disclosed herein, L is a C1-C3 alkylene. In some embodiments of the compounds disclosed herein, L is -CH2-. In some embodiments of the compounds disclosed herein, L is -CH2CH2-. In some embodiments of the compounds disclosed herein, L is -CH2CH2CH2-.

[0479] In some embodiments of the compounds disclosed herein, R is independently a halogen, -CN, -OH, -SF5, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl. In some embodiments of the compounds disclosed herein, R is independently a halogen, -CN, -OH, -SF5, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl. In some embodiments of the compounds disclosed herein, R is independently a halogen, -CN, -OH, -SF5, -NH2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl. In some embodiments of the compounds disclosed herein, R is independently a halogen, -CN, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl.In some embodiments of the compounds disclosed herein, R is independently a halogen, -CN, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy. In some embodiments of the compounds disclosed herein, R is independently a halogen, -CN, -OH, -NH2, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments of the compounds disclosed herein, R is independently a halogen, -CN, -OH, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments of the compounds disclosed herein, R is independently a halogen, -CN, -OH, -C(=O)OH, -C(=O)OC1-C3 alkyl, C1-C3 alkyl, or C1-C3 haloalkyl.

[0480] In some embodiments, radiopharmaceutical conjugates comprising covalent radioisotopes are disclosed herein. In some embodiments of formula (AC), (AC'), (BC), (BC'), (CC), or (CC'), R 30 L contains a covalent radioactive isotope. In some embodiments of formula (AC), (BC), or (CC), TL1 contains a covalent radioactive isotope. In some embodiments of formula (AC), (BC), or (CC), TL2 contains a covalent radioactive isotope. In some embodiments of formula (AC), (BC), or (CC), L A, contains a covalently bonded radioactive isotope. In some embodiments of formula (AC'), (BC'), or (CC'), one or both of the TL1 units contain a covalently bonded radioactive isotope. In some embodiments of formula (AC'), (BC'), or (CC'), one or both of the TL2 units contain a covalently bonded radioactive isotope. In some embodiments of formula (AC'), (BC'), or (CC'), L B X contains a covalent radioactive isotope. In some embodiments of formula (BC), (BC'), (CC), or (CC'), X contains a covalent radioactive isotope.

[0481] In some embodiments of formulas (AC), (AC'), (BC), (BC'), (CC), or (CC'), R 30 This is the albumin-binding site.

[0482] In some embodiments of formulas (AC), (AC'), (BC), (BC'), (CC), or (CC'), R 30 This is the payload portion. In some embodiments, the payload portion is based on the payload and L A or L B It includes a linker that binds to it. In some embodiments, the payload portion is a payload having cytotoxic, therapeutic, or diagnostic properties. In some embodiments, the payload portion includes a radioisotope. In some embodiments, the payload portion includes a covalently bound radioisotope. In some embodiments, the payload portion includes a chelating agent. In some embodiments, the payload portion includes a chelating agent and a radioisotope that binds to the chelating agent. In some embodiments, the payload is a toxin. In some embodiments, the payload is a therapeutic agent. In some embodiments, the payload portion includes a cleavable linker and a toxin (e.g., auristatin such as auristatin E or a derivative thereof). An example of a cleavable linker can be found, for example, in U.S. Patent No. 9962454B2.

[0483] In some embodiments, the toxin is a taxane, a topoisomerase inhibitor, a vinca alkaloid, or the same.

[0484] In some embodiments, the toxin may be selected from, for example, DNA ligators (e.g., enediyne and lexitropsin, CBI compounds, see also U.S. Patent No. 6,130,237), duocalmycin, taxanes (e.g., paclitaxel and docetaxel), puromycin, and vinca alkaloids. Other cytotoxic agents include, for example, CC-1065, SN-38, topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholino-doxorubicin, echinomycin, combretastatin, netropsin, epotilon A and B, estramustine, cryptophysin, semadotin, mytansinoids, discodermolds, eryuterobin, and mitoxantrone.

[0485] In some embodiments, the toxin is an antitubulin agent. Examples of antitubulin agents include auristatin, taxanes (e.g., Taxol® (paclitaxel), Taxotere® (docetaxel)), T67 (Tularik), and vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine). Further examples of antitubulin agents include baccatin derivatives, taxane analogs (e.g., epothyron A and B), nocodazole, colchicine and colcimid, estramustine, cryptophycin, semadotine, mytansinoids, combretastatin, discodermolide, and eryuterobin.

[0486] In some embodiments, the toxin is a mytansinoid, which is an antitubulin agent from another group. For example, in some embodiments, the mytansinoid is meitansin or DM-1.

[0487] In some embodiments, the toxin is dorastatin. In some embodiments, the toxin is of the auristatin class. In some embodiments, the toxin is MMAE. In some embodiments, the toxin is AFP.

[0488] In some embodiments of formulas (AC), (AC'), (BC), (BC'), (CC), or (CC'), R 30 These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d R is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently and appropriately substituted (for example, with one or more R). In some embodiments of formula (AC), (AC'), (BC), (BC'), (CC), or (CC'), R 30It is hydrogen.

[0489] All combinations of the groups described above for various variables are considered herein. Throughout this specification, the groups and their substituents are selected by those skilled in the art to give stable moieties and compounds.

[0490] Metal chelating agents In one embodiment, a conjugate comprising a metal chelating agent, for example, one represented by CL in the formula described herein, is described herein.

[0491] In some embodiments, the metal chelating agent binds to a radionuclide. In some embodiments, the conjugate described herein comprises two or more independent metal chelating agents, e.g., two, three, four, five, or more metal chelating agents. In some embodiments, the conjugate described herein comprises two metal chelating agents, which may be the same or different. In some embodiments, the conjugate described herein comprises two or more metal chelating agents. In some embodiments, the conjugate comprises two radionuclides bound to a metal chelating agent.

[0492] In some embodiments, the metal chelating agent can bond with a radioactive atom. The bond may be direct; for example, the metal chelating agent may form a hydrogen bond or electrostatic interaction with the radioactive atom. The bond may also be indirect; for example, the metal chelating agent bonds to a molecule containing the radioactive atom. In some embodiments, the metal chelating agent contains or is a macrocyclic molecule. In some embodiments, the metal chelating agent contains or is 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). In some embodiments, the metal chelating agent contains a macrocyclic molecule (e.g., a macrocyclic molecule containing an oxygen atom and / or a nitrogen atom, DOTA, NOTA, one or more amines, one or more ethers, one or more carboxylic acids, EDTA, DTPA, TETA, DO3A, PCTA, or desferrioxamine).

[0493] In some embodiments, the metal chelating agent comprises multiple amines. In some embodiments, the metal chelating agent comprises four or more nitrogen atoms, four or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelating agent does not contain sulfur. In some embodiments, the metal chelating agent comprises a ring. In some embodiments, the ring comprises an oxygen atom and / or a nitrogen atom. In some embodiments, the metal chelating agent is a ring comprising three or more nitrogen atoms, three or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelating agent is polydentate.

[0494] In some embodiments, the metal chelating agents (or CL) described herein include DOTA, DOTA-GA, pBn-DOTA, pBn-SCN-DOTA, NH2-DOTA, NH2-DOTA-GA, p-NCS-Bn-DOTA-GA, p-NH2-Bn-oxo-DO3A, p-SCN-Bn-oxo-DO3A, NOTA, NODA-GA, NH2-NODA-GA, p-NCS-Bn-NODA-GA, p-NH2-Bn-NOTA, and p-SCN-Bn-NO These are TA, NCS-MP-NODA, NH2-MPAA-NODA, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-HEHA, H2-MACROPA-NCS, H1-MACROPA, H2-MACROPA-NH2, H4-OCTAPA, tetra-(S,S,S,S)-Me-DOTA, tetra-(S,S,S,S)-Et-DOTA, tetra-(S,S,S,S)-iBu-DOTA, or maleimide-nBu-DOTA.

[0495] In some embodiments, the metal chelating agents (or CL) described herein include cyclic chelating agents. Examples of cyclic chelating agents include AAZTA, BAT, BAT-TM, Crown, Cyclen, DO2A, CB-DO2A, DO3A, H3HP-DO3A, Oxo-DO3A, p-NH2-Bn-oxo-DO3A, DOTA, DOTA-3py, DOTA-PA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-1py, p-SCN-Bn-DOTA, CHX-A”-EDTA, and MeO-DOTA-NCS. EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A , MM-TE2A, NOTA, NOTP, HEHA, HEHA-NCS, p-SCN-Bn-HEHA, DTPA, CHX-A”-DTPA, p-NH2-Bn-CHX-A”-DTPA, p-SCN-DTP A, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA, p-SCN-Bn1B-DTPA, p-SCN-Bn-1B4M-DTPA, p-SCN-Bn-CHX-A”-DTPA, PEPA, p-SCN-Bn-PEPA, TETPA, DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene-tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L 1 H3L 4 ,H2azapa,H5decapa,bispa 2 , H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4octapa, p-SCN-Bn-H4octapa, TTHA, p-NO2-Bn-neunpa, H4octox, H2macropa, H2bispa 2H4phospa, H6phospa, p-SCN-Bn-H6phospa, TETA, p-NO2-Bn-TETA, TRAP, TPA, HBED SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, TGA, BAL, THROAT, THROAT (Bis -thioseminarabazone)、p-SCN-NOTE、nNOTE、NODAGA、CB-TE1A1P、3P-C-NETA-NCS、 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycup1A1B, pycup2A, THP. DEDPA, H2DEDPA, p-SCN-Bn-H2DEDPA, p-SCN-Bn-TCMC, glucose, NTA, NOC, 3p-C-NET A, p-NH2-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256 C-NE3TA, C-NE3TA-NCS, NODASE, NETA-モアド, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DF O-ChX-Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD, BAPEN, TACHPYR, NEC-SP, L pyExamples include, but are not limited to, L1, L2, L3, and EuK-106. In some embodiments, the metal chelating agents are DOTA, TRITA, TETA, DOTA-MA, DO3A-HP, DOTMA, DOTA-pNB, DOTP, DOTMP, DOTEP, DOTMPE, F-DOTPME, DOTPP, DOTBzP, DOTA-monoamide, p-NCS-DOTA, p-NCS-PADOTA, BAT, DO3TMP-Monoamide, p-NCS-TRITA, NOTA, or CHX-A”-DTPA. In some embodiments, the metal chelating agents described herein include acyclic chelating agents. Examples of acyclic chelating agents include DTA, CyEDTA, EDTMP, DTPMP, DTPA, Examples include, but are not limited to, CyDTPA, Cy2DTPA, DTPA-MA, DTPA-BA, and BOPA. In some embodiments, the metal chelating agents described herein include DOTA, DOTP, DOTMA, DOTAM, DTPA, NTA, EDTA, DO3A, DO2A, NOC, NOTA, TETA, TACN, DiAmSar, CB-Cyclam, CB-TE2A, DOTA-4AMP, or NOTP. In some embodiments, the metal chelating agents described herein include H4pypa, H4octox, H4octapa, p-NO2-Bn-neunpa, p-SCN-Bn-H4neunpa, TTHA, t Bu4pypa-C7-NHS, H4neunpa, H2macropa, HP-DO3A, BT-DO3A, DO3A-Nprop, DO3AP, DO2A2P, DOA3P, DOTP, DOTPMB, DOTAMAE, DOTAMAP, DO3AM Bu , DOTMA, TCE-DOTA, DEPA, PCTA, p-NO2-Bn-PCTA, p-NO2-Bn-DOTA, symPC2APA, symPCA2PA, asymPC2APA, asymPCA2PA, TRAP, AAZTA, DATA m Includes THP, HEHA, or HBED.

[0496] In some embodiments, the metal chelating agent (or CL) is DO3A. In some embodiments, the metal chelating agent is PEPA. In some embodiments, the metal chelating agent is EDTA. In some embodiments, the metal chelating agent is CHX-A''-DTPA. In some embodiments, the metal chelating agent is HEHA. In some embodiments, the metal chelating agent is DOTMP. In some embodiments, the metal chelating agent is t-Bu-calix[4]arene-tetracarboxylic acid. In some embodiments, the metal chelating agent is macropa. In some embodiments, the metal chelating agent is macropa-NCS. In some embodiments, the metal chelating agent is H4pypa. In some embodiments, the metal chelating agent is H4octapa. In some embodiments, the metal chelating agent is H4CHXoctapa. In some embodiments, the metal chelating agent is DOTP. In some embodiments, the metal chelating agent is crown.

[0497] Examples of metal chelating agents are further described in WO2012 / 174136;US20130183235A1;US20120219495A1; Ramogidaand et al., EJNMMI radiopharm. chem. 4, 21 (2019); Thiele et al., Cancer Biotherapy and Radiopharmaceuticals 2018; Li et al., Bioconjugate Chem. 2019, 30, 5, 1539-1553; and Baranyai et al., Eur. J. Inorg. Chem. 36-56 (2020), Dai et al., Nature Communications (2018) 9:857, each of which is incorporated herein by reference as a whole.

[0498] In some embodiments, the metal chelating agent (or CL) is DOTA. In some embodiments, the metal chelating agent is a chiral derivative of DOTA. In some embodiments, the metal chelating agent is 2,2',2'',2'''-((2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid.

[0499] In some embodiments, the metal chelating agent (or CL) is [ka] And here, R e Each is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, or amino acid side chains. In some embodiments, the metal chelating agent is [ka] And here, R e Each of these is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, or an amino acid side chain.

[0500] In some embodiments, the metal chelating agent (or CL) is [ka] In some embodiments, the metal chelating agent is [ka] In some embodiments, the metal chelating agent is [ka] In some embodiments, the metal chelating agent is [ka] In some embodiments, the metal chelating agent is [ka] In some embodiments, the metal chelating agent is [ka] In some embodiments, the metal chelating agent is [ka] In some embodiments, the metal chelating agent (or CL) is [ka] In some embodiments, the metal chelating agent is [ka] That is the case.

[0501] Examples of metal chelating agents are also illustrated in Figures 1 to 19.

[0502] In some embodiments, the conjugate disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is one of the compounds in Table 1. [Table 1] [Table 2] Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 [Table 56] [Table 57] [Table 58] [Table 59] [Table 60] [Table 61]

[0503] In some embodiments, the conjugate disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is one of the compounds listed in Table 2. [Table 62]

[0504] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include cis, trans, syn, anti, entgegen (E), and tuzhanmen (Z) isomers, as well as corresponding mixtures thereof. In some cases, the compounds described herein have one or more chiral centers, each center existing in either an R or S configuration. The compounds described herein include all diastereomer, enantiomer, and epimer forms, as well as corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomer compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, separable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and are separated by utilizing these differences. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered together with a resolving agent by practical means that do not cause racemization.

[0505] isotope labeled compounds Unless otherwise specified, the compounds described herein may exhibit their natural isotopic abundance or may be artificially enriched with specific isotopes in which one or more atoms have the same atomic number but different atomic masses or mass numbers from those predominantly found in nature. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are included within the scope of this disclosure. For example, hydrogen has 1 H (protium), 2 H (deuterium), and 3 There are three naturally occurring isotopes of hydrogen, represented as H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enrichment of deuterium may yield several therapeutic benefits, such as increased in vivo half-life and / or exposure, or may yield compounds useful for investigating in vivo pathways of drug elimination and metabolism.

[0506] For example, the compounds described herein may be artificially enriched with one or more specific isotopes. In some embodiments, the compounds described herein may be artificially enriched with one or more isotopes that are not primarily found in nature. In some embodiments, the compounds described herein are enriched with deuterium ( 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 The compounds described herein may be artificially enriched with one or more isotopes selected from C). In some embodiments, the compounds described herein are 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S,35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125 The isotopes are artificially enriched with one or more isotopes selected from I. In some embodiments, the abundance of the enriched isotopes is, independently, at least 1 mol%, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, or 100 mol%.

[0507] In some embodiments, the compound is deuterated at at least one position. In some embodiments, the compounds disclosed herein are partially or entirely deuterated. 1 H atom 2 It is substituted with a hydrogen atom.

[0508] Methods for synthesizing deuterium-containing compounds are known in the art, and not limited to these, include, but only a few examples, the methods described in U.S. Patent Nos. 5,846,514 and 6,334,997, as well as the following synthetic methods. For example, deuterium-substituted compounds can be synthesized using various methods as described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0509] Deuterated starting materials are readily available and, when used in the synthesis methods described herein, provide for the synthesis of deuterium-containing compounds. Numerous deuterium-containing reagents and components are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0510] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0511] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with a plurality of inorganic or organic bases, as well as either inorganic or organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their stereoisomers, or separately by reacting the purified compounds in their free form with a suitable acid or base and then isolating the salts thus formed.

[0512] Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds described herein with mineral acids, organic acids, or inorganic bases, such as acetates, acrylates, adipicates, alginates, aspartates, benzoates, benzenesulfons, bisulfates, bisulfites, bromides, butyrates, butyn-1,4-dioate, camphorates, camphorsulfons, capronates, caprylates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, diglucons, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyn-1,6-dioate, hydroxybenzoates, γ-hydroxybutyrates, hydrochlorides, and bromine. Examples include hydrochlorides, hydroiodides, 2-hydroxyethanesulfonates, iodides, isobutyrates, lactates, maleates, malons, methanesulfonates, mandelates, metaphosphates, methanesulfonates, methoxybenzoates, methylbenzoates, monohydrogen phosphates, 1-naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, palmoate, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, pyrosulfates, pyrophosphates, propions, phthalates, phenylacetates, phenylbutyrates, propanesulfonates, salicylates, succinates, sulfates, sulfites, succinates, suberinates, sebacinates, sulfonates, tartrates, thiocyansates, tosylates, undecanoates, and xylenesulfonic acid.

[0513] Furthermore, the compounds described herein include compounds in free base form, inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like), and organic acids [e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2 These compounds can be prepared as pharmaceutically acceptable salts formed by reacting them with pharmaceutically acceptable inorganic or organic acids, including, but not limited to, hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2,2,2]octa-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, which are not pharmaceutically acceptable themselves, are used to prepare salts that are useful as intermediates in obtaining the compounds disclosed herein or their stereoisomers and their pharmaceutically acceptable acid addition salts.

[0514] In some embodiments, the compounds described herein containing a free acid group react with a suitable base (e.g., pharmaceutically acceptable metal cation hydroxides, carbonates, bicarbonates, sulfates, etc.), ammonia, or pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amines. Typical salts include alkali salts or alkaline earth salts such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts and similar compounds. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2. + (C 1-4 Examples include alkyl(4) and similar compounds.

[0515] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and similar compounds. The compounds described herein should be understood to also include quaternization of any basic nitrogen-containing group contained in the compound. In some embodiments, water-soluble, oil-soluble, or dispersible products are obtained by such quaternization.

[0516] Tautomers In some cases, compounds exist as tautomers. The compounds described herein include all tautomers that may exist within the range of formulas described herein. Tautomers are compounds that can be interconverted by the movement of hydrogen atoms, involving the switching of single bonds and adjacent double bonds. A chemical equilibrium of tautomers exists in bond configurations where tautomerization can occur. All tautomer forms of the compounds disclosed herein are considered. The exact ratio of tautomers varies depending on several factors, including physical state, temperature, solvent, and pH.

[0517] Radioactive pharmaceutical conjugates Radiopharmaceutical conjugates, including conjugates disclosed herein that bind to radionuclides, are disclosed herein. Generally, the types of radionuclides used in therapeutic radiopharmaceuticals may be specially prepared depending on the specific type of cancer, the type of targeted portion (e.g., binding peptide), etc. Radionuclides that undergo alpha decay produce particles composed of two neutrons and two protons, while radionuclides that undergo beta decay emit energy electrons from their nuclei. Some radionuclides may also emit Auger electrons through electron capture processes. In some embodiments, the conjugate includes an alpha-particle emitting radionuclide. Alpha radiation can cause direct and irreversible double-strand DNA breaks, compared to gamma and beta radiation (which can cause single-strand breaks via indirect DNA damage). The range of these particles in tissue and the half-life of the radionuclide may be considered when designing the radiopharmaceutical conjugate. Table 3 below describes some characteristics of example radionuclides. [Table 63] [Table 64]

[0518] In some embodiments, the radiopharmaceutical conjugates described herein include radionuclides selected from Table 3. In some embodiments, conjugates comprising compounds from Table 1, or salts or stereoisomers thereof, that form complexes with radionuclides selected from Table 3 are disclosed herein. In some embodiments, compositions comprising compounds from Table 1, or salts or stereoisomers thereof, that form complexes with radionuclides selected from Table 3 are disclosed herein. In some embodiments, conjugates comprising compounds from Table 2, or salts or stereoisomers thereof, that form complexes with radionuclides selected from Table 3 are disclosed herein. In some embodiments, compositions comprising compounds from Table 2, or salts or stereoisomers thereof, that form complexes with radionuclides selected from Table 3 are disclosed herein.

[0519] In some embodiments, the radiopharmaceutical conjugate described herein comprises one or more independent radionuclides. In some embodiments, the radiopharmaceutical conjugate comprises two radionuclides. In some embodiments, one or more radionuclides are each bound to a metal chelating agent of the radiopharmaceutical conjugate. In some embodiments, the two radionuclides of the radiopharmaceutical conjugate are bound to the same metal chelating agent. In some embodiments, the two radionuclides of the radiopharmaceutical conjugate are bound to two independent metal chelating agents. In some embodiments, one or more radionuclides are each alpha-emitting radionuclides.

[0520] In some embodiments, the radiopharmaceutical conjugate described herein includes an alpha-particle emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate includes an alpha-particle emitting radionuclide bound to a metal chelating agent. In some embodiments, the alpha-particle emitting radionuclide is actinium-225( 225 Ac), Radium-223 ( 223 Ra), Radium-224 224 Ra), Bismuth-209 ( 209 Bi), Bismuth-213 213 Bi), Gadolinium-148 ( 148 Gd), Terbium-149 ( 149 Tb), Polonium-213 ( 213 Po), Francium-223 ( 223 Fr), Thorium-227 ( 227 Th), Thorium-229 ( 229 Th), or lead-212( 212 Pb) is the alpha particle emitting radionuclide. 225 Ac, 223 Ra, 209 Bi, 213 Bi, 148 Gd, 149 Tb, 213 Po, 223 Fr, 227 Th, 229 Th, and212 Selected from Pb. In some embodiments, the alpha particle emitting radionuclide is 225 It is Ac. In some embodiments, the alpha particle-emitting radionuclide is 213 It is Bi. In some embodiments, the alpha particle-emitting radionuclide is 212 It is Bi. In some embodiments, the alpha particle-emitting radionuclide is 212 It is Pb. In some embodiments, the alpha particle-emitting radionuclide is 224 It is Ra. In some embodiments, the alpha particle emitting radionuclide is 223 It is Ra. In some embodiments, the alpha particle emitting radionuclide is 227 It is Th. In some embodiments, the alpha particle-emitting radionuclide is 149 It's a Tb.

[0521] In some embodiments, the radiopharmaceutical conjugate described herein is 62 Cu, 64 Cu, 67 Cu, 90 Y, 109 Pd, 111 Ag, 134 Ce, 149 PM, 153 Sm, 166 Ho, 99m Tc, 67 Ga, 68 Ga, 111 In, 90 Y, 177 Lu, 186 Re, 188 Re, 197 Au, 198 Au, 199 Au, 105 Rh, 165 Ho, 161 Tb, 149 PM, 153 PM, 44 Sc, 47 Sc, 213 Po, 212 Pb, 209 Bi, 212 Bi, 213 Bi, 225 Ac,117m Sn, 67 Ga, 149 Tb, 152 Tb, 167 Tm, 175 Yb, 223 Ra, 223 Fr, 227 Th, 229 Th, 201 Tl, 148 Gd, 160 Gd, 148 Nd, 89 Sr, and 89 It includes radionuclides selected from Zr. In some embodiments, the radionuclides are 62 Cu, 64 Cu, 67 Cu, 68 Ga, 89 Zr, 90 Y, 99m Tc, 105 Rh, 111 In, 134 Ce, 148 Gd, 149 Tb, 152 Tb, 153 PM, 167 Tm, 175 Yb, 177 Lu, 209 Bi, 212 Pb, 213 Po, 213 Bi, 223 Ra, 223 Fr, 227 Th, 225 Ac, and 229 Selected from Th. In some embodiments, the radionuclide is 225 It is Ac. In some embodiments, the radionuclide is 221 Fr, 217 At, 213 Bi, 213 Po, 209 Tl, 209 Pb, or 209 Bi and others 225 It is a decay daughter nuclide of Ac. In some embodiments, the radiopharmaceutical conjugate is two 225 It contains Ac radionuclides. In some embodiments, the radionuclides are177 It is Lu. In some embodiments, the radiopharmaceutical conjugate is two 177 Contains Lu radionuclides. In some embodiments, the radionuclides are carrier-free (i.e., non-carrier-added or nca). 177 It is Lu. In some embodiments, the radionuclide is carrier-free (i.e., non-carrier-added or nca). 225 It is Ac. In some embodiments, the radioactive nuclide does not contain long-lived radioactive impurities and by-products. 177 It is Lu. In some embodiments, the radionuclide is a carrier-free radionuclide. In some embodiments, the radionuclide is a pseudo-radioactive metal. In some embodiments, the pseudo-radioactive metal is [ 18 F] Aluminum fluoride ([ 18 [F]AlF) complex.

[0522] In some embodiments, the radiopharmaceutical conjugate described herein comprises a β-particle emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a β-particle emitting radionuclide bound to a metal chelating agent. In some embodiments, the β-particle emitting radionuclide is copper-67, rhodium-105, ytterbium-175, thulium-167, promethium-153, yttrium-90, samarium-153, or lutetium-177. In some embodiments, the β-particle emitting radionuclide is copper-67, yttrium-90, samarium-153, or lutetium-177. In some embodiments, the β-particle emitting radionuclide is lutetium-177.

[0523] In some embodiments, the radiopharmaceutical conjugate described herein comprises a gamma-particle emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a gamma-particle emitting radionuclide bound to a metal chelating agent. In some embodiments, the gamma-particle emitting radionuclide is indium-111 or tin-117m.

[0524] In some embodiments, the radiopharmaceutical conjugate described herein comprises a positron-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a positron-emitting radionuclide bound to a metal chelating agent. In some embodiments, the positron-emitting radionuclide is gallium-68, copper-61, copper-62, copper-64, zirconium-89, or terbium-152. In some embodiments, the radionuclide is zirconium-89. In some embodiments, the radionuclide is gallium-68.

[0525] In some embodiments, the conjugate described herein includes a radionuclide suitable for imaging or diagnostic purposes. In some embodiments, the radionuclide suitable for imaging is: 62 Cu, 64 Cu, 89 Zr, 134 Ce, 152 Tb, 68 Ga, 111 In, and 99m Selected from Tc. In some embodiments, the radionuclide is suitable for PET imaging. In some embodiments, the radionuclide suitable for PET imaging is, 62 Cu, 64 Cu, 89 Zr, 134 Ce, 152 Tb, and 68 Selected from Ga. In some embodiments, the radionuclide is suitable for SPECT imaging. In some embodiments, the radionuclide suitable for SPECT imaging is, 111 In and 99m Selected from Tc.

[0526] In some embodiments, the radiopharmaceutical conjugates described herein do not contain any hot radionuclides, i.e., they are cold conjugates. For example, in some examples, the radionuclides may be replaced with surrogates for testing and experimentation. (e.g., 225Ac is replaced with lanthanum. In some embodiments, hot lutetium (Lu-177) is replaced with cold lutetium (Lu-175).

[0527] Metal chelating agents such as DOTA can connect to radionuclides via one or more functional groups and / or atoms (e.g., 177 Lu or 225 It can interact with Ac). For example, a metal chelating agent can interact with a radionuclide via nitrogen and / or oxygen atoms. In another example, a metal chelating agent can interact with a radionuclide via the carbonyl, carboxylic acid, amino, and / or amide groups of the metal chelating agent. In some embodiments, the interaction between the metal chelating agent and the radionuclide of the conjugate disclosed herein is as follows: [ka] This can be illustrated as follows. In some embodiments, the interaction between the metal chelating agent of the conjugate disclosed herein and the radionuclide is as follows: [ka] This can be illustrated as follows. In some embodiments, the interaction between the metal chelating agent of the conjugate disclosed herein and the radionuclide is as follows: [ka] This can be illustrated as follows. In some embodiments, the interaction between the metal chelating agent of the conjugate disclosed herein and the radionuclide is as follows: [ka] This can be illustrated as follows. In some embodiments, the interaction between the metal chelating agent of the conjugate disclosed herein and the radionuclide is as follows: [ka] This is illustrated. In some embodiments, the interaction between the metal chelating agent of the conjugate disclosed herein and the radionuclide is as follows: [ka] This is illustrated. In some embodiments, the radioactive nuclide is in a positively charged oxidized state, for example, 225 Ac 3+ , 177 Lu 3+ It exists as such. In some embodiments, for example, under certain aqueous conditions, the radionuclide exists in the form of a salt, for example, 225 Ac 3+ , 177 Lu 3+ It exists as such. In some embodiments, for example, under certain acidic aqueous conditions, the radionuclide exists in the form of a salt, for example, 225 Ac 3+ , 177 Lu 3+ It exists as such. In some embodiments, the conjugate is in the form of a salt. In some embodiments, one or more carboxylic acid groups of the conjugate may exist as carboxylate anions. In some embodiments, one or more carboxylate anions of the conjugate may coordinate to a radionuclide. Those skilled in the art will recognize that the dissociation of the acid varies depending on the pH value and pK value of the environment. Therefore, in some embodiments, the conjugates described herein may exist in a fully ionized, partially ionized, or non-ionized form.

[0528] In some embodiments, the radiopharmaceutical conjugate is selected from the conjugates listed in Table 4a or 4b. [Table 65] [Table 66] [Table 67] [Table 68] [Table 69] [Table 70] [Table 71] *The radionuclides in Tables 4a and 4b bind to the chelating agents of their corresponding compounds.

[0529] In some embodiments, the radiopharmaceutical conjugate is selected from the conjugates listed in Table 5a or 5b. [Table 72] [Table 73] [Table 74] [Table 75] [Table 76] [Table 77] [Table 78] *The radionuclides in Tables 5a and 5b bind to the chelating agents of their corresponding compounds.

[0530] In some embodiments, radiopharmaceutical conjugates comprising covalent radioisotopes are disclosed herein. In some embodiments of formula (AC), (AC'), (BC), (BC'), (CC), or (CC'), R 30L contains a covalent radioactive isotope. In some embodiments of formula (AC), (BC), or (CC), TL1 contains a covalent radioactive isotope. In some embodiments of formula (AC), (BC), or (CC), TL2 contains a covalent radioactive isotope. In some embodiments of formula (AC), (BC), or (CC), L A , contains a covalently bonded radioactive isotope. In some embodiments of formula (AC'), (BC'), or (CC'), one or both of the TL1 units contain a covalently bonded radioactive isotope. In some embodiments of formula (AC'), (BC'), or (CC'), one or both of the TL2 units contain a covalently bonded radioactive isotope. In some embodiments of formula (AC'), (BC'), or (CC'), L B X includes a covalent radioactive isotope. In some embodiments of formula (BC), (BC'), (CC), or (CC'), X includes a covalent radioactive isotope. In some embodiments, the covalent radioactive isotope is 11 C, 13 N, 15 O, 18 F, 70 As, 71 As, 72 As, 73 As, 74 As, 76 As, 77 As, 76 Br, 123 I, 124 I, 125 I, 131 I, and 211 Selected from At. In some embodiments, the covalently bonded radioactive isotope is 131 I. In some embodiments, the covalent radioactive isotope is 211 At. In some embodiments, the covalent radioactive isotope is 18 It is F.

[0531] In some embodiments, the compounds of formula (AC), (AC'), (BC), (BC'), (CC), or (CC'), or their pharmaceutically acceptable salts or stereoisomers, include a covalent radioisotope (represented as R*), where the compound is of formula (Va), formula (Vb), formula (Vc), formula (Vd), or formula (Ve): [ka] It includes a structure represented by the formula, in which, R* is a covalently bonded radioactive isotope (e.g., fluorine-18( 18 F), Iodine-131 ( 131 I) Iodine-123 ( 123 I) Iodine-124 ( 124 I) Iodine-125 ( 125 I) or astatine 211 ( 211 At) etc.) R b is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C2-C9 heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be appropriately substituted (for example, they may be appropriately substituted with one or more R as described herein).

[0532] In some embodiments of formulas (AC), (AC'), (BC), (BC'), (CC), or (CC'), R 30 This includes structures represented by formula (Va), formula (Vb), formula (Vc), formula (Vd), or formula (Ve).

[0533] In some embodiments of formula (Va), formula (Vb), formula (Vc), formula (Vd), or formula (Ve), alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl independently comprises one or more halogens, amino, -OH, -NO2, oxo, -CN, C 1-3 Alkoxyl, C 1-3 Alkyl, and C 1-3 In some embodiments, R b is hydrogen. In some embodiments, R b is a C1-C4 alkyl group. In some embodiments, R b is a C1-C4 cycloalkyl group. In some embodiments, R* is 131 It is I.

[0534] In some embodiments, the structures represented by formulas (Va), (Vb), (Vc), (Vd), and (Ve) are as follows: [ka] Selected from.

[0535] In some embodiments, radiopharmaceutical conjugates containing the covalent radionuclides described herein may be synthesized from boronic acids, borates, or stannane precursors. Boronic acids, borates, and stannane precursors may be formed according to the following general reactions.

[0536] Reaction 1: [ka] In the formula, R is a variable chemical moiety, such as alkyl or hydrogen. A halogen on ring Y, such as chloro, bromo, or iodine, can undergo palladium-mediated coupling reactions with boronic acids, borates, or stannane compounds to form intermediate compounds in which group M is substituted with halogen X.

[0537] Radioactive isotopes, for example R* (for example fluorine-18( 18 F), Iodine-131 ( 131 I) Iodine-123 ( 123 I) Iodine-124 ( 124 I) Iodine-125 ( 125 I) or astatine 211 ( 211 At), or any other radioactive isotopes in Tables 5A and 5B, can be formed from intermediate compounds, for example, according to the following general reactions:

[0538] Reaction 2: [ka]

[0539] Reaction 3: [ka]

[0540] Reaction 4: [ka] In the formula, R is a variable chemical moiety, such as alkyl or hydrogen.

[0541] In some embodiments, the radiolabeled conjugates described herein may be synthesized from chloro, bromo, or iodine precursors according to the following general reactions: [ka] In the formula, R * This refers to radioactive isotopes, such as fluorine-18( 18 F), Iodine-131 ( 131 I) Iodine-123 ( 123 I) Iodine-124 ( 124 I) Iodine-125 ( 125 I), Astatine 211 ( 211 At), or the radioactive isotopes listed in Tables 5A and 5B.

[0542] The radiolabeling reactions described above are used as example procedures in the synthesis of radiolabeled conjugates described herein. Further reactions, including nucleophilic substitution, electrophilic substitution, isotope exchange, bromine-radioactive iodine exchange, radioactive iodine destanylation, radioactive iodine deboronation, and transition metal-mediated halogen exchange, are considered and can be found in Berdal et al., “Investigation on the reactivity of nucleophilic radiohalogens with arylboronic acids in water: access to an efficient single-step method for the radioiodination and astatination of antibodies” Chemical Science 2021, 12, 1458 and Dubost et al., “Recent Advances in Synthetic Methods for Radioiodination” J. Org. Chem, 2020, 85, 13, 8300-8310, both of which are incorporated herein by reference in their entirety.

[0543] Treatment method A method for treating a CA-IX-mediated disease or disorder in a subject requiring treatment is disclosed herein, characterized by administering a radiopharmaceutical conjugate disclosed herein to the subject. In some embodiments, the CA-IX-mediated disease or disorder is cancer.

[0544] A method for treating cancer in a subject requiring treatment is disclosed herein, characterized by administering a radiopharmaceutical conjugate disclosed herein to the subject.

[0545] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a recurrent or refractory cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is hypoxic.

[0546] In some embodiments, cancer includes any of the various malignant tumors characterized by the proliferation of undifferentiated cells that tend to invade surrounding tissues and metastasize to new sites of the body. Non-limiting examples of cancers suitable for treatment with the radiopharmaceutical conjugates disclosed herein include: anal cancer, appendiceal cancer, bile duct cancer, bladder cancer, bone cancer, breast cancer, central nervous system cancer, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gallbladder cancer, gastrointestinal carcinoid tumors, glioma, head and neck cancer, leukemia (e.g., acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, or hairy cell leukemia), liver cancer, lung cancer, lymphoma (e.g., non-Hodgkin lymphoma, Hodgkin lymphoma, B-cell lymphoma, or Burkitt lymphoma), multiple myeloma, neuroblastoma, oral squamous cell carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, pleural cancer, prostate cancer, rectal cancer, kidney cancer (e.g., renal cell carcinoma), and skin cancer (e.g., melanoma). Examples include small intestine cancer, stomach / gastric cancer, testicular cancer, and thyroid cancer.

[0547] In some embodiments, cancer is clear cell renal cell carcinoma (ccRCC), endometrial cancer, basal cell carcinoma, liver cancer, colon cancer, gastric cancer, cervical squamous cell carcinoma, oral squamous cell carcinoma, pancreatic cancer, breast cancer, ovarian cancer, glioblastoma, head and neck cancer, or lung cancer. In some embodiments, cancer is clear cell renal cell carcinoma (ccRCC). In some embodiments, lung cancer is squamous cell carcinoma of the lung or non-small cell lung cancer. In some embodiments, pancreatic cancer is ductal carcinoma. In some embodiments, lung cancer is squamous cell carcinoma of the lung.

[0548] In some embodiments, methods for killing cells are provided herein, comprising contacting the cells with a radiopharmaceutical conjugate or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the cells express a CA-IX receptor. In some embodiments, the radiopharmaceutical conjugate or a pharmaceutically acceptable salt or stereoisomer emits a plurality of alpha particles by spontaneous radioactive decay. In some embodiments, the radiopharmaceutical conjugate or a pharmaceutically acceptable salt or stereoisomer emits a plurality of beta particles, gamma rays, and / or Auger electrons by spontaneous radioactive decay. The radiopharmaceutical conjugates described herein can kill cells by radiation. In some embodiments, the radiopharmaceutical conjugate directly kills cells by radiation. In some embodiments, the radiopharmaceutical conjugate kills cells by inducing double-strand DNA breaks. In some embodiments, the cells are cancer cells. In some embodiments, the method comprises killing cells with an alpha particle-emitting radionuclide. After contact with cells, the radiopharmaceutical conjugates described herein may be taken up by the cells. Uptake can be mediated by cell receptors, cell membrane endocytosis, and the like. In some embodiments, the radiopharmaceutical conjugate or its pharmaceutically acceptable salt or stereoisomer is configured to treat cancer by eliminating tumor cells.

[0549] In addition to the therapeutic methods described above, the radiopharmaceutical conjugates and compositions described herein may be used for imaging and / or as part of the treatment of disease. For imaging applications, such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET), conjugates may contain radionuclides suitable for use as imaging isotopes (e.g., Dx in Table 3), such as the isotopes in Table 3. Thus, radiopharmaceutical conjugates may be administered as companion diagnostics.

[0550] In one embodiment, a therapeutic method is described herein, characterized by administering a first radiopharmaceutical conjugate and a second radiopharmaceutical conjugate. The first radiopharmaceutical conjugate can be used as a companion diagnostic agent, and the second radiopharmaceutical conjugate can be used for therapeutic purposes. In some embodiments, the first radiopharmaceutical conjugate and the second radiopharmaceutical conjugate have the same structure except for the radionuclide. In some embodiments, the first radiopharmaceutical conjugate contains a γ-particle emitting radionuclide. In some embodiments, the first radiopharmaceutical conjugate contains a radionuclide designated Dx in Table 3. In some embodiments, the first radiopharmaceutical conjugate contains a radionuclide selected from Lu-177, In-111, Ga-68, Cu-64, and Zr-89. In some embodiments, the second radiopharmaceutical conjugate contains an α or β-particle emitting radionuclide. In some embodiments, the second radiopharmaceutical conjugate comprises a radionuclide denoted as Tx in Table 3. In some embodiments, the second radiopharmaceutical conjugate comprises Ac-225. In some embodiments, the method is characterized by administering (i) a first radiopharmaceutical conjugate comprising a radionuclide configured for companion diagnostics (e.g., PET imaging) and (ii) a second radiopharmaceutical conjugate comprising a radionuclide selected from α or β particle emitters, wherein the first and second radiopharmaceutical conjugates have identical structures except for the radionuclide.

[0551] In one embodiment, a method for diagnosing or imaging cancer in a subject requiring diagnosis or imaging is described herein, characterized by administering a radiopharmaceutical conjugate or pharmaceutical composition described herein to the subject.

[0552] In some embodiments, the target age range is 1 to 100 years. In some embodiments, the target age range is 5 to 10, 5 to 15, 5 to 18, 5 to 25, 5 to 35, 5 to 45, 5 to 55, 5 to 65, 5 to 75, 10 to 15, 10 to 18, 10 to 25, 10 to 35, 10 to 45, 10 to 55, 10 to 65, 10 to 75, 15 to 18, 15 to 25, 15 to 35, 15 to 45, 15 to 55, 15 The ages are ~65, 15~75, 18~25, 18~35, 18~45, 18~55, 18~65, 18~75, 25~35, 25~45, 25~55, 25~65, 25~75, 35~45, 35~55, 35~65, 35~75, 45~55, 45~65, 45~75, 55~65, 55~75, or 65~75. In some embodiments, the subjects are at least 5, 10, 15, 18, 25, 35, 45, 55, or 65 years old. In some embodiments, the subjects are at most 10, 15, 18, 25, 35, 45, 55, 65, or 75 years old.

[0553] Administration In certain embodiments, compositions containing the radiopharmaceutical conjugates described herein are administered for therapeutic purposes. In certain therapeutic uses, the radiopharmaceutical conjugates described herein are administered to a patient already suffering from a disease or disorder in an amount sufficient to treat, or at least partially cessate, at least one of the symptoms of that disease or disorder. The effective amount for this use will vary depending on the severity and course of the disease or disorder, previous treatments, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The amount of the radiopharmaceutical conjugate or its pharmaceutically acceptable salts or stereoisomers and / or pharmaceutical compositions administered may be sufficient to deliver a therapeutically effective amount to a particular subject. In some embodiments, the dose of the radiopharmaceutical conjugate may be about 0.1 pg to about 50 mg per kilogram of body weight. In some embodiments, the dose of the radiopharmaceutical conjugate or its pharmaceutically acceptable salts or stereoisomers for the method described herein is about 0.001 mg to about 1000 mg per dose for the subject being treated.

[0554] In some examples, the efflux profile of the conjugate can be regulated by reversible binding between the conjugate and plasma proteins such as albumin. A suitable affinity between the conjugate and plasma proteins allows the plasma proteins to be utilized as reservoirs for the conjugate, improving the efflux profile by binding and retaining the conjugate at high concentrations and releasing it at low concentrations. In some embodiments, the dissociation constant (Kd) between the conjugate and human serum albumin is at most 500 μM when determined at room temperature under human serum conditions. In some embodiments, Kd is about 0.1 nM to about 1000 μM. In some embodiments, Kd is at most 100 μM. In some embodiments, Kd is at most 15 μM. In some embodiments, Kd is about 1 nM to about 10 μM. In some embodiments, Kd is about 10 nM to about 10 μM. In some embodiments, Kd is about 50 nM to about 1 μM. In some embodiments, Kd is approximately 100 nM to approximately 10 μM.

[0555] Route of administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, mucosal, percutaneous, vaginal, otorhinolaryngeal, nasal, and topical administration. Furthermore, parenteral delivery, though only a few examples, includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0556] Pharmaceutical composition / formulation The compounds described herein are administered in pharmaceutical compositions, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, to subjects in need of treatment, in accordance with standard pharmaceutical practices. In some embodiments, the compounds described herein are administered to animals.

[0557] In another embodiment, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient is provided herein. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable formulation. The appropriate formulation depends on the selected route of administration. Outlines of the pharmaceutical compositions described herein are, for example, found in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference to such disclosures. [Examples]

[0558] A: Compound synthesis Overview With either a Bruker Avance III 400 (400MHz) or a Bruker Avance 300 (400MHz) spectrometer 11H NMR spectra were recorded. Chemical shifts are reported in ppm along with solvent resonances as internal standards (CDCl3: 7.27 ppm, DMSO-d6: 2.50 ppm, CD3OD: 3.31 ppm). Data are reported as follows: chemical shift, integral value, multiplicity (s=single, d=double, t=triple, q=quadul, p=quintul, m=multiple), and coupling constant (Hz).

[0559] Liquid chromatography was performed using forced flow (flash chromatography) with silica gel (SiO2, 1000 mesh) or column chromatography (silica gel, 1000 mesh). Thin-layer chromatography (TLC) was performed on 20-25 μm silica gel glass plates. Preparative TLC was performed on 40-45 μm silica gel glass plates. Visualization was performed using ultraviolet light (254 nm), iodide, water, or KMnO4.

[0560] A1. Synthesis of Intermediate 1 Scheme A1 [ka] 1.1 Preparation of Compound 1B Solutions of methyl 3-ethynylbicyclo[1.1.1]pentane-1-carboxylate (6.5 g, 43.3 mmol, 1 eq) and LiOH.H2O (2.72 g, 64.9 mmol, 1.5 eq) were stirred at 20°C for 1 hour in THF (20 mL), MeOH (20 mL), and H2O (20 mL). The reaction mixture was concentrated under reduced pressure to remove organic matter, and the aqueous phase was adjusted to pH=5 by adding 1 M HCl. A white solid precipitated and was filtered. The filtered cake was collected and dried under reduced pressure to obtain compound 1B (5.4 g, 92% yield) as a white solid;137.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1 H), 3.12 (s, 1 H), 2.21 (s, 6 H).

[0561] 1.2 Preparation of Intermediate 1 To a solution of compound 1B (7.0 g, 51.4 mmol, 1 eq) and 5-amino-1,3,4-thiadiazole-2-sulfonamide (9.27 g, 51.4 mmol, 1 eq) in THF (4 mL) and DIEA (44.8 mL, 257 mmol, 5 eq), a solution of T3P (36.7 mL, 61.7 mmol, 1.2 eq in HCl, 50% w / w solution) was added dropwise at 20°C. The mixture was stirred at 20°C for 2 hours. The mixture was diluted with H2O (40 mL) and extracted with HCl (3 x 50 mL). The combined organic layers were washed with saturated brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was tritulated with H2O (20 mL), filtered, and concentrated under reduced pressure to obtain intermediate 1 (6.0 g, 39% yield) as a white solid; LCMS [M+H]: 299.0; 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (brs, 1H), 8.32 (s, 2H), 3.19 (s, 1H), 2.40 (s, 6H).

[0562] A2. Synthesis of Intermediate 2 Scheme A2 [ka] 1.3 Preparation of Compound 2B To a solution of compound 2A (3.5 g, 19.0 mmol, 1 eq) in THF (50 mL), 1M BH3.THF (17.1 mL, 0.9 eq) at -20°C was added. The mixture was stirred at 0°C for 0.5 hours, quenched with MeOH (20 mL) at 0°C, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: Depositphotos) to obtain compound 2B (2.0 g, 62% yield) as a white oil. 1H NMR (400 MHz, CDCl3) δ 3.71 (s, 2H), 3.68 (s, 3H), 1.99 - 1.94 (m, 2H), 1.80 (br d, J = 1.4 Hz, 2H), 1.68 - 1.63 (m, 2H), 1.41 (dd, J = 1.9, 4.1 Hz, 2H).

[0563] 1.4 Preparation of Compound 2C To a solution of compound 2B (3.1 g, 18.2 mmol, 1 eq) in DCM (30 mL), TEA (25.4 mL, 182 mmol, 10 eq) and a solution of PySO3 (8.70 g, 54.6 mmol, 3 eq) in DMSO (10 mL) were added. The mixture was stirred at 25°C for 16 hours. The residue was diluted with H2O (50 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with saturated brine (3 × 30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to obtain crude compound 2C (3.0 g, 98% yield) as a yellow oil, which was then used directly in the next reaction.

[0564] 1.5 Preparation of Compound 2D In 30 mL of MeOH, a solution of compound 2C (3.0 g, 17.8 mmol, 1 eq) and Bestmann's reagent (4.11 g, 21.4 mmol, 1.2 eq) was prepared, to which K2CO3 (4.93 g, 35.7 mmol, 2 eq) was added at 0°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was partitioned with MTBE (150 mL) and H2O (300 mL). The organic phase was separated, washed with saturated brine (3 × 50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: SiO2) to obtain compound 2D (1.7 g, 58% yield) as a white oil. 1 H NMR (400 MHz, CDCl3) δ 3.62 (s, 3H), 2.19 (s, 1H), 2.01 - 1.97 (m, 2H), 1.87 (s, 4H), 1.62 (dd, J = 2.0, 4.2 Hz, 2H).

[0565] 1.6 Preparation of Compound 2E In a 2:2:1 THF:MeOH:H2O (10 mL) solution, compound 2D (1.6 g, 9.74 mmol, 1 eq) was dissolved in LiOH.H2O (818 mg, 19.5 mmol, 2 eq). The mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with H2O (8 mL), and acidified with 1 M HCl (150 mL). A white solid precipitated, the suspension was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2E (1.6 g, 98% yield, 90% purity) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 2.24 (s, 1H), 2.02 (br s, 2H), 1.91 (s, 4H), 1.66 (dd, J = 1.9, 4.1 Hz, 2H).

[0566] 1.7 Preparation of Intermediate 2 Oxalyl chloride (991 μL, 11.3 mmol, 1.7 eq) was added at 0°C to a solution of compound 2E (1.0 g, 6.7 mmol, 1 eq) in DCM (5 mL). The mixture was stirred at 25°C for 1 hour. The mixture was quenched with MeOH and concentrated under reduced pressure. The yellow oil was taken into THF (10 mL) and added at 0°C to a solution of 5-amino-1,3,4-thiadiazole-2-sulfonamide (1.23 g, 6.85 mmol) and pyridine (2.63 mL, 32.6 mmol) in THF (10 mL). The solution was stirred at 15°C for 1 hour and concentrated under reduced pressure. The residue was triturated with H2O (120 ml) at 15°C for 20 minutes to obtain intermediate 2 (2.0 g, 98% yield) as a white solid; LCMS [M+H]: 313.0; 1H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.33 (s, 2H), 3.21 (s, 1H), 2.11 (br d, J = 1.3 Hz, 2H), 2.02 - 1.98 (m, 2H), 1.92 - 1.87 (m, 2H), 1.79 (dd, J = 1.9, 4.0 Hz, 2H).

[0567] A3. Synthesis of Intermediate 3 Scheme A3 [ka] 1.8 Preparation of Compound 3B A solution of compound 3A (9.0 g, 24.4 mmol, 1 eq) and TEA (68 mL, 244 mmol, 10 eq) was added to a solution of PySO3 (23.3 g, 73.3 mmol, 3 eq) in DMSO (40 mL) at 0°C. The mixture was stirred at 15°C for 15 minutes, then at 30°C for 16 hours. The mixture was diluted with DCM (100 mL), extracted with H2O (10 × 50 mL), dried to (Na2SO4), filtered, and concentrated under reduced pressure to obtain crude compound 3B (3.8 g) as a colorless oil.

[0568] 1.9 Preparation of Compound 3C In 90 mL of MeOH, a solution of compound 3B (8.5 g, 23.3 mmol, 1 eq) and Bestmann reagent (10.8 g, 28.0 mmol, 1.2 eq) was prepared, to which K2CO3 (12.9 g, 46.7 mmol, 2 eq) was added at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was diluted with MTBE (80 mL), extracted with H2O (3 × 50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: SiO2) to obtain compound 3C (7.3 g, 88% yield) as a white solid.

[0569] 1.10 Preparation of Compound 3D In a 25 mL 2:2:1 THF:MeOH:H2O solution, compound 3C (7.3 g, 20.5 mmol, 1 eq) was added to LiOH.H2O (2.58 g, 30.7 mmol, 1.5 eq). The mixture was stirred at 30°C for 4 hours and then concentrated under reduced pressure. The residue was diluted with H2O (8 mL) and acidified with 1 M HCl (150 mL). A white solid precipitated, the suspension was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3D (6.1 g, 91% yield) as a white solid.

[0570] 1.11 Preparation of Intermediate 3 To a solution of compound 3D (6.10 g, 18.6 mmol, 1 eq) in 2-MeTHF (30 mL), DMF (286 μL, 1.86 mmol, 0.1 eq) and SOCl2 (5.38 mL, 37.2 mmol, 2 eq) were added at 0°C. The mixture was stirred at 25°C for 1 hour and then concentrated under reduced pressure. In 20 mL of DMF, the residue was added dropwise to a solution of 5-amino-1,3,4-thiadiazole-2-sulfonamide (8.04 g, 44.6 mmol, 1.2 eq) and pyridine (9.0 mL, 112 mmol, 3 eq) in 20 mL of DMF at 0°C. The solution was stirred at 15°C for 1 hour, and the reaction mixture was concentrated under reduced pressure. The residue was tritulated with H2O (120 ml) at 15°C for 20 minutes to obtain intermediate 3 (10.3 g, 85% yield) as a white solid; LCMS [M+H]: 327.0; 1 H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.32 (s, 2H), 3.08 (d, J = 1.1 Hz, 1H), 2.03 - 1.94 (m, 4H), 1.88 - 1.66 (m, 6H).

[0571] A4. Synthesis of Intermediate 4 Scheme A4 [ka] 1.12 Preparation of Compound 4B In 50 mL of MeOH, a mixture of compound 4A (2.0 g, 10.2 mmol, 1 eq) and Bestmann's reagent (2.35 g, 12.2 mmol, 1.2 eq) was mixed with K2CO3 (2.82 g, 20.4 mmol, 2 eq) at 0°C. The mixture was stirred at 0°C for 2 hours, followed by stirring at 20°C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with MTBE (3 × 50 mL). The combined organic layer was washed with saturated brine (25 mL), dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: SiO2) to obtain compound 4B (1.82 g, 93% yield) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.64 (s, 3H), 2.09 (s, 1H), 1.80 (s, 12H).

[0572] 1.13 Preparation of Compound 4C In a 1:1:1 THF:MeOH:H2O (60 mL) solution, compound 4B (1.82 g, 9.47 mmol, 1 eq) was dissolved in LiOH:H2O (1.39 g, 33.1 mmol, 3.5 eq). The mixture was stirred at 15°C for 3 hours. The reaction mixture was washed with 1 M HCl (43 mL), filtered, and concentrated under reduced pressure to obtain compound 4C (1.58 g, 94% yield) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.27 (s, 1H), 2.10 (s, 1H), 1.85 - 1.80 (m, 12H).

[0573] 1.14 Preparation of Intermediate 4 T3P (2.50 mL, 4.21 mmol, 50% purity, 1.5 eq) was added dropwise at 0°C to a mixture of compound 4C (500 mg, 2.81 mmol, 1 eq), 5-amino-1,3,4-thiadiazole-2-sulfonamide (607 mg, 3.37 mmol, 1.2 eq), and DIEA (1.47 mL, 8.42 mmol, 3 eq) in THF (10 mL). The mixture was stirred at 40°C for 16 hours, diluted with water (20 mL), and extracted with SiO2 (3 × 20 mL). The combined organic layers were washed with saturated saline (10 mL), dried, filtered, and concentrated under reduced pressure. The crude product was triturated with dimethyl phosphate at 15°C for 5 minutes to obtain intermediate 4 (131 mg, 14% yield) as a white solid; LCMS [M+H]: 341.1.

[0574] A5. Synthesis of Intermediate 5 Scheme A5 [ka] 1.15 Preparation of Compound 5B To a solution of compound 5A (2.0 g, 12.0 mmol, 1 eq) in THF (10 mL) and H2O (10 mL), LiOH.H2O (656 mg, 15.6 mmol, 1.3 eq) was added. The mixture was stirred at 20°C for 2 hours and then concentrated under reduced pressure. The residue was diluted with H2O (8 mL) and acidified with 1 M HCl (30 mL). The white precipitate was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from H2O to obtain compound 5B (1.72 g, 94% yield) as a white solid; LCMS [M+H]: 153.1; 1 H NMR (400 MHz, METHANOL-d4) δ ppm 2.31 (d, J = 2.32 Hz, 1 H) 2.26 (br d, J = 3.42 Hz, 2 H), 1.98 (br d, J = 9.78 Hz, 4 H), 1.32 - 1.50 (m, 5 H).

[0575] 1.16 Preparation of Intermediate 5 To a solution of compound 5B (1.52 g, 9.99 mmol, 1 eq) in DCM (5 mL), DMF (77 μL, 999 μmol, 0.1 eq) and oxalyl chloride (870 μL, 9.99 mmol, 1 eq) were added at 0°C. The reaction mixture was stirred at 20°C for 30 minutes and concentrated under reduced pressure. This oil was taken into DMF (5 mL) and added to a solution of 5-amino-1,3,4-thiadiazole-2-sulfonamide (1.80 g, 9.96 mmol, 1 eq) and pyridine (804 μL, 9.96 mmol, 1 eq) in DMF (3 mL) at 0°C. The solution was stirred at 20°C for 4 hours, diluted with ELISA (100 mL), and extracted with H2O (3 × 50 mL). The combined organic layers were washed with saturated brine (2 × 30 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was further purified by recrystallization from H₂O (10 mL) to obtain intermediate 5 (3.03 g, 97% yield) as a white solid; LCMS [M+H]: 315.1; 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.98 (s, 1 H), 8.31 (s, 2 H), 2.73 (s, 1 H), 2.31 (br dd, J=12.9, 2.0 Hz, 2 H), 1.84 - 2.02 (m, 4 H), 1.23 - 1.52 (m, 4H).

[0576] A6. Synthesis of Intermediate 6 Scheme A6 [ka] 1.17 Preparation of Compound 6B To a solution of compound 6A (12.5 g, 79.0 mmol, 1 eq) in THF (250 mL), NaH (3.79 g, 94.8 mmol, 60% purity, 1.2 eq) was added at 0°C under a nitrogen atmosphere. 3-bromopropa-1-yne (17 mL, 158 mmol, 80% purity, 2 eq) was added dropwise, and the reaction mixture was stirred at 15°C for 12 hours. The mixture was purified by column chromatography (SiO2, petroleum ether: SiO2) to obtain compound 6B (2.5 g, 8.1% yield) as a yellow oil.

[0577] 1.18 Preparation of Compound 6C To a solution of compound 6B (2.5 g, 12.7 mmol, 1.0 eq) in 1:1:1 THF:MeOH:H2O (15 mL), LiOH:H2O (535 mg, 12.74 mmol, 1 eq) was added at 15°C under a nitrogen atmosphere. The mixture was stirred at 15°C for 12 hours. The reaction product was concentrated under reduced pressure. The residue was adjusted to pH 5-6 with 1 M HCl (15 mL) and filtered. The filtered cake was vacuum-dried to obtain compound 6C (1.4 g, 30% yield) as a yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.20 (d, 2H), 3.56 - 3.43 (m, 1H), 2.42 (t, J = 2.3 Hz, 1H), 2.37 - 2.28 (m, 1H), 2.16 - 2.02 (m, 4H), 1.57 - 1.48 (m, 2H), 1.37 - 1.32 (m, 2H).

[0578] 1.19 Preparation of Intermediate 6 Oxalyl chloride (576 μL, 6.59 mmol, 1 eq) was added dropwise at 0°C to a solution of compound 6C (1.2 g, 6.59 mmol, 1 eq) and DMF (51 μL, 659 μmol, 0.1 eq) in DCM (12 mL). The mixture was stirred at 20°C for 0.5 hours and then concentrated under reduced pressure. The yellow oil was taken into DCM (8 mL) and added at 0°C to a solution of 5-amino-1,3,4-thiadiazole-2-sulfonamide (1.17 g, 6.48 mmol, 1 eq) and pyridine (523 μL, 6.48 mmol, 1 eq) in DMF (8 mL). The mixture was stirred at 20°C for 1 hour, poured into H2O (50 mL), stirred at 20°C for 10 minutes, filtered, and the filtered cake was dried under reduced pressure. The crude product was triturated with 1:1 petroleum ether:MTBE (20 mL) at 20°C for 20 minutes to obtain intermediate 6 (1.3 g, 51% yield, 88% purity) as a yellow solid; 1 H NMR (400 MHz, METHANOL-d4) δ 4.21 (d, J=2.5 Hz, 2 H) 3.54 (tt, J=10.7, 4.2 Hz, 1 H) 2.82 (t, J=2.4 Hz, 1 H) 2.5 (tt, J=11.8, 3.6 Hz, 1 H) 2.12 - 2.23 (m, 2 H) 1.96 - 2.07 (m, 2 H) 1.54 - 1.69 (m, 2 H) 1.25 - 1.38 (m, 2 H).

[0579] A7. Synthesis of Intermediate 7 Scheme A7 [ka] 1.20 Preparation of Compound 7B 1.3 M i-PrMgCl.LiCl (18.4 mL, 9 eq) was added dropwise to DIPA (3.76 mL, 26.6 mmol, 10 eq), and the mixture was stirred at 10°C for 3 hours. A solution of compound 7A (400 mg, 2.66 mmol, 1 eq) and 2-chloroacetic acid (899 μL, 7.99 mmol, 3 eq) in THF (9 mL) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours, followed by warming to 10°C for 1 hour. The reaction mixture was quenched by adding 1 M HCl (30 mL) at 0°C, and extracted with ELISA (3 × 15 mL). The combined organic layers were washed with saturated brine, dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: SiO2) to obtain compound 7B (372 mg, 83% yield) as a white solid; 1 H NMR (400 MHz, METHANOL-d4) δ 4.44 - 4.35 (m, 2H), 2.51 (s, 1H), 2.34 (s, 6H).

[0580] 1.21 Preparation of Intermediate 7 A mixture of compound 7B (280 mg, 1.66 mmol, 1 eq) and 5-amino-1,3,4-thiadiazole-2-sulfonamide (299 mg, 1.66 mmol, 1 eq) was heated in EtOH (4 mL) at 80°C for 24 hours under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was triturated with RINKAN at 10°C for 10 minutes to obtain a white solid. The solid was dissolved in MeOH (3 mL) and 1 M NaHCO3 (995 μL) was added. The mixture was stirred at 65°C for 0.5 hours under a nitrogen atmosphere, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with H2O at 15°C for 10 minutes to obtain intermediate 7 (183 mg, 62% yield) as a white solid. 1 H NMR (400 MHz, METHANOL-d4) δ 7.88 (s, 1H), 2.48 (s, 1H), 2.35 (s, 6H).

[0581] The intermediates in Table 7.1 were prepared by the procedure shown in Scheme A7. [Table 79]

[0582] A8. Synthesis of Intermediate 8 Scheme A8 [ka] 1.22 Preparation of Intermediate 8 Compound 8A (2.0 g, 13.7 mmol, 1 eq) was added to SOCl2 (20 mL) at 0°C under a nitrogen atmosphere, and the mixture was stirred at 15°C for 1 hour. The reaction mixture was concentrated under reduced pressure and incorporated into DMF (20 mL):pyridine (2.21 mL, 27.3 mmol, 2 eq). 5-amino-1,3,4-thiadiazole-2-sulfonamide (2.25 g, 13.7 mmol, 1 eq) was added at 0°C, and the mixture was stirred at 50°C for 12 hours. The crude product was triturated with H2O at 15°C for 10 minutes, and then triturated with RINKAN at 15°C for 10 minutes to obtain crude intermediate 8 (4.2 g) as a yellow solid; LCMS [M+H]: 309.0; 1 H NMR (400 MHz, DMSO-d6) δ 13.85 - 13.34 (m, 1H), 8.38 (s, 2H), 8.14 (br d, J = 8.3 Hz, 2H), 7.68 (br d, J = 8.1 Hz, 2H), 4.59 - 4.42 (m, 1H).

[0583] The intermediates in Table 6.1 were prepared by the procedure shown in Scheme A8. [Table 80]

[0584] A9. Synthesis of Intermediate 9 Scheme A9 [ka] 1.23 Preparation of Compound 9B To a solution of compound 9A (2.50 g, 11.6 mmol, 1 eq) in DCM (50 mL), (COCl)2 (5.09 mL, 58.1 mmol, 5 eq) and DMF (1.5 mL) were added at 0°C, and the mixture was stirred at 25°C for 2 hours. The reaction was repeated. The two reaction products were combined and concentrated under reduced pressure to obtain crude compound 9B (5.4 g) as a yellow oil, which was then used directly in the next reaction.

[0585] 1.24 Preparation of Compound 9C In 54 mL of DMF, pyridine (1.33 mL, 16.5 mmol, 1 eq) was added to a solution of 5-amino-1,3,4-thiadiazole-2-sulfonamide (2.97 g, 16.5 mmol, 1 eq). In 10 mL of DMF, a solution of compound 9B (2.69 g, 11.5 mmol, 0.7 eq) was added at 0°C, and the mixture was stirred at 25°C for 2 hours. The reaction was repeated and the mixture was mixed. The reaction mixture was poured into H2O (100 mL) and extracted with RINKAN (3 × 50 mL). The combined organic layers were washed with saturated brine (100 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250*70 mm, 15 um); mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 24%~54% over 28.0 minutes), and compound 9C (3.0 g, 24% yield) was obtained as a white solid; LCMS [M+2H]: 379.0.

[0586] 1.25 Preparation of Compound 9D To a solution of compound 9C (1.2 g, 3.18 mmol, 1 eq) in THF (24 mL), Pd(PPh3)2Cl2 (223 mg, 318 μmol, 0.1 eq), CuI (121 mg, 636 μmol, 0.2 eq), TEA (2.53 mL, 18.2 mmol), and ethyl(trimethyl)silane (1.32 mL, 9.54 mmol) were added. The mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether: SiO2) to obtain compound 9D (2.4 g, 83% yield, 87% purity) as a yellow solid; LCMS [M+H]: 395.2.

[0587] 1.26 Preparation of Intermediate 9 In 40 mL of MeOH, a solution of compound 9D (2.0 g, 5.07 mmol, 1 eq) was added to K2CO3 (1.05 g, 7.60 mmol, 1.5 eq) at 50°C, and the mixture was stirred at 50°C for 2 hours. The mixture was adjusted to pH=3 with 1 M HCl, the solid was filtered, and the filtered cake was concentrated to obtain intermediate 9 (1.4 g, 86% yield) as a yellow solid, which was used directly in the next reaction; LCMS [M+H]: 323.1; 1 H NMR (400 MHz, DMSO-d6) δ 13.52 (br s, 1H), 8.38 (s, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.52 - 7.40 (m, 2H), 4.40 (s, 1H), 2.40 (s, 3H).

[0588] The intermediates in Table 6.2 were prepared by the procedure shown in Scheme A9. [Table 81]

[0589] A10. Synthesis of Intermediate 10 Scheme A10 [ka] 1.27 Preparation of Compound 10B To a solution of compound 10A (10 g, 99.9 mmol, 1 eq) in DCM (100 mL), TEA (27.8 mL, 200 mmol, 2 eq) and MsCl (11.6 mL, 150 mmol, 1.5 eq) were added at 0°C under a nitrogen atmosphere. The mixture was stirred at 20°C for 1 hour. The reaction mixture was washed with NaHCO3 (50 mL), NH4Cl (50 mL), H2O (20 mL), and saturated brine (20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to obtain compound 10B (17.8 g, 100% yield) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.44 - 4.36 (m, 2H), 4.25 - 4.17 (m, 2H), 3.85 - 3.73 (m, 2H), 3.10 - 3.03 (m, 3H), 2.52 - 2.42 (m, 1H).

[0590] 1.28 Preparation of Compound 10C Potassium ethanethioate (22.8 g, 200 mmol, 2 eq) was added to a solution of compound 10B (17.8 g, 99.9 mmol, 1 eq) in DMF (200 mL) at 20°C under a nitrogen atmosphere. The mixture was stirred at 40°C for 2 hours. The residue was dissolved in SiO2 (500 mL) and washed with H2O (2 × 100 mL) and saturated brine (2 × 100 mL). The organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: SiO2) to obtain compound 10C (9.2 g, 58% yield) as a pale yellow liquid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.16 (d, J = 2.4 Hz, 2H), 3.66 (t, J = 6.4 Hz, 2H), 3.11 (t, J = 6.4 Hz, 2H), 2.44 (t, J = 2.4 Hz, 1H), 2.34 (s, 3H).

[0591] 1.29 Preparation of Compound 10E In 100 mL of EtOH, a solution of compound 10C (7.11 g, 44.9 mmol, 1 eq) and compound 10D (11.1 g, 44.9 mmol, 1 eq) was prepared by adding K2CO3 (31.1 g, 225 mmol, 5 eq) at 20°C. The mixture was stirred at 40°C for 16 hours. The reaction mixture was diluted with H2O (160 mL) and extracted with SiO2 (3 × 400 mL). The combined organic layers were dried over (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: SiO2) to obtain compound 10E (6.4 g, 41% yield) as a white solid; LCMS [M+H]: 344.0. 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 2H), 4.10 (d, J = 2.4 Hz, 2H), 3.64 (t, J = 5.8 Hz, 2H), 3.38 (t, J = 2.4 Hz, 1H), 3.24 (t, J = 5.8 Hz, 2H).

[0592] 1.30 Preparation of Compound 10F To a solution of compound 10E (2.0 g, 5.83 mmol, 1 eq) in MeOH (24 mL) and THF (8 mL), oxone (14.3 g, 23.3 mmol, 4 eq) was added in H2O (16 mL) at 0°C. The mixture was stirred at 30°C for 16 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: SiO2) to obtain compound 10F (1.4 g, 64% yield) as a white solid; LCMS [MH]: 373.9; 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 4.02 (d, J = 2.4 Hz, 2H), 3.96 - 3.90 (m, 2H), 3.89 - 3.84 (m, 2H), 3.36 (t, J = 2.4 Hz, 1H).

[0593] 1.31 Preparation of Intermediate 10 To a solution of compound 10F (1.2 g, 3.20 mmol, 1 eq) in DMSO (12 mL), TEA (890 μL, 6.39 mmol, 2 eq) and (S)-1-cyclopropylethane-1-amine (408 mg, 4.80 mmol, 1.5 eq) were added under a nitrogen atmosphere. The mixture was stirred at 65°C for 3 hours. The residue was diluted with H2O (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with saturated brine (2 × 10 mL), dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, petroleum ether: SiO2) to obtain intermediate 10 (840 mg, 60% yield) as yellow oil; LCMS [MH]: 439.3; 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 2H), 6.51 (br d, J = 8.6 Hz, 1H), 4.05 (d, J = 2.4 Hz, 2H), 3.86 (d, J = 1.8 Hz, 4H), 3.39 (t, J = 2.4 Hz, 1H), 3.14 (td, J = 6.4, 8.4 Hz, 1H), 1.29 - 1.08 (m, 5H), 0.97 - 0.78 (m, 1H), 0.51 - 0.35 (m, 2H), 0.28 - 0.14 (m, 2H).

[0594] The intermediates in Table 6.3 were prepared by the procedure shown in Scheme A10. [Table 82]

[0595] A11. Synthesis of Intermediate 11 Scheme A11 [ka] 1.32 Preparation of Intermediate 11 To a solution of compound 11A (1.7 g, 4.95 mmol, 1 eq) in DMSO (17 mL), TEA (1.38 mL, 9.90 mmol, 2 eq) and cyclooctaneamine (1.26 g, 9.90 mmol, 2 eq) were added. The mixture was stirred at 60°C for 16 hours, diluted with H2O (40 mL), and extracted with SiO2 (2 × 40 mL). The combined organic layers were dried over (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: SiO2) to obtain intermediate 11 (1.4 g, 63% yield) as a yellow oil; LCMS [MH]: 449.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 2H), 6.38 - 6.25 (m, 1H), 4.11 (d, J = 2.4 Hz, 2H), 3.71 (br dd, J = 3.8, 7.8 Hz, 1H), 3.61 (t, J = 6.2 Hz, 2H), 3.38 (t, J = 2.4 Hz, 1H), 3.17 (t, J = 6.2 Hz, 2H), 1.87 - 1.74 (m, 2H), 1.70 - 1.59 (m, 2H), 1.57 - 1.37 (m, 10H).

[0596] A12. Synthesis of Intermediate 12 Scheme A12 [ka] 1.33 Preparation of Compound 12B To a solution of compound 12A (4.0 g, 31.7 mmol, 1 eq) in acetone (160 mL) and H2O (2.8 mL), DBDMH (9.07 g, 31.7 mmol, 1 eq) and imidazolidine-2-thione (486 mg, 4.76 mmol, 0.15 eq) were added at 25°C. The reaction mixture was stirred at 45°C for 12 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether: SiO2) to obtain compound 12B (3.8 g, 54% yield) as a yellow solid.1 H NMR (400 MHz,CDCl3) δ ppm 7.96 (2 H, d, J=8.44 Hz) 7.61 (2 H, d, J=8.44 Hz) 4.44 (2 H, s) 3.30 (1 H, s). Preparation of 1.34 Intermediate 12

[0597] To a solution of compound 12B (1.9 g, 8.52 mmol, 1 eq) in EtOH (19 mL), 5-amino-1,3,4-thiadiazole-2-sulfonamide (1.53 g, 8.52 mmol, 1 eq) was added, and the mixture was stirred at 80°C for 12 hours. This procedure was repeated. Two batches were mixed and filtered. The filtered cake was collected and purified by preparative HPLC (column: Phenomenex Titank C18 Bulk 250*70 mm 10 u; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 25%~65% B over 20.0 mins) to obtain intermediate 12 (2.0 g, 39% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.75 (s, 2H), 7.97 - 7.88 (m, 2H), 7.55 (d, J = 8.4 Hz, 2H), 4.25 (s, 1H).

[0598] A13. Synthesis of Intermediate 13 Scheme A13 [ka] 1.35 Preparation of Compound 13B To a solution of compound 13A (2.0 g, 9.47 mmol, 1 eq) and NaOH (398 mg, 9.94 mmol, 1.05 eq) in H2O (24 mL), NH3.H2O (7.24 mL, 52.6 mmol, 28% purity, 5.6 eq) was added dropwise. NaClO (3.44 mL, 2.93 mmol, 5.3% purity) was added dropwise at 0°C, and the resulting mixture was stirred at 0-5°C for 1 hour. The mixture was filtered, and the filter cake was washed with H2O (3 mL) to obtain crude compound 13B (2.78 g) as a white solid; LCMS [M+H]: 227.0; 1 H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.54 (m, 2H), 7.03 - 6.95 (m, 1H), 4.88 (s, 2H), 4.13 - 4.02 (m, 2H), 1.34 (t, J = 7.0 Hz, 3H).

[0599] 1.36 Preparation of Compound 13C To a solution of compound 13B (2.78 g, 12.3 mmol, 1 eq) in acetone (60 mL) and H2O (60 mL), a solution of KMnO4 (3.88 g, 24.6 mmol, 2 eq) in H2O (90 mL) was added dropwise at 0°C. The reaction mixture was stirred at 10°C for 2 hours. The mixture was treated with activated carbon and 10 N NaOH (4 mL), stirred for 30 minutes, filtered, and washed with SiO2 (50 mL). H2O (50 mL) was added to the filtrate, and the mixture was extracted with SiO2 (3 × 50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: SiO2) to obtain compound 13C (2.1 g, 66% yield) as a white solid; LCMS [M+H]: 259.0; 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 2H), 8.03 (d, J = 9.1 Hz, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.29 - 7.19 (m, 1H), 4.20 - 4.06 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H).

[0600] 1.37 Preparation of Compound 13D In 39 mL of DCE, a mixture of compound 13C (2.5 g, 9.68 mmol, 1 eq) was added to AlCl3 (2.38 mL, 43.6 mmol, 4.5 eq), and the mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was quenched with H2O (6 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: RINKAN) to obtain compound 13D (2.13 g, 96% yield) as a white solid; LCMS [M+H]: 230.9; 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.18 (s, 2H), 7.95 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.14 - 7.07 (m, 1H).

[0601] 1.38 Preparation of Compound 13E To a solution of compound 13D (0.5 g, 2.17 mmol, 1 eq) in DMF (5 mL), DMF-DMA (1.91 mL, 14.4 mmol) was added at 20°C. The mixture was stirred at 40°C for 4 hours. The mixture was concentrated, the residue was dissolved in DMF (5 mL), NaH (130 mg, 3.26 mmol, 60% purity, 1.50 eq) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. To DMF (0.5 mL), 3-bromopropa-1-yne (373 μL, 3.46 mmol, 1.59 eq) was added at 0°C, and the mixture was stirred at 20°C for 2 hours. The residue was poured into a mixture of water (5 mL) and toluene (5 mL). The mixture was filtered, the filtered cake was collected, dissolved in DCM (10 mL), and washed with saturated NaHCO3 aqueous solution (3 × 8 mL). The residue was purified by column chromatography (SiO2, DCM / MeOH) to obtain compound 13E (240 mg, 34% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1 H), 8.06 (br d, J=9.0 Hz, 1 H), 7.74 - 7.88 (m, 1 H), 7.28 (br dd, J=9.01, 2.00 Hz, 1 H), 4.92 (br d, J=1.75 Hz, 2 H), 3.63 (s, 1 H), 3.24 (s, 3 H), 2.99 (s, 3 H).

[0602] 1.39 Preparation of Intermediate 13 A solution of compound 13E (0.24 g, 742 μmol, 1 eq) in NH3 / MeOH (10 mL) was stirred at 20°C for 2 hours. The mixture was adjusted to pH=2 with concentrated HCl and concentrated under reduced pressure. The solid was tritulated with ice water (5 mL), filtered, and the filtered cake was concentrated to obtain intermediate 13 (0.16 g, 80% yield) as a yellow solid; LCMS [M+H]: 269.0.

[0603] A14. Synthesis of Intermediate 14 Scheme A14 [ka] 1.40 Preparation of Compound 14B In 300 mL of DCM, a solution of compound 14A (20 g, 74.3 mmol, 1 eq) was added to a solution of Ghosez reagent (11.8 mL, 89.1 mmol, 1.2 eq), and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 14B (21 g, 98% yield) as a yellow oil, which was then used directly in the next reaction.

[0604] 1.41 Preparation of Compound 14C In 200 mL of THF, a solution of 5-amino-1,3,4-thiadiazole-2-sulfonamide (12.5 g, 70 mmol, 1 eq) was mixed with pyridine (11.2 mL, 139 mmol, 2 eq). In 20 mL of THF, a solution of compound 14B (20 g, 69.5 mmol, 1 eq) was added at 0°C, and the mixture was stirred at 25°C for 2 hours. The aqueous layer was extracted with SiO2 (2 × 300 mL). The combined organic layers were washed with saturated brine (300 mL), dried, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether:SiO2 (200 mL), stirred for 5 minutes, filtered, and the filter cake was collected to obtain compound 14C (24 g, 80% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.31 (s, 2H), 3.42 - 3.36 (m, 1H), 3.30 - 3.24 (m, 2H), 3.23 - 3.10 (m, 2H), 2.12 - 1.97 (m, 4H), 1.58 - 1.49 (m, 2H), 1.47 - 1.31 (m, 11H).

[0605] 1.42 Preparation of Intermediate 14 To a solution of compound 14C (25 g, 57.9 mmol, 1 eq) in DCM (500 mL), 4 M HCl:dioxane (579 mL, 40 eq) was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure...

Claims

1. Formula (A): 【Chemistry 1】 [In the formula, TL １ This represents the first targeting site that binds to carbonic anhydrase IX; TL ２ This represents the second targeting site that binds to carbonic anhydrase IX; L Ａ This represents the linker; s is either 0 or 1; Ring A is a optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; [CL stands for metal chelating agent] A conjugate of, or a pharmaceutically acceptable salt or stereoisomer thereof.

2. Formula (A'): 【Chemistry 2】 [In the formula, TL １ Each of these independently represents the first targeting site that binds to carbonic anhydrase IX; TL ２ Each of these independently represents a second targeting site that binds to carbonic anhydrase IX; L Ｂ This represents the linker; Each ring A is independently a optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; [CL stands for metal chelating agent] A conjugate of, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl rings may be appropriately substituted with one or more R rings; R is, independently of each other, halogen, -CN, -OH, -SF ５ , -SH, -S(=O)C １ -C ３ alkyl, -S(=O) ２ C １ -C ３ alkyl, -S(=O) ２ NH ２ , -S(=O) ２ NHC １ -C ３ alkyl, -S(=O) ２ N(C １ -C ３ alkyl) ２ , -NH ２ , -NHC １ -C ３ alkyl, -N(C １ -C ３ alkyl) ２ , -C(=O)C １ -C ３ alkyl, -C(=O)OH, -C(=O)OC １ -C ３ alkyl, -C(=O)NH ２ , -C(=O)NHC １ -C ３ alkyl, -C(=O)N(C １ -C ３ alkyl) ２ , C １ -C ３ alkyl, C １ -C ３ alkoxy, C １ -C ３ haloalkyl, C １ -C ３ haloalkoxy, C １ -C ３ hydroxyalkyl, C １ -C ３ aminoalkyl, C １ -C ３ heteroalkyl, C ３ -C ６ cycloalkyl, or 3-6 membered heterocycloalkyl; Alternatively, two R atoms on the same atom form an oxo. The conjugate according to claim 1 or 2. 【Request Item 4】 【Chemistry 3】 but, 【Chemistry 4】 The conjugate according to any one of claims 1 to 3. 【Request Item 5】 【Chemistry 5】 but, 【Transformation 6】 The conjugate according to any one of claims 1 to 3.

6. TL １ However, equation (IA): 【Transformation 7】 [In the formula, W １ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR １１ -, -C(=O)-, -C(=O)NR １１ -, -NR １１ C(=O)-, -S(=O) ２ NR １１ -, or -NR １１ S (=O) ２ And; X １ C may be appropriately substituted with one or more R. １ -C １０ It is an alkylene, and here C １ -C １０ The one, two, three, or four carbon atoms of alkylene are -S-, -S(=O)-, and -S(=O). ２ -, -O-, or -NR １１ It may be replaced with - as appropriate; A １ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl that does not exist, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be appropriately substituted with one or more R; T １ C may not exist or may be appropriately replaced with one or more R's. １ -C ３ It is an alkylene, and here C １ -C ３ Each carbon atom in an alkylene is -C(=O)-, -S-, -S(=O)-, -S(=O) ２ -, -O-, or -NR １１ It may be replaced with - as appropriate; B １ C does not exist. １ -C １０ Alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be appropriately substituted with one or more R, and the C １ -C １０ The one, two, three, or four carbon atoms of alkylene are -S-, -S(=O)-, and -S(=O). ２ -, -O-, -NR １１ It may be replaced with - as appropriate; S １ is C which does not exist or may be appropriately substituted by one or more Rs １ -C ３ is alkylene, where the C １ -C ３ one or two carbon atoms of the alkylene are optionally substituted by -S-, -S(=O)-, -S(=O) ２ -, -O-, or -NR １１ -; Y １ is absent, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR １１ -, -C(=O)-, -C(=O)NR １１ -, -NR １１ C(=O)-, -S(=O) ２ NR １１ -, or -NR １１ S(=O) ２ and; R １１ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ It is heteroalkyl; Ring C １ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １２ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; n is 0, 1, 2, 3, 4, 5, or 6; R ａ Each of them is independent of C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; R ｂ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; R ｃ and R ｄ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; Alternatively, R ｃ and R ｄ Together with the atoms to which they are bonded, they form a heterocycloalkyl group which may be appropriately substituted with one or more R atoms; L may not exist or may be appropriately replaced with one or more R's. １ -C ３ It is alkylene; R is independently halogen, -CN, -OH, -SF ５ , -SH, -S(=O)C １ -C ３ Alkyl, -S (=O) ２ C １ -C ３ Alkyl, -S (=O) ２ NH ２ , -S (=O) ２ NHC １ -C ３ Alkyl, -S (=O) ２ N(C) １ -C ３ Alkyl) ２ , -NH ２ , - NHC １ -C ３ Alkyl, -N(C) １ -C ３ Alkyl) ２ , -C(=O)C １ -C ３ Alkyl, -C(=O)OH, -C(=O)OC １ -C ３ Alkyl, -C(=O)NH ２ , -C(=O)NHC １ -C ３ Alkyl, -C(=O)N(C １ -C ３ Alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, C １ -C ３ Hydroxyalkyl, C １ -C ３ Aminoalkyl, C １ -C ３ Heteroalkyl, C ３ -C ６ It is a cycloalkyl or a 3- to 6-membered heterocycloalkyl; Alternatively, two R atoms on the same atom may form an oxo; Alternatively, two R atoms, one on the same or different atoms, may together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group. A conjugate according to any one of claims 1 to 5, as represented by the above.

7. W １ However, -C(=O)- does not exist, or -C(=O)NR １１ - The conjugate according to claim 6.

8. X １ However, C １ -C ４ The conjugate according to claim 6 or 7, wherein the conjugate is alkylene. 【Request Item 9】 【Transformation 8】 but, 【Chemistry 9】 The conjugate according to claim 6. 【Request Item 10】 【Chemistry 10】 but, 【Chemistry 11】 The conjugate according to claim 6 or 9.

11. A １ but, 【Chemistry 12】 The conjugate according to any one of claims 6 to 10, wherein R' is hydrogen or R.

12. T １ However, it does not exist, or C １ -C ３ The conjugate according to any one of claims 6 to 11, wherein the conjugate is alkylene.

13. B １ However, C １ -C ６ The conjugate according to any one of claims 6 to 12, wherein the conjugate is alkylene.

14. B １ The conjugate according to any one of claims 6 to 12, wherein the conjugate is a cycloalkyl group which may be appropriately substituted with one or more R groups.

15. B １ The conjugate according to any one of claims 6 to 12, wherein the conjugate is a bicyclic cycloalkyl group which may be appropriately substituted with one or more R groups.

16. B １ The conjugate according to any one of claims 6 to 12, wherein the conjugate is bicyclo[1.1.1]pentanyl.

17. S １ However, the conjugate described in any one of claims 6 to 16 does not exist. 【Request Item 18】 【Chemistry 13】 but, 【Chemistry 14】 The conjugate according to any one of claims 12 to 17. 【Request Item 19】 【Chemistry 15】 but, 【Chemistry 16】 The conjugate according to any one of claims 12 to 18. 【Request Item 20】 【Chemistry 17】 but, [Chemistry 18] The conjugate according to any one of claims 12 to 19.

21. Y １ However, there are no -O-, -S-, -S (=O) ２ -, -C(=O)NR １１ -, or -NR １１ A conjugate according to any one of claims 6 to 20, wherein C(=O)-.

22. Ring C １ The conjugate according to any one of claims 6 to 21, wherein the conjugate is a heteroaryl or phenyl.

23. Ring C １ The conjugate according to any one of claims 6 to 21, wherein the conjugate is a monocyclic heteroaryl.

24. Ring C １ The conjugate according to any one of claims 6 to 21, wherein the conjugate is a bicyclic heteroaryl. 【Request Item 25】 【Chemistry 19】 but, 【Chemistry 20】 And here, Z １ These are, independently, -N- or -CR １２’ - and; Z ２ is -O-, -S-, or -NR １２’’ - and; R １２’ These are, independently, hydrogen, halogen, -CN, -OH, and -OR. ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ They are haloalkyl, cycloalkyl, or heterocycloalkyl; R １２’’ This is hydrogen, -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ It is a haloalkyl, cycloalkyl, or heterocycloalkyl. The conjugate according to any one of claims 6 to 21. 【Request Item 26】 【Chemistry 21】 but, 【Chemistry 22】 The conjugate according to any one of claims 6 to 21. 【Request Item 27】 【Chemistry 23】 but, 【Chemistry 24】 The conjugate according to any one of claims 6 to 21. 【Request Item 28】 【Chemistry 25】 but, 【Chemistry 26】 The conjugate according to any one of claims 6 to 21.

29. TL ２ However, equation (IIA): 【Chemistry 27】 [In the formula, W ２ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR ２１ -, -C(=O)-, -C(=O)NR ２１ -, -NR ２１ C(=O)-, -S(=O) ２ NR ２１ -, or -NR ２１ S (=O) ２ And; X ２ C may not exist or may be appropriately replaced with one or more R's. １ -C １０ It is an alkylene, and here C １ -C １０ The one, two, three, or four carbon atoms of alkylene are -S-, -S(=O)-, and -S(=O). ２ -, -O-, or -NR ２１ It may be replaced with - as appropriate; Y ２ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR ２１ -, -C(=O)-, -C(=O)NR ２１ -, -NR ２１ C(=O)-, -S(=O) ２ NR ２１ -, or -NR ２１ S (=O) ２ And; A ２ C does not exist. １ -C １０ Alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R ２２ It may be replaced as appropriate; R ２２ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; S ２ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR ２１ -, -C(=O)-, -C(=O)NR ２１ -, -NR ２１ C(=O)-, -S(=O) ２ NR ２１ -, or -NR ２１ S (=O) ２ And; T ２ C may not exist or may be appropriately replaced with one or more R's. １ -C １０ It is an alkylene, and here C １ -C １０ The one, two, three, or four carbon atoms of alkylene are -S-, -S(=O)-, and -S(=O). ２ -, -O-, or -NR ２１ It may be replaced with - as appropriate; R ２１ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ It is heteroalkyl; (i) B ２ It does not exist; or (ii) B ２ is -N(R ２３ ) ２ And; R ２３ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; or (iii) B ２ -CF ３ And; or (iv) B ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R ２４ It may be replaced as appropriate; R ２４ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; or (v) B ２ teeth, 【Chemistry 28】 And; Ring C ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２５ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; m is 0, 1, 2, 3, or 4; R ２６ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ It is heteroalkyl; Ring D ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２７ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; p is 0, 1, 2, 3, or 4; R ａ Each of them is independent of C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; R ｂ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; R ｃ and R ｄ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; Alternatively, R ｃ and R ｄ Together with the atoms to which they are bonded, they form a heterocycloalkyl group which may be appropriately substituted with one or more R atoms; L may not exist or may be appropriately replaced with one or more R's. １ -C ３ It is alkylene; R is independently halogen, -CN, -OH, -SF ５ , -SH, -S(=O)C １ -C ３ Alkyl, -S (=O) ２ C １ -C ３ Alkyl, -S (=O) ２ NH ２ , -S (=O) ２ NHC １ -C ３ Alkyl, -S (=O) ２ N(C) １ -C ３ Alkyl) ２ , -NH ２ , - NHC １ -C ３ Alkyl, -N(C) １ -C ３ Alkyl) ２ , -C(=O)C １ -C ３ Alkyl, -C(=O)OH, -C(=O)OC １ -C ３ Alkyl, -C(=O)NH ２ , -C(=O)NHC １ -C ３ Alkyl, -C(=O)N(C １ -C ３ Alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, C １ -C ３ Hydroxyalkyl, C １ -C ３ Aminoalkyl, C １ -C ３ Heteroalkyl, C ３ -C ６ It is a cycloalkyl or a 3- to 6-membered heterocycloalkyl; Alternatively, two R atoms on the same atom may form an oxo; Alternatively, two R atoms, one on the same or different atoms, may together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group. A conjugate according to any one of claims 1 to 28, as represented by the following:

30. W ２ However, there is no -C(=O)- or -NR ２１ The conjugate according to claim 29, wherein C(=O)-.

31. X ２ However, C may be appropriately substituted with one or more R. １ -C ４ The conjugate according to claim 29 or 30, wherein the conjugate is alkylene.

32. X ２ However, -CH ２ - The conjugate according to any one of claims 29 to 31.

33. Y ２ However, it does not exist -NR ２１ -, or -NR ２１ A conjugate according to any one of claims 29 to 32, wherein C(=O)-.

34. Y ２ However, -NR ２１ A conjugate according to any one of claims 29 to 33, wherein C(=O)-. 【Request Item 35】 【Chemistry 29】 but, 【Transformation 30】 The conjugate according to claim 29. 【Request Item 36】 【Chemistry 31】 but, 【Chemistry 32】 The conjugate according to claim 29.

37. A ２ However, one or more R ２２ C may be replaced as appropriate. １ -C ６ The conjugate according to any one of claims 29 to 36, wherein the conjugate is alkylene.

38. A ２ However, one or more R ２２ The conjugate according to any one of claims 29 to 36, wherein the heterocycloalkyl may be appropriately substituted with the other.

39. A ２ However, each of these is pyrrolidinil, piperidinil, piperazinil, or morpholinil, and each contains one or more R ２２ The conjugate according to any one of claims 29 to 36, which may be appropriately substituted with the following.

40. A ２ However, one or more R ２２ The conjugate according to any one of claims 29 to 36, wherein piperidinyl may be appropriately substituted with the piperidinyl.

41. A ２ However, one or more R ２２ It may be replaced as appropriate. 【Transformation 33】 The conjugate according to any one of claims 29 to 36.

42. A ２ but, 【Transformation 34】 The conjugate according to any one of claims 29 to 36.

43. R ２２ However, each is independent of -C (=O) OR ｂ or -C(=O)NR ｃ R ｄ The conjugate according to any one of claims 29 to 42.

44. R ２２ However, each is independent of -C(=O)NR ｃ R ｄ The conjugate according to any one of claims 29 to 43.

45. S ２ However, it does not exist -NR ２１ -, -C (=O)-, or -NR ２１ A conjugate according to any one of claims 29 to 44, wherein C(=O)-.

46. T ２ However, C may not exist or may be appropriately replaced with one or more R's. １ -C ６ The conjugate according to any one of claims 29 to 45, wherein the conjugate is alkylene. 【Request Item 47】 【Chemistry 35】 but, 【Transformation 36】 The conjugate according to claim 45 or 46. 【Request Item 48】 【Chemistry 37】 but, 【Transformation 38】 The conjugate according to any one of claims 45 to 47.

49. B ２ However, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more R ２４ The conjugate according to any one of claims 29 to 48, which may be appropriately substituted with the following.

50. R ２４ However, each is independent of halogen, -OH, and C. １ -C ６ Alkyl, or C １ -C ６ The conjugate according to any one of claims 29 to 49, wherein it is a haloalkyl.

51. B ２ but, 【Chemistry 39】 And; During the ceremony, Ring C ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２５ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; m is 0, 1, 2, 3, or 4; R ２６ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ It is heteroalkyl; Ring D ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２７ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; p is 0, 1, 2, 3, or 4. The conjugate according to any one of claims 29 to 48.

52. B ２ but, 【Chemistry 40】 The conjugate according to any one of claims 29 to 48.

53. Formula (B): 【Chemistry 41】 [In the formula, L Ａ This represents the linker; s is either 0 or 1; CL stands for metal chelating agent; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL １ Equation (IB): 【Chemistry 42】 [In formula (IB), W １ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR １１ -, -C(=O)-, -C(=O)NR １１ -, -NR １１ C(=O)-, -S(=O) ２ NR １１ -, or -NR １１ S (=O) ２ And; X １ C may be appropriately substituted with one or more R. １ -C １０ It is an alkylene, and here C １ -C １０ The one, two, three, or four carbon atoms of alkylene are -S-, -S(=O)-, and -S(=O). ２ -, -O-, or -NR １１ It may be replaced with - as appropriate; A １ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl that does not exist, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be appropriately substituted with one or more R; T １ C may not exist or may be appropriately replaced with one or more R's. １ -C ３ It is an alkylene, and here C １ -C ３ Each carbon atom in an alkylene is -C(=O)-, -S-, -S(=O)-, -S(=O) ２ -, -O-, -NR １１ It may be replaced with - as appropriate; B １ is a cycloalkyl, heterocycloalkyl, or aryl, where the cycloalkyl, heterocycloalkyl, and aryl may be appropriately substituted with one or more Rs; or B １ is a heteroaryl substituted with one or more R; S １ C may not exist or may be appropriately replaced with one or more R's. １ -C ３ It is an alkylene, and here C １ -C ３ One or two carbon atoms in an alkylene are -C(=O)-, -S-, -S(=O)-, -S(=O) ２ -, -O-, or -NR １１ It may be replaced with - as appropriate; Y １ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR １１ -, -C(=O)-, -C(=O)NR １１ -, -NR １１ C(=O)-, -S(=O) ２ NR １１ -, or -NR １１ S (=O) ２ And; R １１ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ It is heteroalkyl; Ring C １ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １２ is, independently of each other, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ , -NR ｃ C(=O)NR ｄ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ , -NR ２ S(=O) ａ R ａ , -C(=O)R ｂ , -C(=O)OR ｃ , -C(=O)NR ｄ R １ , C ６ , -C １ alkyl, C ６ , -C １ haloalkyl, C ６ , -C １ hydroxyalkyl, C ６ , -C １ aminoalkyl, C ６ , -C ２ heteroalkyl, C ６ , -C ２ alkenyl, C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each independently be optionally substituted with one or more R; n is 0, 1, 2, 3, 4, 5, or 6. It is represented by; TL ２ Equation (IIB): 【Chemistry 43】 [In formula (IIB), W ２ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR ２１ -, -C(=O)-, -C(=O)NR ２１ -, -NR ２１ C(=O)-, -S(=O) ２ NR ２１ -, or -NR ２１ S (=O) ２ And; X ２ C may not exist or may be appropriately replaced with one or more R's. １ -C １０ It is an alkylene, and here C １ -C １０ The one, two, three, or four carbon atoms of alkylene are -S-, -S(=O)-, and -S(=O). ２ -, -O-, or -NR ２１ It may be replaced with - as appropriate; Y ２ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR ２１ -, -C(=O)-, -C(=O)NR ２１ -, -NR ２１ C(=O)-, -S(=O) ２ NR ２１ -, or -NR ２１ S (=O) ２ And; A ２ C does not exist. １ -C １０ Alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R ２２ It may be replaced as appropriate; R ２２ is, independently of one another, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ , -NR ｃ C(=O)NR ｄ R ｂ , -NR ａ C(=O)R ｂ , -NR ｂ C(=O)OR ｂ , -NR ２ S(=O) ａ R ａ , -C(=O)R ｂ , -C(=O)OR ｃ , -C(=O)NR ｄ R １ , -C ６ -C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each independently be optionally substituted with one or more R; S ２ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR ２１ -, -C(=O)-, -C(=O)NR ２１ -, -NR ２１ C(=O)-, -S(=O) ２ NR ２１ -, or -NR ２１ S (=O) ２ And; T ２ C may not exist or may be appropriately replaced with one or more R's. １ -C １０ It is an alkylene, and here C １ -C １０ The one, two, three, or four carbon atoms of alkylene are -S-, -S(=O)-, and -S(=O). ２ -, -O-, or -NR ２１ It may be replaced with - as appropriate; R ２１ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ It is heteroalkyl; (i) B ２ It does not exist; or (ii) B ２ is -N(R ２３ ) ２ And; R ２３ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; or (iii) B ２ -CF ３ And; or (iv) B ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R ２４ It may be replaced as appropriate; R ２４ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; or (v) B ２ teeth, 【Chemistry 44】 And; Ring C ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２５ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; m is 0, 1, 2, 3, or 4; R ２６ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ It is heteroalkyl; Ring D ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２７ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; p is 0, 1, 2, 3, or 4; R ａ Each of them is independent of C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; R ｂ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; R ｃ and R ｄ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; Alternatively, R ｃ and R ｄ Together with the atoms to which they are bonded, they form a heterocycloalkyl group which may be appropriately substituted with one or more R atoms; L may not exist or may be appropriately replaced with one or more R's. １ -C ３ It is alkylene; R is independently halogen, -CN, -OH, -SF ５ , -SH, -S(=O)C １ -C ３ Alkyl, -S (=O) ２ C １ -C ３ Alkyl, -S (=O) ２ NH ２ , -S (=O) ２ NHC １ -C ３ Alkyl, -S (=O) ２ N(C) １ -C ３ Alkyl) ２ , -NH ２ , - NHC １ -C ３ Alkyl, -N(C) １ -C ３ Alkyl) ２ , -C(=O)C １ -C ３ Alkyl, -C(=O)OH, -C(=O)OC １ -C ３ Alkyl, -C(=O)NH ２ , -C(=O)NHC １ -C ３ Alkyl, -C(=O)N(C １ -C ３ Alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, C １ -C ３ Hydroxyalkyl, C １ -C ３ Aminoalkyl, C １ -C ３ Heteroalkyl, C ３ -C ６ It is a cycloalkyl or a 3- to 6-membered heterocycloalkyl; Alternatively, two R atoms on the same atom may form an oxo; Alternatively, two R atoms, one on the same or different atoms, may together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group. [represented by] A conjugate of, or a pharmaceutically acceptable salt or stereoisomer thereof.

54. T １ However, it does not exist, or C １ -C ３ The conjugate according to claim 53, wherein the conjugate is alkylene.

55. B １ The conjugate according to claim 53 or 54, wherein the conjugate is a cycloalkyl group which may be appropriately substituted with one or more R groups.

56. B １ The conjugate according to any one of claims 53 to 55, wherein the conjugate is bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.1.1]hexanyl.

57. B １ The conjugate according to any one of claims 53 to 55, wherein the conjugate is bicyclo[1.1.1]pentanyl.

58. S １ However, the conjugate described in any one of claims 53 to 57 does not exist. 【Request Item 59】 【Chemistry 45】 but, 【Chemistry 46】 The conjugate according to claim 53. [Request Item 60] [Chemistry 47] but, 【Chemistry 48】 The conjugate according to claim 53. 【Request Item 61】 【Chemistry 49】 but, [Transformation 50] The conjugate according to claim 53.

62. A ２ However, one or more R ２２ C may be replaced as appropriate. １ -C ６ The conjugate according to any one of claims 53 to 61, wherein the conjugate is alkylene.

63. A ２ However, one or more R ２２ The conjugate according to any one of claims 53 to 61, wherein the heterocycloalkyl may be appropriately substituted with the other.

64. A ２ However, each of these is pyrrolidinil, piperidinil, piperazinil, or morpholinil, and each contains one or more R ２２ The conjugate according to any one of claims 53 to 61, which may be appropriately substituted with the following.

65. A ２ However, one or more R ２２ The conjugate according to any one of claims 53 to 61, wherein piperidinyl may be appropriately substituted with the piperidinyl.

66. A ２ However, one or more R ２２ It may be replaced as appropriate. 【Chemistry 51】 The conjugate according to any one of claims 53 to 61.

67. R ２２ However, each is independent of -C (=O) OR ｂ or -C(=O)NR ｃ R ｄ The conjugate according to any one of claims 53 to 66.

68. R ２２ However, each is independent of -C(=O)NR ｃ R ｄ The conjugate according to any one of claims 53 to 67.

69. Formula (C): 【Chemistry 52】 [In the formula, L Ａ This represents the linker; s is either 0 or 1; CL stands for metal chelating agent; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL １ The formula is (IC): 【Chemistry 53】 [In formula (IC), W １ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR １１ -, -C(=O)-, -C(=O)NR １１ -, -NR １１ C(=O)-, -S(=O) ２ NR １１ -, or -NR １１ S (=O) ２ And; X １ C may be appropriately substituted with one or more R. １ -C １０ It is an alkylene, and here C １ -C １０ The one, two, three, or four carbon atoms of alkylene are -S-, -S(=O)-, and -S(=O). ２ -, -O-, or -NR １１ It may be replaced with - as appropriate; A １ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl that does not exist, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be appropriately substituted with one or more R; T １ C may not exist or may be appropriately replaced with one or more R's. １ -C ３ It is an alkylene, and here C １ -C ３ Each carbon atom in an alkylene is -C(=O)-, -S-, -S(=O)-, -S(=O) ２ -, -O-, -NR １１ It may be replaced with - as appropriate; B １ C does not exist. １ -C １０ Alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be appropriately substituted with one or more R, and the C １ -C １０ The one, two, three, or four carbon atoms of alkylene are -S-, -S(=O)-, and -S(=O). ２ -, -O-, -NR １１ It may be replaced with - as appropriate; S １ C may not exist or may be appropriately replaced with one or more R's. １ -C ３ It is an alkylene, and here C １ -C ３ One or two carbon atoms in an alkylene are -S-, -S(=O)-, -S(=O) ２ -, -O-, or -NR １１ It may be replaced with - as appropriate; Y １ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR １１ -, -C(=O)-, -C(=O)NR １１ -, -NR １１ C(=O)-, -S(=O) ２ NR １１ -, or -NR １１ S (=O) ２ And; R １１ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ It is heteroalkyl; Ring C １ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １２ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; n is 0, 1, 2, 3, 4, 5, or 6. It is represented by; TL ２ Equation (IIC): 【Chemistry 54】 [In formula (IIC), W ２ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR ２１ -, -C(=O)-, -C(=O)NR ２１ -, -NR ２１ C(=O)-, -S(=O) ２ NR ２１ -, or -NR ２１ S (=O) ２ And; X ２ C may not exist or may be appropriately replaced with one or more R's. １ -C １０ It is an alkylene, and here C １ -C １０ The one, two, three, or four carbon atoms of alkylene are -S-, -S(=O)-, and -S(=O). ２ -, -O-, or -NR ２１ It may be replaced with - as appropriate; Y ２ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR ２１ -, -C(=O)-, -C(=O)NR ２１ -, -NR ２１ C(=O)-, -S(=O) ２ NR ２１ -, or -NR ２１ S (=O) ２ And; A ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R ２２ It may be replaced as appropriate; R ２２ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; S ２ It does not exist, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR ２１ -, -C(=O)-, -C(=O)NR ２１ -, -NR ２１ C(=O)-, -S(=O) ２ NR ２１ -, or -NR ２１ S (=O) ２ And; T ２ C may not exist or may be appropriately replaced with one or more R's. １ -C １０ It is an alkylene, and here C １ -C １０ The one, two, three, or four carbon atoms of alkylene are -S-, -S(=O)-, and -S(=O). ２ -, -O-, or -NR ２１ It may be replaced with - as appropriate; R ２１ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ It is heteroalkyl; (i) B ２ It does not exist; or (ii) B ２ is -N(R ２３ ) ２ And; R ２３ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; or (iii) B ２ -CF ３ And; or (iv) B ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are one or more R ２４ It may be replaced as appropriate; R ２４ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; or (v) B ２ teeth, 【Transformation 55】 And; Ring C ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２５ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; m is 0, 1, 2, 3, or 4; R ２６ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ It is heteroalkyl; Ring D ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２７ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; p is 0, 1, 2, 3, or 4; R ａ Each of them is independent of C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; R ｂ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; R ｃ and R ｄ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; Alternatively, R ｃ and R ｄ Together with the atoms to which they are bonded, they form a heterocycloalkyl group which may be appropriately substituted with one or more R atoms; L may not exist or may be appropriately replaced with one or more R's. １ -C ３ It is alkylene; R is independently halogen, -CN, -OH, -SF ５ , -SH, -S(=O)C １ -C ３ Alkyl, -S (=O) ２ C １ -C ３ Alkyl, -S (=O) ２ NH ２ , -S (=O) ２ NHC １ -C ３ Alkyl, -S (=O) ２ N(C) １ -C ３ Alkyl) ２ , -NH ２ , - NHC １ -C ３ Alkyl, -N(C) １ -C ３ Alkyl) ２ , -C(=O)C １ -C ３ Alkyl, -C(=O)OH, -C(=O)OC １ -C ３ Alkyl, -C(=O)NH ２ , -C(=O)NHC １ -C ３ Alkyl, -C(=O)N(C １ -C ３ Alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, C １ -C ３ Hydroxyalkyl, C １ -C ３ Aminoalkyl, C １ -C ３ Heteroalkyl, C ３ -C ６ It is a cycloalkyl or a 3- to 6-membered heterocycloalkyl; Alternatively, two R atoms on the same atom may form an oxo; Alternatively, two R atoms, one on the same or different atoms, may together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group. [represented by] A conjugate of, or a pharmaceutically acceptable salt or stereoisomer thereof.

70. T １ However, the conjugate described in claim 69 does not exist.

71. B １ However, C １ -C ６ The conjugate according to claim 69 or 70, wherein the conjugate is alkylene.

72. B １ The conjugate according to any one of claims 69 to 71, wherein the conjugate is a cycloalkyl group which may be appropriately substituted with one or more R groups.

73. B １ The conjugate according to any one of claims 69 to 71, wherein the conjugate is a monocyclic cycloalkyl that may be appropriately substituted with one or more R.

74. B １ The conjugate according to any one of claims 69 to 71, wherein the conjugate is a bicyclic cycloalkyl group which may be appropriately substituted with one or more R groups.

75. B １ The conjugate according to any one of claims 69 to 71, wherein the conjugate is bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.1.1]hexanyl.

76. B １ The conjugate according to any one of claims 69 to 71, wherein the conjugate is bicyclo[1.1.1]pentanyl.

77. S １ However, the conjugate described in any one of claims 69 to 76 does not exist. 【Request Item 78】 【Transformation 56】 but, 【Chemistry 57】 The conjugate according to claim 69. 【Request Item 79】 【Chemistry 58】 but, 【Chemistry 59】 The conjugate according to claim 69. [Request Item 80] [Transformation 60] but, 【Chemistry 61】 The conjugate according to claim 69.

81. A ２ However, one or more R ２２ The conjugate according to any one of claims 69 to 80, wherein the heterocycloalkyl may be appropriately substituted with the other.

82. A ２ However, each of these is pyrrolidinil, piperidinil, piperazinil, or morpholinil, and each contains one or more R ２２ The conjugate according to any one of claims 69 to 80, which may be appropriately substituted with the following.

83. A ２ However, one or more R ２２ The conjugate according to any one of claims 69 to 80, wherein piperidinyl may be appropriately substituted with the piperidinyl.

84. A ２ However, one or more R ２２ It may be replaced as appropriate. 【Transformation 62】 The conjugate according to any one of claims 69 to 80.

85. A ２ but, 【Transformation 63】 The conjugate according to any one of claims 69 to 80.

86. R ２２ However, each is independent of -C (=O) OR ｂ or -C(=O)NR ｃ R ｄ The conjugate according to any one of claims 69 to 85.

87. R ２２ However, each is independent of -C(=O)NR ｃ R ｄ The conjugate according to any one of claims 69 to 86.

88. The conjugate according to any one of claims 53 to 87, wherein X is CH.

89. The conjugate according to any one of claims 53 to 87, wherein X is a heterocycloalkyl which may be appropriately substituted.

90. W １ However, -C(=O)- does not exist, or -C(=O)NR １１ - The conjugate according to any one of claims 53 to 89.

91. X １ However, C １ -C ４ The conjugate according to any one of claims 53 to 90, wherein the conjugate is alkylene. 【Request Item 92】 【Chemistry 64】 but, 【Transformation 65】 The conjugate according to any one of claims 53 to 91. 【Request Item 93】 【Transformation 66】 but, 【Transformation 67】 The conjugate according to any one of claims 53 to 92.

94. A １ The conjugate according to any one of claims 53 to 93, wherein the conjugate is a heteroaryl which may be appropriately substituted with one or more R.

95. A １ The conjugate according to any one of claims 53 to 93, wherein the triazolyl may be appropriately substituted with one or more R.

96. A １ but, 【Transformation 68】 The conjugate according to any one of claims 53 to 92, wherein R' is hydrogen or R.

97. T １ However, it does not exist, or C １ -C ３ The conjugate according to any one of claims 53 to 96, wherein the conjugate is alkylene.

98. Y １ However, there are no -O-, -S-, -S (=O) ２ -, -C(=O)NR １１ -, or -NR １１ A conjugate according to any one of claims 53 to 97, wherein C(=O)-.

99. Ring C １ The conjugate according to any one of claims 53 to 98, wherein the conjugate is a heteroaryl or phenyl.

100. Ring C １ The conjugate according to any one of claims 53 to 98, wherein the conjugate is a monocyclic heteroaryl.

101. Ring C １ The conjugate according to any one of claims 53 to 98, wherein the conjugate is a bicyclic heteroaryl. 【Request Item 102】 【Chemistry 69】 but, 【Transformation 70】 And here, Z １ These are, independently, -N- or -CR １２’ - and; Z ２ is -O-, -S-, or -NR １２’’ - and; R １２’ These are, independently, hydrogen, halogen, -CN, -OH, and -OR. ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ They are haloalkyl, cycloalkyl, or heterocycloalkyl; R １２’’ This is hydrogen, -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ It is a haloalkyl, cycloalkyl, or heterocycloalkyl. The conjugate according to any one of claims 53 to 98. 【Request Item 103】 【Chemistry 71】 but, 【Chemistry 72】 The conjugate according to any one of claims 53 to 98. 【Request Item 104】 【Chemistry 73】 but, 【Chemistry 74】 The conjugate according to any one of claims 53 to 98. 【Request Item 105】 【Chemistry 75】 but, 【Transformation 76】 The conjugate according to any one of claims 53 to 98.

106. W ２ However, there is no -C(=O)- or -NR ２１ A conjugate according to any one of claims 53 to 105, wherein C(=O)-.

107. X ２ However, C may be appropriately substituted with one or more R. １ -C ４ The conjugate according to any one of claims 53 to 106, wherein the conjugate is alkylene.

108. X ２ However, -CH ２ - The conjugate according to any one of claims 53 to 107.

109. Y ２ However, it does not exist -NR ２１ -, or -NR ２１ A conjugate according to any one of claims 53 to 108, wherein C(=O)-.

110. Y ２ However, -NR ２１ A conjugate according to any one of claims 53 to 109, wherein C(=O)-. 【Request Item 111】 【Chemistry 77】 but, 【Transformation 78】 The conjugate according to any one of claims 53 to 110.

112. S ２ However, it does not exist -NR ２１ -, -C (=O)-, or -NR ２１ A conjugate according to any one of claims 53 to 111, wherein C(=O)-.

113. T ２ However, C may not exist or may be appropriately replaced with one or more R's. １ -C ６ The conjugate according to any one of claims 53 to 112, wherein the conjugate is alkylene. 【Request Item 114】 【Chemistry 79】 but, 【Chemistry 80】 The conjugate according to any one of claims 53 to 113. 【Request Item 115】 【Chemistry 81】 but, 【Chemistry 82】 The conjugate according to any one of claims 53 to 114.

116. B ２ However, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more R ２４ The conjugate according to any one of claims 53 to 115, which may be appropriately substituted with the following.

117. R ２４ However, each is independent of halogen, -OH, and C. １ -C ６ Alkyl, or C １ -C ６ The conjugate according to any one of claims 53 to 116, wherein it is a haloalkyl.

118. B ２ but, 【Chemistry 83】 And; During the ceremony, Ring C ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２５ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; m is 0, 1, 2, 3, or 4; R ２６ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ It is heteroalkyl; Ring D ２ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２７ These are, independently, halogen, -CN, and -NO. ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may each be independently substituted with one or more R as appropriate; p is 0, 1, 2, 3, or 4. The conjugate according to any one of claims 53 to 115.

119. B ２ but, 【Chemical 84】 The conjugate according to any one of claims 53 to 115.

120. The conjugate according to any one of claims 1 to 119, wherein s is 0.

121. The conjugate according to any one of claims 1 to 119, wherein s is 1.

122. The aforementioned linker L Ａ However, equation (L-1): 【Chemical 85】 [In the formula, L ０ These are independently -O- and -NR Ｌ -, -N(R Ｌ ) ２ ＋ -, -OP (=O) (OR Ｌ )O-, -S-, -S(=O)-, -S(=O) ２ -, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR Ｌ -, -NR Ｌ C(=O)-, -OC(=O)NR Ｌ -, -NR Ｌ C(=O)O-, -NR Ｌ C(=O)NR Ｌ -, -NR Ｌ C(=S)NR Ｌ -, -CR Ｌ =N-, -N=CR Ｌ , -NR Ｌ S (=O) ２ -, -S (=O) ２ NR Ｌ -, -C(=O)NR Ｌ S (=O) ２ -, -S (=O) ２ NR Ｌ C(=O)-, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, C １ -C ３０ Alkylene, C ２ -C ３０ Alkenylene, C ２ -C ３０ Alkinylene, C １ -C ３０ Heteroalkylene, -(C １ -C ３０ Alkylene)-O-,-O-(C １ -C ３０ Alkylene) -, -(C １ -C ３０ Alkylene)-NR Ｌ -, -NR Ｌ - (C １ -C ３０ Alkylene) -, -(C １ -C ３０ Alkylene)-N(R Ｌ ) ２ ＋ -, or -N(R Ｌ ) ２ ＋ - (C １ -C ３０ Alkylene) - where cycloalkylene, heterocycloalkylene, arylene, heteroarylene, alkylene, alkenylene, alkynylene, and heteroalkylene may each be independently substituted with one or more R as appropriate; R Ｌ These are, independently, hydrogen and C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C １ -C ４ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ It is alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; k is between 1 and 20; R is independently halogen, -CN, -OH, -SF ５ , -SH, -S(=O)C １ -C ３ Alkyl, -S (=O) ２ C １ -C ３ Alkyl, -S (=O) ２ NH ２ , -S (=O) ２ NHC １ -C ３ Alkyl, -S (=O) ２ N(C) １ -C ３ Alkyl) ２ , -NH ２ , - NHC １ -C ３ Alkyl, -N(C) １ -C ３ Alkyl) ２ , -C(=O)C １ -C ３ Alkyl, -C(=O)OH, -C(=O)OC １ -C ３ Alkyl, -C(=O)NH ２ , -C(=O)NHC １ -C ３ Alkyl, -C(=O)N(C １ -C ３ Alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Haloalkoxy, C １ -C ３ Hydroxyalkyl, C １ -C ３ Aminoalkyl, C １ -C ３ Heteroalkyl, C ３ -C ６ It is a cycloalkyl or a 3- to 6-membered heterocycloalkyl; Alternatively, two R atoms on the same atom may form an oxo. A conjugate according to any one of claims 1 to 119 or 121, having the structure of a conjugate.

123. The aforementioned linker L Ａ However, equation (L-1a): 【Chemical 86】 [In the formula, L １ does not exist, -O-, -NR Ｌ -, -N(R Ｌ ) ２ ＋ -, -S-, -S(=O)-, -S(=O) ２ -, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR Ｌ -, -NR Ｌ C(=O)-, -OC(=O)NR Ｌ -, -NR Ｌ C(=O)O-, -NR Ｌ C(=O)NR Ｌ -, -NR Ｌ S (=O) ２ -, -S (=O) ２ NR Ｌ -, -C(=O)NR Ｌ S (=O) ２ - or -S (=O) ２ NR Ｌ C (= O) - is; L ２ teeth, 【Transformation 87】 , C １ -C １０ An alkylene, or a heterocycloalkylene which may be appropriately substituted with one or more R; L ３ It does not exist, or C １ -C １０ It is alkylene; L ４ does not exist, -O-, -NR Ｌ -, -N(R Ｌ ) ２ ＋ -, -S-, -S(=O)-, -S(=O) ２ -, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR Ｌ -, -NR Ｌ C(=O)-, -OC(=O)NR Ｌ -, -NR Ｌ C(=O)O-, -NR Ｌ C(=O)NR Ｌ -, -NR Ｌ S (=O) ２ -, -S (=O) ２ NR Ｌ -, -C(=O)NR Ｌ S (=O) ２ - or -S (=O) ２ NR Ｌ C (= O) - The conjugate according to claim 122, having the structure.

124. The aforementioned linker L Ａ but, 【Chemical 88】 The conjugate according to any one of claims 1 to 119 or 121 to 123.

125. The aforementioned metal chelating agent 【Chemistry 89】 The conjugate according to claim 124.

126. The conjugate according to any one of claims 1 to 125, as listed in Table 1.

127. The conjugate according to any one of claims 1 to 126, further comprising a radionuclide that binds to the metal chelating agent to form a radiopharmaceutical conjugate.

128. The radiopharmaceutical conjugate according to claim 127, wherein the radioactive nuclide is an alpha-particle emitting radionuclide.

129. The radiopharmaceutical conjugate according to claim 128, wherein the alpha particle-emitting radionuclide is Ac-225.

130. The radiopharmaceutical conjugate according to claim 127, wherein the radioactive nuclide is a beta particle-emitting radionuclide.

131. The radiopharmaceutical conjugate according to claim 130, wherein the beta particle-emitting radionuclide is lutetium-177.

132. The radiopharmaceutical conjugate according to claim 127, wherein the radioactive nuclide is a positron-emitting radionuclide.

133. A conjugate having the structure of formula (AC), (AC'), (BC), (BC'), (CC), or (CC'), wherein each of the formulas is as described herein.

134. A pharmaceutical composition comprising a radiopharmaceutical conjugate according to any one of claims 128 to 133, and a pharmaceutically acceptable excipient or carrier.

135. A method for diagnosing or imaging a disease or disorder in a subject requiring diagnosis or imaging, characterized by administering to the subject a radiopharmaceutical conjugate according to any one of claims 128 to 133 or a pharmaceutical composition according to claim 134.

136. A method for treating a disease or disorder in a subject requiring treatment, characterized by administering to the subject a radiopharmaceutical conjugate according to any one of claims 128 to 133 or a pharmaceutical composition according to claim 134.

137. The method according to claim 135 or 136, wherein the disease or disorder is cancer.

138. The method according to claim 137, wherein the cancer is hypoxic.

139. The method according to claim 137 or 138, wherein the cancer is cellular renal cell carcinoma (ccRCC).

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