Radiopharmaceutical compositions targeting carbonic anhydrase ix and uses thereof

Abstract

Described herein are conjugates and compositions targeting carbonic anhydrase IX and uses thereof. The subject conjugates and compositions are useful for the treatment of cancer.

Description

RADIOPHARMACEUTICAL COMPOSITIONS TARGETING CARBONIC ANHYDRASE IX AND USES THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application Serial No.63 / 499,666 filed May 2, 2023 which is hereby incorporated by reference in its entirety. BACKGROUND

[0002] The expression of distinct proteins on the surface of tumor cells offers the opportunity to diagnose and characterize disease by probing the phenotypic identity and biochemical composition and activity of the tumor. Radioactive molecules that selectively bind to specific tumor cell surface proteins allow the use of noninvasive imaging techniques, such as molecular imaging or nuclear medicine, for detecting the presence and quantity of tumor associated proteins, thereby providing vital information related to the diagnosis and extent of disease, prognosis, and therapeutic management options. In addition, as radiopharmaceuticals can be prepared that are not only capable of imaging disease but also delivering a therapeutic radionuclide to the diseased tissue, therapy, in particular cancer therapy, can be realized. The selective expression of CA-IX on tumors in response to hypoxia makes it an attractive target to exploit for noninvasive imaging as well as targeted radiotherapy.

[0003] In order to grow beyond more than a few millimeters in diameter, tumor micrometastasis need to obtain a supply of oxygen to sustain the high metabolic rate characteristic of rapid growth, and do so by inducing the formation of new blood vessels. The distance that tumor cells reside from blood vessels is inversely proportional to the oxygen pressure of the tumor. Even when angiogenesis occurs and a blood supply is established, the less vascular interior region of the growing tumor mass remains hypoxic and eventually undergoes necrosis.

[0004] Hypoxia is associated with a poor response to radiation therapy, and leads to tumor resistance. Since oxygen is necessary for the cytotoxic actions of free radicals generated by radiation, higher, often incompatible, levels of radiation are required to promote damage to the tumor. Therefore, there is a need for non-invasive techniques to stratify patients based on cancer hypoxia who are not expected to respond to radiation therapy because of low oxygen, and who may be candidates for alternative hypoxia-activated chemotherapies that are becoming available. As hypoxia constitutes a major difference between the tumor and normal tissues, it can be exploited for the development of tumor specific probes.

[0005] Hypoxia is a potent stimulus for the expression of specific genes, several which function to trigger vasculogenesis and therefore supply oxygen to the tumor, increase metabolism to increase the oxygen extraction factor, and promote a favorable environment for tumor growth. The activation of hypoxia inducible genes is in part mediated by a transcription factor, HIF-1α. Under normoxic conditions, HIF-1α is hydroxylated on proline residues that reside in the oxygen induced degradation domain of the protein by proline hydroxylase. Hydroxyproline facilitates binding of Von-Hippel-Lindau Factor (VHL), a tumor suppressor that, when bound, promotes the ubiquitination and degradation of HIF-1α. During hypoxia, proline hydroxylase is inhibited, and VHL no longer binds HIF-1α; the now stabilized HIF-1α translocates to the nucleus and associates with HIF-1α. This heterodimeric transcription factor then binds to HIF-1 responsive DNA sequences in the promoter region of target genes including the carbonic anhydrase isoform CA-IX, as well as VEGF, erythropoietin, and glucose transporters.

[0006] Carbonic anhydrases are a family of enzymes comprised of 16 isozymes that catalyze the reaction: CO2+H2O HCO3−+H+, and therefore play an important role in pH regulation. Specific isozymes are found either in the cytosol, anchored to the membrane, within the mitochondria, or secreted from the cell. The well-studied constitutively expressed isozyme, carbonic anhydrase II, is found in the cytosol of most cell types, and is the primary isoform responsible for the regulation of intracellular pH.

[0007] CA-IX is a membrane-anchored isoform of the enzyme with its catalytic domain in the extracellular space. It has a limited tissue distribution and is found at low levels primarily in the gastrointestinal tract. The expression of CA-IX is under the control of HIF-1α, and this isozyme is highly expressed in tumors cells exposed to hypoxia both in vitro and in vivo. Increased CA-IX expression has been detected in carcinomas of the cervix, ovary, kidney, esophagus, lung, breast, and brain. CA-IX has been reported to promote extracellular acidification. The low extracellular pH as a result of the activity of CA-IX leads to tumorigenic transformation, chromosomal rearrangements, extracellular matrix breakdown, migration and invasion, induction of growth factors, protease activation, and chemoresistance.

[0008] Currently, many small molecule inhibitors for CA-IX show undesired side effects due to inhibition of other CA isozymes present in the target organ. There is a need for a CA-IX selective inhibitor to potentially reduce undesired side effects that may arise from inhibition of other, including non-membrane-associated, CA isozymes. SUMMARY

[0009] Disclosed herein is a conjugate of Formula (A), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (A); wherein: TL1represents a 1sttargeting moiety that binds to carbonic anhydrase IX; TL2represents a 2ndtargeting moiety that binds to carbonic anhydrase IX; LArepresents a linker; s is 0 or 1;Ring A is an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and CL represents a metal chelator.

[0010] Also disclosed herein is a conjugate of Formula (A’), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (A’); wherein: each TL1independently represents a 1sttargeting moiety that binds to carbonic anhydrase IX; each TL2independently represents a 2ndtargeting moiety that binds to carbonic anhydrase IX; LBrepresents a linker; and each Ring A is independently an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and CL represents a metal chelator.

[0011] Also disclosed herein is a conjugate of Formula (B), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (B); wherein: LArepresents a linker; s is 0 or 1; CL represents a metal chelator; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1is of Formula (IB):Formula (IB); and TL2 is of Formula (IIB):Formula (IIB).

[0012] Also provided herein is a conjugate of Formula (C), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (C); wherein: LArepresents a linker; s is 0 or 1; CL represents a metal chelator; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1is of Formula (IC):Formula (IC); and TL2 is of Formula (IIC):Formula (IIC).

[0013] Also disclosed herein is a pharmaceutical composition comprising a radiopharmaceutical conjugate disclosed herein, and a pharmaceutically acceptable excipient or carrier.

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

[0015] Also disclosed herein is a method of diagnosing or imaging a disease or disorder in a subject in need thereof, the method comprising administering to the subject a radiopharmaceutical conjugate disclosed herein, or a pharmaceutical composition disclosed herein.

[0016] Also disclosed herein is a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a radiopharmaceutical conjugate disclosed herein, or a pharmaceutical composition disclosed herein.

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

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

[0019] In some embodiments, the 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 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 cell renal cell carcinoma (ccRCC). INCORPORATION BY REFERENCE

[0022] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawing (also “figure” and “FIG.” herein), of which:

[0024] FIG. 1 to FIG. 19 illustrate the structures of representative metal chelators. DETAILED DESCRIPTION Definitions

[0025] In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0026] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictatesotherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0027] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0028] “oxo” refers to =O.

[0029] “Carboxyl” refers to -COOH.

[0030] “Cyano” refers to -CN.

[0031] “Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six 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, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6alkyl” or “C1-6alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-10alkyl. In some embodiments, the alkyl is a C1-6alkyl. In some embodiments, the alkyl is a C1-5alkyl. In some embodiments, the alkyl is a C1-4alkyl. In some embodiments, the alkyl is a C1-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0032] “Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), 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 the like. Whenever it appears herein, a numerical range such as “C2-C6alkenyl” or “C2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0033] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl” or “C2-6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, - CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0034] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0035] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is as defined above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0036] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged 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). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0037] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15fully saturated cycloalkyl or C3-C15cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10fully saturated cycloalkyl or C3-C10cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8fully saturated cycloalkyl or C3-C8cycloalkenyl), from three to six carbon atoms (e.g., C3-C6fully saturated cycloalkyl or C3-C6cycloalkenyl), from three to five carbon atoms (e.g., C3-C5fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4cycloalkenyl). 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. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, 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, and 7,7- dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0038] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0039] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0040] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by 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. Hydroxyalkyl include, for example,hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0041] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by 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. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0042] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. - NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, - CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, - CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0043] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8fully saturated heterocycloalkyl or C2-C8heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6fully saturated heterocycloalkyl or C2-C6heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5fully saturated heterocycloalkyl or C2-C5heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4fully saturated heterocycloalkyl or C2-C4heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo- thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 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 ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. 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 stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0044] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting ofnitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 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, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0045] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and / or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

[0046] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0047] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0048] “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 the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition. Compounds

[0049] Disclosed herein are conjugates targeting the CA-IX receptor and pharmaceutical compositions thereof. In some embodiments, the conjugate disclosed herein is selective for CA-IX over CA-XII.

[0050] The conjugates and compositions can be useful for treating cancer. The conjugates and compositions can also be useful in imaging and disease diagnosis.

[0051] In one aspect, described herein are conjugates that comprise a targeting ligand that binds to a CA-IX protein. In some embodiments, the conjugates described herein comprise a targeting ligand that binds to a CA-IX protein and a metal chelator that is configured to bind with a radionuclide. In some embodiments, the conjugates described herein comprises a radionuclide.

[0052] Disclosed herein is a conjugate of Formula (A), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (A); wherein: TL1represents a 1sttargeting moiety that binds to carbonic anhydrase IX; TL2represents a 2ndtargeting moiety that binds to carbonic anhydrase IX; LArepresents a linker; s is 0 or 1;Ring A is an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and CL represents a metal chelator.

[0053] Disclosed herein is a conjugate of Formula (AC), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (AC); wherein: TL1represents a 1sttargeting moiety that binds to carbonic anhydrase IX; TL2represents a 2ndtargeting moiety that binds to carbonic anhydrase IX; LArepresents a linker; s is 0 or 1; Ring A is an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R30is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted (e.g., with one or more R); or R30is an albumin binding moiety or a payload moiety ; wherein Ra, Rb, Rc, Rd, and R have their meanings as defined in Formula (IA).

[0054] In some embodiments, the conjugate compound of Formula (AC) comprises a covalently bound radioisotope.

[0055] Disclosed herein is a conjugate of Formula (A’), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (A’); wherein: each TL1independently represents a 1sttargeting moiety that binds to carbonic anhydrase IX; each TL2independently represents a 2ndtargeting moiety that binds to carbonic anhydrase IX; LBrepresents a linker; and each Ring A is independently an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and CL represents a metal chelator.

[0056] Disclosed herein is a conjugate of Formula (AC’), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (AC’); wherein: each TL1 independently represents a 1sttargeting moiety that binds to carbonic anhydrase IX; each TL2independently represents a 2ndtargeting moiety that binds to carbonic anhydrase IX; LBrepresents a linker; each Ring A is independently an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R30is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted (e.g., with one or more R); or R30is an albumin binding moiety or a payload moiety ; wherein Ra, Rb, Rc, Rd, and R have their meanings as defined in Formula (IA).

[0057] In some embodiments, the conjugate compound of Formula (AC’) comprises a covalently bound radioisotope.

[0058] In some embodiments of a compound of Formula (A’) or (AC’), each TL1is the same. In some embodiments of a compound of Formula (A’) or (AC’), each TL1is different. In some embodiments of a compound of Formula (A’) or (AC’), each TL2is the same. In some embodiments of a compound of Formula (A’) or (AC’), each TL2is different. In some embodiments of a compound of Formula (A’) or (AC’), each Ring A is the same. In some embodiments of a compound of Formula (A’) or (AC’), each Ring A is different. In some embodiments of a compound of Formula (A’) or (AC’), each TL1is independently a targeting moiety of Formula (IA). In some embodiments of a compound of Formula (A’) or (AC’), each TL2is independently a targeting moiety of Formula (IIA).

[0059] In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo.

[0060] In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), Ring A is heterocycloalkyl optionally substituted with one or more R.

[0061] In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), Ring A is monocyclic heterocycloalkyl optionally substituted with one or more R.

[0062] In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), Ring A is bicyclic heterocycloalkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), Ring A is spirobicyclic heterocycloalkyl optionally substituted with one or more R.

[0063] In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), Ring A is 4- to 6- membered heterocycloalkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), Ring A is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more R. In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), Ring A is piperidinyl or piperazinyl, each optionally substituted withone or more R. In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), Ring A is piperidinyl optionally substituted with one or more R. In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), Ring A is piperazinyl optionally substituted with one or more R.

[0064] In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’),. In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’),* ***embodiments of a compound of Formula (A), (AC), (A’) or (AC’),*******), ***(AC), (A’) or (AC’),. In some embodiments of Formula (A) or Formula (AC), *** represents the attachment point of ring A to linker LA. In some embodiments of Formula (A), when s is 0, *** represents the attachment point of ring A to metal chelator (CL). In some embodiments of Formula (AC), when s is 0, *** represents the attachment point of ring A to R30. In some embodiments of Formula (A) or Formula (AC), ** represents the attachment point of ring A to TL1, and * represents the attachment point of ring A to TL2. In some embodiments of Formula (A) or Formula(AC), * represents the attachment point of ring A to TL1, and ** represents the attachment point of ring A to TL2. In some embodiments of Formula (A’) or Formula (AC’), *** represents the attachment point of ring A to linker LB. In some embodiments of Formula (A’) or Formula (AC’), ** represents the attachment point of ring A to a TL1, and * represents the attachment point of ring A to a TL2. In some embodiments of Formula (A’) or Formula (AC’), * represents the attachment point of ring A to a TL1, and ** represents the attachment point of ring A to a TL2.

[0065] In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), TL1is of Formula (IA): W1 X1 A1 T1 B1 S1 Y1C1(R12)nFormula (IA); wherein: W1is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR11-, -C(=O)-, -C(=O)NR11-, -NR11C(=O)-, -S(=O)2NR11-, or -NR11S(=O)2; X1is C1-C10alkylene optionally substituted with one or more R and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR11-; A1is absent, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R; T1is absent or C1-C3alkylene optionally substituted with one or more R and wherein one carbon atom of the C1-C3alkylene is optionally replaced with -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -O-, or -NR11-; B1is absent, C1-C10alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R, and wherein one, two, three, or four carbon atoms in the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, -NR11-; S1is absent or C1-C3alkylene optionally substituted with one or more R and wherein one or two carbon atoms of the C1-C3alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or -NR11-; Y1is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR11-, -C(=O)-, -C(=O)NR11-, -NR11C(=O)-, -S(=O)2NR11-, or -NR11S(=O)2; R11is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring C1is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R12is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;n is 0, 1, 2, 3, 4, 5, or 6; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3alkylene optionally substituted with one or more R; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo; or two R on the same or different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0066] In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), TL1 is of Formula (IA):Formula (IA); wherein: W1is absent, -C(=O)-, or -C(=O)NR11-; X1is C1-C10alkylene; A1is absent or heteroaryl optionally substitued with one or more R; T1is absent; B1is C1-C10alkylene or cycloalkyl; S1is absent; Y1is absent, -O-, -S-, -S(=O)2-, -C(=O)NR11-, or -NR11C(=O)-;R11is hydrogen; Ring C1is heteroaryl; each R12is independently halogen, -S(=O)2NRcRd, or -NRcRd; n is 0, 1, 2, or 3; Rcand Rdare each independently hydrogen, C1-C6alkyl, -L-cycloalkyl, or -L-aryl, wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one or more R; L is absent or C1-C3alkylene; and each R is independently C1-C3alkyl or C1-C3alkoxy.

[0067] In some embodiments of a compound of Formula (IA), W1is absent, -O-, -S-, -NR11-, -C(=O)-, -C(=O)NR11-, or -NR11C(=O)-.

[0068] In some embodiments of a compound of Formula (IA), W1is absent, -C(=O)-, or -C(=O)NR11-.

[0069] In some embodiments of a compound of Formula (IA), W1is absent.

[0070] In some embodiments of a compound of Formula (IA), W1is -C(=O)-.

[0071] In some embodiments of a compound of Formula (IA), W1is -C(=O)NR11-.

[0072] In some embodiments of a compound of Formula (IA), X1is C1-C6alkylene optionally substituted with one or more R and wherein one or two carbon atoms of the C1-C6alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or -NR11-.

[0073] In some embodiments of a compound of Formula (IA), X1is C1-C6alkylene.

[0074] In some embodiments of a compound of Formula (IA), X1is C1-C4alkylene.

[0075] In some embodiments of a compound of Formula (IA), X1is -CH2-.

[0076] In some embodiments of a compound of Formula (IA), X1is -CH2CH2-.

[0077] In some embodiments of a compound of Formula (IA), X1is -CH2CH2CH2-.

[0078] In some embodiments of a compound of Formula (IA), X1is -CH2CH2CH2CH2-.

[0079] In some embodiments of a compound of Formula (IA),,.

[0080] In some embodiments of a compound of Formula (IA),.

[0081] In some embodiments of a compound of Formula (IA), A1is absent.

[0082] In some embodiments of a compound of Formula (IA), A1is heteroaryl optionally substitued with one or more R.

[0083] In some embodiments of a compound of Formula (IA), A1is triazolyl optionally substitued with one or more R. In some embodiments of a compound of Formula (IA), A1is unsubstituted triazolyl. some embodiments of a compound of Formulawherein R’ is hydrogen or R. In some embodiments of a compound of Formula (IA), A1iswherein R’ is hydrogen or R. In some embodiments, R’ is hydrogen.

[0085] In some embodiments of a compound of Formula (IA), A1is heterocycloalkyl optionally substitued with one or more R.

[0086] In some embodiments of a compound of Formula (IA), A1is monocyclic heterocycloalkyl optionally substitued with one or more R.

[0087] In some embodiments of a compound of Formula (IA), A1is bicyclic heterocycloalkyl optionally substitued with one or more R.

[0088] In some embodiments of a compound of Formula

[0089] In some embodiments of a compound of Formula (IA), T1is absent or C1-C3alkylene.

[0090] In some embodiments of a compound of Formula (IA), T1is absent.

[0091] In some embodiments of a compound of Formula (IA), B1is C1-C10alkylene or cycloalkyl, wherein the alkylene and cycloalkyl is optionally substitued with one or more R, and wherein one, two, three, or four carbon atoms in the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or -NR11-.

[0092] In some embodiments of a compound of Formula (IA), B1is C1-C10alkylene optionally substitued with one or more R, and wherein one, two, three, or four carbon atoms in the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or -NR11-.

[0093] In some embodiments of a compound of Formula (IA), B1is C1-C10alkylene optionally substitued with one or more R.

[0094] In some embodiments of a compound of Formula (IA), B1is C1-C6alkylene.

[0095] In some embodiments of a compound of Formula (IA), B1is -CH2CH2CH2-.

[0096] In some embodiments of a compound of Formula (IA), B1is -CH2CH2CH2CH2-.

[0097] In some embodiments of a compound of Formula (IA), B1is cycloalkyl optionally substitued with one or more R.

[0098] In some embodiments of a compound of Formula (IA), B1is a monocyclic cycloalkyl optionally substitued with one or more R.

[0099] In some embodiments of a compound of Formula (IA), B1is a bicyclic cycloalkyl optionally substitued with one or more R.

[0100] In some embodiments of a compound of Formula (IA), B1is bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.1.1]hexanyl.

[0101] In some embodiments of a compound of Formula (IA), B1is bicyclo[1.1.1]pentanyl.

[0102] In some embodiments of a compound of Formula (IA), S1is absent.

[0103] In some embodiments of a compound of Formula (IA),is ,embodiments of a compound of Formula

[0104] In some embodiments of a compound of Formula (IA), Y1is absent, -O-, -S-, -S(=O)2-, - C(=O)NR11-, or -NR11C(=O)-.

[0105] In some embodiments of a compound of Formula (IA), Y1is -S(=O)2-.

[0106] In some embodiments of a compound of Formula (IA), Y1is -C(=O)NR11-.

[0107] In some embodiments of a compound of Formula (IA),some embodiments of a compound of Formula (IA),.

[0108] In some embodiments of a compound of Formula (IA), Ring C1is aryl or heteroaryl. In some embodiments of a compound of Formula (IA), Ring C1is phenyl or heteroaryl. In some embodiments of a compound of Formula (IA), Ring C1is heteroaryl. In some embodiments of a compound of Formula (IA), Ring C1is 5- to 12-membered heteroaryl. In some embodiments of a compound of Formula (IA), Ring C1is 5- to 10-membered heteroaryl. In some embodiments of a compound of Formula (IA), Ring C1is 5- to 6-membered heteroaryl. In some embodiments of a compound of Formula (IA), Ring C1is 7- to 10-membered heteroaryl. In some embodiments of a compound of Formula (IA), Ring C1is monocyclic heteroaryl. In some embodiments of a compound of Formula (IA), Ring C1thiadiazolyl or phenyl. In some embodiments of a compound of Formula (IA), Ring C1thiadiazolyl. In some embodiments of a compound of Formula (IA), Ring C1phenyl.

[0109] In some embodiments of a compound of Formula (IA), Ring C1is bicyclic heteroaryl.

[0110] In some embodiments of a compound of Formula (IA), Ring C1is benzothiazolyl or imidazothiadiazolyl.

[0111] In some embodiments of a compound of Formula (IA),iswherein each Z1is independently -N- or -CR12’-; Z2is -O-, -S-, or -NR12’’-; each R12’is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; and R12’’is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1- C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl.

[0112] In some embodiments, Z2is -O- or -S-. In some embodiments, Z2is -S-. In some embodiments, each Z1is -N-.C1(R12)n

[0113] In some embodiments of a compound of Formula (IA), is O O S NH2(R12)n-1. In some embodiments of a compound of Formula (IA),.

[0114] In some embodiments of a compound of Formula (IA), each R12is independently halogen, - CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IA), one of R12is - S(=O)2NRcRd.

[0115] In some embodiments of a compound of Formula (IA), each R12is independently halogen, - CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1- C6haloalkyl.

[0116] In some embodiments of a compound of Formula (IA), each R12is independently halogen, - S(=O)2NRcRd, or -NRcRd.

[0117] In some embodiments of a compound of Formula (IA), each R12is independently halogen or - NRcRd.

[0118] In some embodiments of a compound of Formula (IA), n is 0, 1, 2, 3, 4, or 5. In some embodiments of a compound of Formula (IA), n is 0, 1, 2, 3, or 4. In some embodiments of a compound of Formula (IA), n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (IA), n is 0, 1, or 2. In some embodiments of a compound of Formula (IA), n is 0 or 1.

[0119] In some embodiments of a compound of Formula (IA),.

[0120] In some embodiments of a compound of Formula

[0121] In some embodiments of a compound of Formula (IA),. In some embodiments of a compound of Formula (IA),.

[0122] In some embodiments of a compound of Formula (IA), R11is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IIA), R11is hydrogen.

[0123] In some embodiments of a compound of Formula (IA), each Rais independently C1-C6alkyl;

[0124] In some embodiments of a compound of Formula (IA), each Rbis independently hydrogen or C1-C6alkyl;

[0125] In some embodiments of a compound of Formula (IA), Rcand Rdare each independently hydrogen, C1-C6alkyl, -L-cycloalkyl, or -L-aryl, wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one or more R.

[0126] In some embodiments of a compound of Formula (IA), L is absent or C1-C3alkylene. In some embodiments of a compound of Formula (IA), L is absent. In some embodiments of a compound of Formula (IA), L is C1-C3alkylene.

[0127] In some embodiments of a compound of Formula (IA), each R is independently C1-C3alkyl or C1-C3alkoxy.

[0128] In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), TL1is of Formula (IA):are taken together to form a linking group that comprises 3 to 30 atoms (optionally, 5-25 atoms, 8-20 atoms, 8-15 atoms, or 10-14 atoms, or 8, 9, 10, 11, 12, 13, 14, or 15 atoms) in the linear chain.

[0129] In some embodiments,are taken together to form a linking group that comprises 3 to 30 atoms in the linear chain, which are selected from C, N, and O. In some embodiments, the linking group comprises 3 to 30 atoms in the linear chain, including carbon, 1-5 N and 0-1 O. In some embodiments, the linking group comprises 3 to 30 atoms in the linear chain selected from N and C, including 2, 3, or 4 N. In some embodiments, the linking group comprises one or more cyclic groups, and the atoms in the linear chain comprises a part of the cyclic groups. In some embodiments, both A1and B1are cyclic groups. In some embodiments, the linking group comprises one or more groups selected from -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2,optionally substituted C1-C10alkylene, optionally substituted C1-C10heteroalkylene, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or a combination thereof.

[0130] In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), TL2is of Formula (IIA):Formula (IIA); wherein: W2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; X2is absent or C1-C10alkylene optionally substituted with one or more R, and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR21-; Y2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2;A2is absent, C1-C10alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R22; each R22is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; S2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; T2is absent or C1-C10alkylene optionally substituted with one or more R, and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR21-; R21is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; (i) B2is absent; or (ii) B2is -N(R23)2; each R23is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or (iii) B2is -CF3; or (iv) B2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R24; each R24is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; orRing C2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R25is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; m is 0, 1, 2, 3, or 4; R26is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring D2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R27is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; p is 0, 1, 2, 3, or 4; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3alkylene optionally substituted with one or more R; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo;or two R on the same or different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0131] In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), TL2is of Formula (IIA):Formula (IIA); wherein: W2is absent, -C(=O)-, or -NR21C(=O)-; X2is C1-C10alkylene optionally substituted with one or more R; Y2is absent, -NR21-, or -NR21C(=O)-; A2is C1-C10alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R22; each R22is independently halogen, -CN, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1- C6aminoalkyl; S2is absent, -NR21-, -C(=O)-, or -NR21C(=O)-; T2is absent or C1-C10alkylene; R21is hydrogen; B2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R24; each R24is independently halogen, -OH, -SF5, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl;Ring C2is aryl; each R25is independently halogen, -OH, or C1-C6alkyl; m is 0, 1, or 2; R26is hydrogen or C1-C6alkyl; Ring D2is aryl; each R27is independently halogen, -OH, or C1-C6alkyl; p is 0, 1, or 2; each Rbis independently hydrogen or C1-C6alkyl; Rcand Rdare each independently hydrogen or C1-C6alkyl; and each R is independently -C(=O)OH or -C(=O)NH2.

[0132] In some embodiments of a compound of Formula (IIA), W2is absent, -C(=O)-, or - NR21C(=O)-.

[0133] In some embodiments of a compound of Formula (IIA), W2is -C(=O)-. In some embodiments of a compound of Formula (IIA), W2is absent. In some embodiments of a compound of Formula (IIA), W2is -C(=O)-. In some embodiments of a compound of Formula (IIA), W2is -NR21C(=O)-.

[0134] In some embodiments of a compound of Formula (IIA), X2is C1-C6alkylene optionally substituted with one or more R.

[0135] In some embodiments of a compound of Formula (IIA), X2is C1-C4alkylene optionally substituted with one or more R.

[0136] In some embodiments of a compound of Formula (IIA), X2is -CH2-.

[0137] In some embodiments of a compound of Formula (IIA), X2is -CH2CH[C(=O)OH]- or - CH2CH[C(=O)NH2]-.

[0138] In some embodiments of a compound of Formula (IIA), X2is -CH2CH2CH[(C=O)OH]- or - CH2CH2CH[C(=O)NH2]-.

[0139] In some embodiments of a compound of Formula (IIA), X2is optionally substituted with one or more R, and wherein one or two carbon atoms of the C1-C10alkylene are replaced with -S-, -S(=O)-, - S(=O)2-, -O-, or -NR21-

[0140] In some embodiments of a compound of Formula (IIA), Y2is absent, -O-, -S-, -NR21-, -C(=O)-, -C(=O)NR21-, or -NR21C(=O)-.

[0141] In some embodiments of a compound of Formula (IIA), Y2is absent, -NR21-, or -NR21C(=O)-.

[0142] In some embodiments of a compound of Formula (IIA), Y2is -NR21C(=O)-.

[0143] In some embodiments of a compound of Formula (IIA),is.

[0145] In some embodiments of a compound of Formula (IIA), A2is C1-C10alkylene, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R22.

[0146] In some embodiments of a compound of Formula (IIA), A2is C1-C6alkylene optionally substitued with one or more R22.

[0147] In some embodiments of a compound of Formula (IIA), A2is -CH2CH[C(=O)OH]-.

[0148] In some embodiments of a compound of Formula (IIA), A2is heterocycloalkyl optionally substitued with one or more R22.

[0149] In some embodiments of a compound of Formula (IIA), A2is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substitued with one or more R22.

[0150] In some embodiments of a compound of Formula (IIA), A2is piperidinyl optionally substitued with one or more R22.

[0151] In some embodiments of a compound of Formula (each optionally substitued with one or more R22.

[0152] In some embodiments of a compound of Formula (optionally substitued with one or more R22.

[0153] In some embodiments of a compound of Formula (IIA), A2is aryl or heteroaryl, wherein the aryl and heteroaryl is optionally substitued with one or more R22.

[0154] In some embodiments of a compound of Formula (IIA), A2is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl, each optionally substitued with one or more R22.

[0155] In some embodiments of a compound of Formula (IIA), A2is, each optionally substitued with one or more R22.

[0156] In some embodiments of a compound of Formula (

[0157] In some embodiments of a compound of Formula (IIA), each R22is independently halogen, - CN, -OH, -ORa, -NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, or C1-C6heteroalkyl.

[0158] In some embodiments of a compound of Formula (IIA), each R22is independently -CN, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6aminoalkyl.

[0159] In some embodiments of a compound of Formula (IIA), each R22is independently -C(=O)ORbor -C(=O)NRcRd.

[0160] In some embodiments of a compound of Formula (IIA), each R22is independently - C(=O)NRcRd.

[0161] In some embodiments of a compound of Formula (halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

[0162] In some embodiments of a compound of Formula (C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6aminoalkyl.

[0163]

[0164] In some embodiments of a compound of Formula (C(=O)ORbor -C(=O)NRcRd.

[0165] In some embodiments of a compound of Formula (C(=O)NRcRd..

[0167] In some embodiments of a compound of Formula (IIA), S2is absent, -O-, -S-, -NR21-, -C(=O)-, -C(=O)NR21-, or -NR21C(=O)-.

[0168] In some embodiments of a compound of Formula (IIA), S2is absent, -NR21-, -C(=O)-, or - NR21C(=O)-.

[0169] In some embodiments of a compound of Formula (IIA), S2is -C(=O)- or -NR21C(=O)-.

[0170] In some embodiments of a compound of Formula (IIA), T2is absent or C1-C6alkylene optionally substituted with one or more R.

[0171] In some embodiments of a compound of Formula (IIA), T2is C1-C6alkylene optionally substituted with one or more R.

[0172] In some embodiments of a compound of Formula (IIA), T2is -CH2CH2-.

[0173] In some embodiments of a compound of Formula (IIA), T2is -CH2CH2CH2-.

[0175] In some embodiments of a compound of Formula (IIA), B2is absent.

[0176] In some embodiments of a compound of Formula (IIA), B2is -N(R23)2.

[0177] In some embodiments of a compound of Formula (IIA), B2is -CF3.

[0178] In some embodiments of a compound of Formula (IIA), B2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R24.

[0179] In some embodiments of a compound of Formula (IIA), B2is cycloalkyl optionally substitued with one or more R24.

[0180] In some embodiments of a compound of Formula (IIA), B2is monocyclic cycloalkyl optionally substitued with one or more R24.

[0181] In some embodiments of a compound of Formula (IIA), B2is bicyclic cycloalkyl optionally substitued with one or more R24.

[0182] In some embodiments of a compound of Formula (IIA), B2is phenyl optionally substitued with one or more R24.

[0183] In some embodiments of a compound of Formula (IIA), B2is heteroaryl optionally substitued with one or more R24.

[0184] In some embodiments of a compound of Formula (IIA), B2is 5- to 10-membered heteroaryl (e.g., monocyclic or bicyclic heteroaryl) optionally substitued with one or more R24.

[0185] In some embodiments of a compound of Formula (IIA), B2is 5- to 6-membered heteroaryl optionally substitued with one or more R24.

[0186] In some embodiments of a compound of Formula (IIA), B2is indazolyl, phenyl, pyridyl, pyridininyl, pyrazinyl, pyridazinyl, cyclopropyl, cyclohexyl, cyclobutyl, cycloheptyl, pyrazolyl, oxazolyl, triazolyl, spiroheptanyl, or bicycloheptanyl.

[0187] In some embodiments of a compound of Formula (IIA), each R24is independently halogen, - CN, -OH, -ORa, -NRcRd, -SF5, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R.

[0188] In some embodiments of a compound of Formula (IIA), each R24is independently halogen, - OH, C1-C6alkyl, or C1-C6haloalkyl.

[0189] In some embodiments of a compound of Formula (wherein: Ring C2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R25is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; m is 0, 1, 2, 3, or 4; R26is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring D2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R27is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; p is 0, 1, 2, 3, or 4.

[0190] In some embodiments of a compound of Formula (IIA), Ring C2is phenyl.

[0191] In some embodiments of a compound of Formula (IIA), each R25is independently halogen, - CN, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6hydroxyalkyl. In some embodiments of a compound of Formula (IIA), each R25is independently halogen, -CN, -OH, -ORa, - NRcRd, or C1-C6alkyl. In some embodiments of a compound of Formula (IIA), each R25is independently -OH.

[0192] In some embodiments of a compound of Formula (IIA), m is 0 or 1. In some embodiments of a compound of Formula (IIA), m is 0, 1, or 2. In some embodiments of a compound of Formula (IIA), m is 0. In some embodiments of a compound of Formula (IIA), m is 1. In some embodiments of a compound of Formula (IIA), m is 2. In some embodiments of a compound of Formula (IIA), m is 3.

[0193] In some embodiments of a compound of Formula (IIA), Ring D2is phenyl.

[0194] In some embodiments of a compound of Formula (IIA), each R27is independently halogen, - CN, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6hydroxyalkyl. In some embodiments of a compound of Formula (IIA), each R27is independently halogen, -CN, -OH, -ORa, - NRcRd, or C1-C6alkyl. In some embodiments of a compound of Formula (IIA), each R27is independently -OH.

[0195] In some embodiments of a compound of Formula (IIA), p is 0 or 1. In some embodiments of a compound of Formula (IIA), p is 0, 1, or 2. In some embodiments of a compound of Formula (IIA), p is 0. In some embodiments of a compound of Formula (IIA), p is 1. In some embodiments of a compound of Formula (IIA), p is 2. In some embodiments of a compound of Formula (IIA), p is 3.

[0196] In some embodiments of a compound of Formula (IIA), R26is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IIA), R26is C1-C6alkyl.

[0197] In some embodiments of a compound of Formula (

[0198] In some embodiments of a compound of Formula (IIA), R21is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IIA), R21is hydrogen.

[0199] In some embodiments of a compound of Formula (IIA), each Rais independently C1-C6alkyl;

[0200] In some embodiments of a compound of Formula (IIA), each Rbis independently hydrogen or C1-C6alkyl.

[0201] In some embodiments of a compound of Formula (IIA), Rcand Rdare each independently hydrogen or C1-C6alkyl.

[0202] In some embodiments of a compound of Formula (IIA), each R is independently -C(=O)OH or -C(=O)NH2.

[0203] In some embodiments of a compound of Formula (A), (AC), (A’) or (AC’), TL2is of Formula (IIA):are taken together to form a linking group that comprises 3 to 30 atoms (optionally, 5-25 atoms, 8-20 atoms, 8-15 atoms, or 10-14 atoms, or 8, 9, 10, 11, 12, 13, 14, or 15 atoms) in the linear chain.

[0204] In some embodiments,together form a linking group that comprises 3 to 30 atoms in the linear chain, which are selected from C, N, and O. In some embodiments, the linking group comprises 3 to 30 atoms in the linear chain, including carbon, 1-5 N and 0-1 O. In some embodiments, the linking group comprises 3 to 30 atoms in the linear chain selected from N and C, including 2, 3, or 4 N. In some embodiments, the linking group comprises one or more cyclic groups, and the atoms in the linear chain comprises a part of the cyclic groups. In some embodiments, A2is a cyclic group. In some embodiments, the linking group comprises one or more groups selected from - O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2, optionally substituted C1-C10alkylene, optionally substituted C1-C10heteroalkylene, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or a combination thereof.

[0205] In some embodiments, disclosed herein is radiopharmaceutical conjugate comprising: (i) a radionuclide selected from Table 3 (e.g.,225Ac,177Lu,64Cu, and68Ga) and (ii) a compound of formula (A), or a salt thereof, wherein the CL is selected from a chelator of FIGs 1-19 (e.g., DOTA, DOTA-GA); s is 0; ring A is piperidinyl or piperazinyl, each is optionally substituted;W1 X1 A1 T1 B1 S1 Y1C1(R12)nTL1is of Formula (IA) Formula (IA); wherein: W1is absent, -C(=O)-, or -C(=O)NR11-; X1is C1-C10alkylene; A1is absent or heteroaryl (.e.g, triazolyl) optionally substitued with one or more R; T1is absent; B1is C1-C10alkylene or cycloalkyl (e..g, bicyclo[1.1.1]pentanyl); S1is absent; Y1is absent, -O-, -S-, -S(=O)2-, -C(=O)NR11-, or -NR11C(=O)-; R11is hydrogen; Ring C1is heteroaryl; each R12is independently halogen, -S(=O)2NRcRd, or -NRcRd; and n is 0, 1, 2, or 3; and W2X2Y2A2S2T2B2TL2is of Formula (IIA): Formula (IIA); wherein: W2is absent, -C(=O)-, or -NR21C(=O)-; X2is C1-C10alkylene optionally substituted with one or more R; Y2is absent, -NR21-, or -NR21C(=O)-; A2is C1-C10alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R22; each R22is independently halogen, -CN, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; S2is absent, -NR21-, -C(=O)-, or -NR21C(=O)-; T2is absent or C1- C10alkylene optionally substituted with one or more R, and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or -NR21-; R21is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; B2halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; m is 0, 1, or 2; R26is hydrogen, C1-C6alkyl, or C1-C6haloalkyl; Ring D2is aryl; each R27is independently halogen, -CN, -OH, -ORa, - NRcRd, C1-C6alkyl, or C1-C6haloalkyl; p is 0, 1, or 2.

[0206] Also disclosed herein is a conjugate of Formula (B), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (B); wherein:LArepresents a linker; s is 0 or 1; CL represents a metal chelator; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1is of Formula (IB):Formula (IB); wherein: W1is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR11-, -C(=O)-, -C(=O)NR11-, -NR11C(=O)-, -S(=O)2NR11-, or -NR11S(=O)2; X1is C1-C10alkylene optionally substituted with one or more R and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR11-; A1is absent, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R; T1is absent or C1-C3alkylene optionally substituted with one or more R and wherein one carbon atom of the C1-C3alkylene is optionally replaced with -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -O-, -NR11-; B1is cycloalkyl, heterocycloalkyl, or aryl, wherein the cycloalkyl, heterocycloalkyl, and aryl is optionally substitued with one or more R; or B1is heteroaryl substituted with one or more R; S1is absent or C1-C3alkylene optionally substituted with one or more R and wherein one or two carbon atoms of the C1-C3alkylene are optionally replaced with -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -O-, or - NR11-; Y1is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR11-, -C(=O)-, -C(=O)NR11-, -NR11C(=O)-, -S(=O)2NR11-, or -NR11S(=O)2; R11is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring C1is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R12is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; n is 0, 1, 2, 3, 4, 5, or 6; TL2is of Formula (IIB):W2X2Y2A2S2T2B2Formula (IIB); wherein: W2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; X2is absent or C1-C10alkylene optionally substituted with one or more R, and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR21-; Y2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; A2is absent, C1-C10alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R22; each R22is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; S2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; T2is absent or C1-C10alkylene optionally substituted with one or more R, and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR21-; R21is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; (i) B2is absent; or (ii) B2is -N(R23)2; each R23is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or (iii) B2is -CF3; or (iv) B2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R24;each R24is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;Ring C2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R25is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; m is 0, 1, 2, 3, or 4; R26is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring D2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R27is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; p is 0, 1, 2, 3, or 4; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3alkylene optionally substituted with one or more R; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo; or two R on the same or different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0207] Also disclosed herein is a conjugate of Formula (B), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (B); wherein: LArepresents a linker; s is 0 or 1; CL represents a metal chelator; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1is of Formula (IB):Formula (IB); wherein: W1is absent, -C(=O)-, or -C(=O)NR11-; X1is C1-C10alkylene; A1is absent or heteroaryl optionally substitued with one or more R; T1is absent; B1is cycloalkyl; S1is absent; Y1is absent, -O-, -S-, -S(=O)2-, -C(=O)NR11-, or -NR11C(=O)-;R11is hydrogen; Ring C1is heteroaryl; each R12is independently halogen, -S(=O)2NRcRd, or -NRcRd; and n is 0, 1, 2, or 3; TL2is of Formula (IIB):Formula (IIB); wherein: W2is absent, -C(=O)-, or -NR21C(=O)-; X2is C1-C10alkylene optionally substituted with one or more R; Y2is absent, -NR21-, or -NR21C(=O)-; A2is C1-C10alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R22; each R22is independently halogen, -CN, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1- C6aminoalkyl; S2is absent, -NR21-, -C(=O)-, or -NR21C(=O)-; T2is absent or C1-C10alkylene; R21is hydrogen; B2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R24; each R24is independently halogen, -OH, -SF5, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl;Ring C2is aryl; each R25is independently halogen, -OH, or C1-C6alkyl; m is 0, 1, or 2; R26is hydrogen or C1-C6alkyl; Ring D2is aryl; each R27is independently halogen, -OH, or C1-C6alkyl; p is 0, 1, or 2; each Rbis independently hydrogen or C1-C6alkyl; Rcand Rdare each independently hydrogen, C1-C6alkyl, -L-cycloalkyl, or -L-aryl, wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one or more R; L is absent or C1-C3alkylene; andeach R is independently C1-C3alkyl, C1-C3alkoxy, -C(=O)OH, or -C(=O)NH2.

[0208] Disclosed herein is a conjugate of Formula (BC), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (BC) wherein: R30is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted (e.g., with one or more R); or R30is an albumin binding moiety or a payload moiety; wherein the remaining groups have their meanings as defined in Formula (B).

[0209] In some embodiments, the conjugate compound of Formula (BC) comprises a covalently bound radioisotope.

[0210] Also disclosed herein is a conjugate of Formula (B’), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (B’); wherein: LBrepresents a linker; CL represents a metal chelator; each X is independently N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;each TL1represents a 1sttargeting moiety that binds to carbonic anhydrase IX; and each TL2 represents a 2ndtargeting moiety that binds to carbonic anhydrase IX.

[0211] Also disclosed herein is a conjugate of Formula (BC’), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (BC’); wherein: LBrepresents a linker; each X is independently N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each TL1 represents a 1sttargeting moiety that binds to carbonic anhydrase IX; each TL2represents a 2ndtargeting moiety that binds to carbonic anhydrase IX; R30is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted (e.g., with one or more R); or R30is an albumin binding moiety or a payload moiety ; wherein the remaining groups have their meanings as defined in Formula (B).

[0212] In some embodiments, the conjugate compound of Formula (BC’) comprises a covalently bound radioisotope.

[0213] In some embodiments of a compound of Formula (B’) or (BC’), each TL1is the same. In some embodiments of a compound of Formula (B’) or (BC’), each TL1is different. In some embodiments of a compound of Formula (B’) or (BC’), each TL2is the same. In some embodiments of a compound of Formula (B’) or (BC’), each TL2 is different. In some embodiments of a compound of Formula (B’) or (BC’), each X is the same. In some embodiments of a compound of Formula (B’) or (BC’), each X is different. In some embodiments of a compound of Formula (B’) or (BC’), each TL1is independently atargeting moiety of Formula (IB). In some embodiments of a compound of Formula (B’) or (BC’), each TL2 is independently a targeting moiety of Formula (IIB).

[0214] In some embodiments of a compound of Formula (B’) or (BC’), each TL1is defined in Formula (B). In some embodiments of a compound of Formula (B’) or (BC’), each TL2is defined in Formula (B).

[0215] In some embodiments of a compound of Formula (B), (BC), (B’), (BC’) or (IB), T1is absent or C1-C3alkylene.

[0216] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IB), T1is absent.

[0217] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IB), B1is cycloalkyl optionally substitued with one or more R.

[0218] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IB), B1is a monocyclic cycloalkyl optionally substitued with one or more R.

[0219] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IB), B1is a bicyclic cycloalkyl optionally substitued with one or more R.

[0220] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IB), B1is bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.1.1]hexanyl.

[0221] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IB), B1is bicyclo[1.1.1]pentanyl.

[0222] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IB), B1is heterocycloalkyl, which is optionally substitued with one or more R. In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IB), B1is aryl optionally substitued with one or more R. In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IB), B1is heteroaryl substituted with one or more R.

[0223] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IB), S1is absent.

[0224] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IB),. In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IB),.

[0225] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2is C1- C10alkylene, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R22.

[0226] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2is C1- C6alkylene optionally substitued with one or more R22.

[0227] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2is - CH2CH[C(=O)OH]-.

[0228] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2is heterocycloalkyl optionally substitued with one or more R22.

[0229] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substitued with one or more R22.

[0230] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2is piperidinyl optionally substitued with one or more R22.

[0231] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2ismore R22.

[0232] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2isoptionally substitued with one or more R22.

[0233] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2is aryl or heteroaryl, wherein the aryl and heteroaryl is optionally substitued with one or more R22.

[0234] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl, each optionally substitued with one or more R22.

[0235] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2iseach optionally substitued with one or more R22.

[0236] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2is.

[0237] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), each R22is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

[0238] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), each R22is independently -CN, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6aminoalkyl.

[0239] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), each R22is independently -C(=O)ORbor -C(=O)NRcRd.

[0240] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), each R22is independently -C(=O)NRcRd.

[0241] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2iss halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

[0242] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2is

[0243] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2is

[0244] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2is

[0245] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), A2is, , .

[0246] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), each Rais independently C1-C6alkyl.

[0247] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), each Rbis independently hydrogen or C1-C6alkyl.

[0248] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), Rcand Rdare each independently hydrogen, C1-C6alkyl, -L-cycloalkyl, or -L-aryl, wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one or more R.

[0249] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), L is absent or C1-C3alkylene.

[0250] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), or (IIB), each R is independently C1-C3alkyl, C1-C3alkoxy, -C(=O)OH, or -C(=O)NH2.

[0251] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (IIB), (C), (C’), (CC), (CC’), or (IC), TL1 has a structure ofare taken together to form a linking group that comprises 3 to 30 atoms (optionally, 5-25 atoms, 8-20 atoms, 8-15 atoms, or 10-14 atoms, or 8, 9, 10, 11, 12, 13, 14, or 15 atoms) in the linear chain. In some embodiments,are taken together to form a linking group that comprises 3 to 30 atoms in the linear chain, which are selected from C, N, and O. In some embodiments, the linking group comprises 3 to 30 atoms in the linear chain, including carbon, 1-5 N and 0-1 O. In some embodiments, the linking group comprises 3 to 30 atoms in the linear chain selected from N and C, including 2, 3, or 4 N. In some embodiments, the linking group comprises one or more cyclic groups, and the atoms in the linear chain comprises a part of the cyclic groups. In some embodiments, both A1and B1are cyclic groups. In some embodiments, the linking group comprises one or more groups selected from - O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2, optionally substituted C1-C10alkylene, optionally substituted C1-C10heteroalkylene, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or a combination thereof.

[0252] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (IIB), (C), (C’), (CC), (CC’), or (IC), TL2is of the structure ofare taken together to form a linking group that comprises 3 to 30 atoms (optionally, 5-25 atoms, 8-20 atoms, 8-15 atoms, or 10-14 atoms, or 8, 9, 10, 11, 12, 13, 14, or 15 atoms) in the linear chain. In some embodiments,together form a linking group that comprises 3 to 30 atoms in the linear chain, which are selected from C, N, and O. In some embodiments, the linking group comprises 3 to 30 atoms in the linear chain, including carbon, 1-5 N and 0-1 O. In some embodiments, the linking group comprises 3 to 30 atoms in the linear chain selected from N and C, including 2, 3, or 4 N. In some embodiments, the linking group comprises one or more cyclic groups, and the atoms in the linear chain comprises a part of the cyclic groups. In some embodiments, A2is a cyclic group. In some embodiments, the linking group comprises one or more groups selected from -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, - S(=O)2NR21-, or -NR21S(=O)2,optionally substituted C1-C10alkylene, optionally substituted C1- C10heteroalkylene, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or a combination thereof.

[0253] Also disclosed herein is a conjugate of Formula (C), or a pharmaceutically acceptable salt or stereoisomer thereof: TL1(LA)sXTL2Formula (C); wherein: LArepresents a linker; s is 0 or 1; CL represents a metal chelator; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1is of Formula (IC): W1 X1 A1 T1 B1 S1 Y1C1(R12)nFormula (IC); wherein: W1is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR11-, -C(=O)-, -C(=O)NR11-, -NR11C(=O)-, -S(=O)2NR11-, or -NR11S(=O)2; X1is C1-C10alkylene optionally substituted with one or more R and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR11-; A1is absent, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R; T1is absent or C1-C3alkylene optionally substituted with one or more R and wherein one carbon atom of the C1-C3alkylene is optionally replaced with -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -O-, -NR11-; B1is absent, C1-C10alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R, and wherein one, two, three, or four carbon atoms in the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, -NR11-; S1is absent or C1-C3alkylene optionally substituted with one or more R and wherein one or two carbon atoms of the C1-C3alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or -NR11-; Y1is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR11-, -C(=O)-, -C(=O)NR11-, -NR11C(=O)-, -S(=O)2NR11-, or -NR11S(=O)2; R11is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring C1is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R12is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; n is 0, 1, 2, 3, 4, 5, or 6;TL2is of Formula (IIC):Formula (IIC); wherein: W2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; X2is absent or C1-C10alkylene optionally substituted with one or more R, and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR21-; Y2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; A2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R22; each R22is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; S2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; T2is absent or C1-C10alkylene optionally substituted with one or more R, and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR21-; R21is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; (i) B2is absent; or (ii) B2is -N(R23)2; each R23is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or (iii) B2is -CF3; or (iv) B2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R24;each R24is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;Ring C2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R25is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; m is 0, 1, 2, 3, or 4; R26is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring D2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R27is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; p is 0, 1, 2, 3, or 4; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3alkylene optionally substituted with one or more R; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo; or two R on the same or different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0254] Also disclosed herein is a conjugate of Formula (C), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (C); wherein: LArepresents a linker; s is 0 or 1; CL represents a metal chelator; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1is of Formula (IC): W1 X1 A1 T1 B1 S1 Y1C1(R12)nFormula (IC); wherein: W1is absent, -C(=O)-, or -C(=O)NR11-; X1is C1-C10alkylene; A1is absent or heteroaryl optionally substitued with one or more R; T1is absent; B1is C1-C10alkylene or cycloalkyl; S1is absent; Y1is absent, -O-, -S-, -S(=O)2-, -C(=O)NR11-, or -NR11C(=O)-;R11is hydrogen; Ring C1is heteroaryl; each R12is independently halogen, -S(=O)2NRcRd, or -NRcRd; and n is 0, 1, 2, or 3; TL2is of Formula (IIC):Formula (IIC); wherein: W2is absent, -C(=O)-, or -NR21C(=O)-; X2is C1-C10alkylene optionally substituted with one or more R; Y2is absent, -NR21-, or -NR21C(=O)-; A2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R22; each R22is independently halogen, -CN, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1- C6aminoalkyl; S2is absent, -NR21-, -C(=O)-, or -NR21C(=O)-; T2is absent or C1-C10alkylene; R21is hydrogen; B2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R24; each R24is independently halogen, -OH, -SF5, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl;Ring C2is aryl; each R25is independently halogen, -OH, or C1-C6alkyl; m is 0, 1, or 2; R26is hydrogen or C1-C6alkyl; Ring D2is aryl; each R27is independently halogen, -OH, or C1-C6alkyl; p is 0, 1, or 2; each Rbis independently hydrogen or C1-C6alkyl; Rcand Rdare each independently hydrogen, C1-C6alkyl, -L-cycloalkyl, or -L-aryl, wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one or more R; L is absent or C1-C3alkylene; andeach R is independently C1-C3alkyl, C1-C3alkoxy, -C(=O)OH, or -C(=O)NH2.

[0255] Disclosed herein is a conjugate of Formula (CC), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (CC) wherein: R30is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted (e.g., with one or more R); or R30is an albumin binding moiety or a payload moiety; wherein the remaining groups have their meanings as defined in Formula (C).

[0256] In some embodiments, the conjugate compound of Formula (CC) comprises a covalently bound radioisotope.

[0257] Also disclosed herein is a conjugate of Formula (C’), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (C’); wherein: LBrepresents a linker; CL represents a metal chelator; each X is independently N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each TL1represents a 1sttargeting moiety that binds to carbonic anhydrase IX; andeach TL2represents a 2ndtargeting moiety that binds to carbonic anhydrase IX.

[0258] Also disclosed herein is a conjugate of Formula (CC’), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (CC’); wherein: LBrepresents a linker; each X is independently N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each TL1represents a 1sttargeting moiety that binds to carbonic anhydrase IX; each TL2 represents a 2ndtargeting moiety that binds to carbonic anhydrase IX; and R30is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted (e.g., with one or more R); or R30is an albumin binding moiety or a payload moiety.

[0259] In some embodiments, the conjugate compound of Formula (CC’) comprises a covalently bound radioisotope.

[0260] In some embodiments of a compound of Formula (C’) or (CC’), each TL1is the same. In some embodiments of a compound of Formula (C’) or (CC’), each TL1 is different. In some embodiments of a compound of Formula (C’) or (CC’), each TL2is the same. In some embodiments of a compound of Formula (C’) or (CC’), each TL2is different. In some embodiments of a compound of Formula (C’) or (CC’), each X is the same. In some embodiments of a compound of Formula (C’) or (CC’), each X is different. In some embodiments of a compound of Formula (C’) or (CC’), each TL1 is independently a targeting moiety of Formula (IC). In some embodiments of a compound of Formula (C’) or (CC’), each TL2is independently a targeting moiety of Formula (IIC).

[0261] In some embodiments of a compound of Formula (C’) or (CC’), each TL1is defined in Formula (C). In some embodiments of a compound of Formula (C’) or (CC’), each TL2 is defined in Formula (C).

[0262] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), T1is absent or C1-C3alkylene.

[0263] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), T1is absent.

[0264] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), B1is C1- C10alkylene or cycloalkyl, wherein the alkylene and cycloalkyl is optionally substitued with one or more R, and wherein one, two, three, or four carbon atoms in the C1-C10alkylene are optionally replaced with - S-, -S(=O)-, -S(=O)2-, -O-, or -NR11-.

[0265] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), B1is C1- C10alkylene optionally substitued with one or more R, and wherein one, two, three, or four carbon atoms in the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or -NR11-.

[0266] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), B1is C1- C10alkylene optionally substitued with one or more R.

[0267] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), B1is C1- C6alkylene.

[0268] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), B1is - CH2CH2CH2-.

[0269] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), B1is - CH2CH2CH2CH2-.

[0270] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), B1is cycloalkyl optionally substitued with one or more R.

[0271] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), B1is a monocyclic cycloalkyl optionally substitued with one or more R.

[0272] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), B1is a bicyclic cycloalkyl optionally substitued with one or more R.

[0273] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), B1is bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.1.1]hexanyl.

[0274] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), B1is bicyclo[1.1.1]pentanyl.

[0275] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC), S1is absent.

[0276] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IC),c

[0277] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2is heterocycloalkyl, aryl, or heteroaryl, wherein the heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R22.

[0278] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2is heterocycloalkyl optionally substitued with one or more R22.

[0279] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substitued with one or more R22.

[0280] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2is piperidinyl optionally substitued with one or more R22.

[0281] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2ismore R22.

[0282] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2isoptionally substitued with one or more R22.

[0283] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2is aryl or heteroaryl, wherein the aryl and heteroaryl is optionally substitued with one or more R22.

[0284] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl, each optionally substitued with one or more R22.

[0285] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2is.

[0287] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), each R22is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

[0288] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), each R22is independently -CN, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6aminoalkyl.

[0289] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), each R22is independently -C(=O)ORbor -C(=O)NRcRd.

[0290] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), each R22is independently -C(=O)NRcRd.

[0291] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2iss halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

[0292] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2isC6alkyl, or C1-C6aminoalkyl.

[0293] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2is

[0294] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2is

[0295] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), A2is

[0296] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), each Rais independently or C1-C6alkyl.

[0297] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), each Rbis independently hydrogen or C1-C6alkyl.

[0298] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), Rcand Rdare each independently hydrogen, C1-C6alkyl, -L-cycloalkyl, or -L-aryl, wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one or more R.

[0299] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), L is absent or C1-C3alkylene.

[0300] In some embodiments of a compound of Formula (C), (C’), (CC), (CC’), or (IIC), each R is independently C1-C3alkyl, C1-C3alkoxy, -C(=O)OH, or -C(=O)NH2.

[0301] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is CH. In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is CH optionally substituted with halogen or C1-C6alkyl. In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is N.

[0302] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo.

[0303] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is optionally substituted heterocycloalkyl.

[0304] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is heterocycloalkyl optionally substituted with one or more R.

[0305] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is monocyclic heterocycloalkyl optionally substituted with one or more R.

[0306] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is bicyclic heterocycloalkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is spirobicyclic heterocycloalkyl optionally substituted with one or more

[0307] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is 4- to 6-membered heterocycloalkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more R. In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is piperidinyl or piperazinyl, each optionally substituted with one or more R. In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is piperidinyl optionally substituted with one or more R. In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’), X is piperazinyl optionally substituted with one or more R.

[0308] In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or. In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), *some embodiments of a compound of Formula *embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C), (C’), (CC), or (CC’),*is. In some embodiments of a compound of Formula (B), (B’), (BC), (BC’), (C),(C’), (CC), or (CC’),.

[0309] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), W1is absent, -O-, -S-, -NR11-, -C(=O)-, -C(=O)NR11-, or -NR11C(=O)-.

[0310] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), W1is absent, -C(=O)-, or -C(=O)NR11-.

[0311] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), W1is absent.

[0312] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), W1is -C(=O)-.

[0313] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), W1is -C(=O)NR11-.

[0314] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), X1is C1-C6alkylene optionally substituted with one or more R and wherein one or two carbon atoms of the C1-C6alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or -NR11-.

[0315] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), X1is C1-C6alkylene.

[0316] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), X1is C1-C4alkylene.

[0317] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), X1is -CH2-.

[0318] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), X1is -CH2CH2-.

[0319] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), X1is -CH2CH2CH2-.

[0320] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), X1is -CH2CH2CH2CH2-.

[0321] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’),

[0323] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), A1is absent.

[0324] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), A1is heteroaryl optionally substitued with one or more R.

[0325] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), A1is triazolyl optionally substitued with one or more R.

[0326] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’),some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), orwherein R’ is hydrogen or R. In some embodiments, R’ is hydrogen.

[0327] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), A1is heterocycloalkyl optionally substitued with one or more R.

[0328] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), A1is monocyclic heterocycloalkyl optionally substitued with one or more R.

[0329] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), A1is bicyclic heterocycloalkyl optionally substitued with one or more R.

[0330] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’),

[0331] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), T1is absent or C1-C3alkylene.

[0332] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), T1is absent.

[0333] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), B1is cycloalkyl optionally substitued with one or more R.

[0334] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), B1is a monocyclic cycloalkyl optionally substitued with one or more R.

[0335] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), B1is a bicyclic cycloalkyl optionally substitued with one or more R.

[0336] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), B1is bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.1.1]hexanyl.

[0337] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), B1is bicyclo[1.1.1]pentanyl.

[0338] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), S1is absent.

[0339] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’),

[0342] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Y1is absent, -O-, -S-, -S(=O)2-, -C(=O)NR11-, or -NR11C(=O)-.

[0343] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Y1is -S(=O)2-.

[0344] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Y1is -C(=O)NR11-.

[0345] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’),

[0346] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Ring C1is aryl or heteroaryl. In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Ring C1is phenyl or heteroaryl. In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Ring C1is heteroaryl. In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Ring C1is 5- to 12-membered heteroaryl. In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Ring C1is 5- to 10-membered heteroaryl. In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Ring C1is 5- to 6-membered heteroaryl. In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Ring C1is 7- to 10-membered heteroaryl. In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Ring C1is monocyclic heteroaryl. In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Ring C1thiadiazolyl or phenyl. In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Ring C1thiadiazolyl. In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Ring C1phenyl.

[0347] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Ring C1is bicyclic heteroaryl.

[0348] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), Ring C1is benzothiazolyl or imidazothiadiazolyl.

[0349] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’),wherein each Z1is independently -N- or -CR12’-; Z2is -O-, -S-, or -NR12’’-; each R12’is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; and R12’’is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1- C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl.

[0350] In some embodiments, Z2is -O- or -S-. In some embodiments, Z2is -S-. In some embodiments, each Z1is -N-.

[0351] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’),

[0352] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’),

[0353] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), each R12is independently halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl.

[0354] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), each R12is independently halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl.

[0355] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), each R12is independently halogen, -S(=O)2NRcRd, or -NRcRd.

[0356] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), each R12is independently halogen or -NRcRd. In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), one of R12is -S(=O)2NRcRd.

[0357] In some embodiments of a compound 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 a compound 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 a compound ofFormula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), n is 0, 1, or 2. In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’), n is 0 or 1.

[0358] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’),

[0360] In some embodiments of a compound of Formula (B), (B’), (IB), (C), (C’), (IC), (BC), (BC’), (CC), or (CC’),. In some embodiments of a compound of

[0361] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), W2is absent, -C(=O)-, or -NR21C(=O)-.

[0362] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), W2is -C(=O)-.

[0363] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), W2is absent. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), W2is -C(=O)-.

[0364] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), X2is C1-C6alkylene optionally substituted with one or more R.

[0365] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), X2is C1-C4alkylene optionally substituted with one or more R.

[0366] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), X2is -CH2-.

[0367] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), X2is -CH2CH[C(=O)OH]- or -CH2CH[C(=O)NH2]-.

[0368] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), X2is -CH2CH2CH[(C=O)OH]- or -CH2CH2CH[C(=O)NH2]-.

[0369] In embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), X2is X2is optionally substituted with one or more R, and wherein one or two carbon atoms of the C1-C10alkylene are replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or -NR21-.

[0370] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), Y2is absent, -O-, -S-, -NR21-, -C(=O)-, -C(=O)NR21-, or -NR21C(=O)-.

[0371] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), Y2is absent, -NR21-, or -NR21C(=O)-.

[0372] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), Y2is -NR21C(=O)-.

[0373] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’),

[0375] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), S2is absent, -O-, -S-, -NR21-, -C(=O)-, -C(=O)NR21-, or -NR21C(=O)-.

[0376] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), S2is absent, -NR21-, -C(=O)-, or -NR21C(=O)-.

[0377] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), S2is -C(=O)- or -NR21C(=O)-.

[0378] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), T2is absent or C1-C6alkylene optionally substituted with one or more R.

[0379] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), T2is C1-C6alkylene optionally substituted with one or more R.

[0380] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), T2is -CH2CH2-.

[0381] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), T2is -CH2CH2CH2-.

[0382] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’),

[0383] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), B2is absent.

[0384] In embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), B2is -N(R23)2. In embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), B2is -CF3.

[0385] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), B2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R24.

[0386] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), B2is cycloalkyl optionally substitued with one or more R24.

[0387] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), B2is monocyclic cycloalkyl optionally substitued with one or more R24.

[0388] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), B2is bicyclic cycloalkyl optionally substitued with one or more R24.

[0389] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), B2is phenyl optionally substitued with one or more R24.

[0390] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), B2is heteroaryl optionally substitued with one or more R24.

[0391] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), B2is 5- to 10-membered heteroaryl (e.g., monocyclic or bicyclic heteroaryl) optionally substitued with one or more R24.

[0392] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), B2is 5- to 6-membered heteroaryl optionally substitued with one or more R24.

[0393] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), B2is indazolyl, phenyl, pyridyl, pyridininyl, pyrazinyl, pyridazinyl, cyclopropyl, cyclohexyl, cyclobutyl, cycloheptyl, pyrazolyl, oxazolyl, triazolyl, spiroheptanyl, or bicycloheptanyl.

[0394] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), each R24is independently halogen, -CN, -OH, -ORa, -NRcRd, -SF5, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R.

[0395] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), each R24is independently halogen, -OH, C1-C6alkyl, or C1-C6haloalkyl.

[0396] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’),wherein: Ring C2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R25is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; m is 0, 1, 2, 3, or 4; R26is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring D2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R27is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; p is 0, 1, 2, 3, or 4.

[0397] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), Ring C2is phenyl.

[0398] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), each R25is independently halogen, -CN, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6hydroxyalkyl. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), each R25is independently halogen, -CN, -OH, -ORa, - NRcRd, or C1-C6alkyl. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), each R25is independently -OH.

[0399] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), m is 0 or 1. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), m is 0, 1, or 2. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), m is 0. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), m is 1. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), m is 2. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), m is 3.

[0400] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), Ring D2is phenyl.

[0401] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), each R27is independently halogen, -CN, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6hydroxyalkyl. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), each R27is independently halogen, -CN, -OH, -ORa, - NRcRd, or C1-C6alkyl. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), each R27is independently -OH.

[0402] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), p is 0 or 1. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), p is 0, 1, or 2. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), p is 0. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), p is 1. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), p is 2. In someembodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), p is 3.

[0403] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), R26is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), R26is C1-C6alkyl.

[0404] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’),

[0405] In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), R11is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (B), (B’), (IIB), (C), (C’), (IIC), (BC), (BC’), (CC), or (CC’), R11is hydrogen.

[0406] In some embodiments of a compound of Formula (A’), (A), (B), (B’), (C), (C’), (AC), (AC'), (BC), (BC'), (CC), or (CC'), TL1 and TL2 bind to different sites of the same carbonic anhydrase IX protein. In some embodiments of a compound of Formula (A’), (A), (B), (B’), (C), (C’), (AC), (AC'), (BC), (BC'), (CC), or (CC'), TL1is a targeting moiety that binds to a carbonic anhydrase IX protein at a first binding site. In some embodiments of a compound of Formula (A’), (A), (B), (B’), (C), (C’), (AC), (AC'), (BC), (BC'), (CC), or (CC'), TL1 is a targeting moiety that binds to a carbonic anhydrase IX protein at a site that is different from the binding site of TL2. In some embodiments of a compound of Formula (A’), (A), (B), (B’), (C), (C’), (AC), (AC'), (BC), (BC'), (CC), or (CC'), TL2is a targeting moiety that binds to carbonic anhydrase IX protein at a second binding site. In some embodiments of a compound of Formula (A’), (A), (B), (B’), (C), (C’), (AC), (AC'), (BC), (BC'), (CC), or (CC'), TL2 is a targeting moiety that binds to a carbonic anhydrase IX protein at a site that is different from the binding site of TL1.

[0407] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), s is 0.

[0408] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), s is 1.

[0409] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker comprises 1 to 30 intervening atoms selected from C, N, O, S, and Si between the metal chelator (CL) and the targeting ligand (TL).

[0410] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker comprises 1 to 20 intervening atoms selected from C, N, O, S, and Si between the metal chelator (CL) and the targeting ligand (TL).

[0411] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker comprises 1 to 10 intervening atoms selected from C, N, O, S, and Si between the metal chelator (CL) and the targeting ligand (TL).

[0412] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the intervening atoms comprise C, N, or O. In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the intervening atoms comprise at least one N atom.

[0413] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the intervening atoms comprise at least one O atom.

[0414] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker comprises one or more amino acid residues.

[0415] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker comprises one or more PEG moieties. In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker comprises between 2 and 8 PEG moieties. In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker comprises 2 PEG moieties. In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker comprises 8 PEG moieties

[0416] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker LAhas a structure of Formula (L-1)Formula (L-1), wherein: each L0is independently -O-, -NRL-, -N(RL)2+-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)- , -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, - NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, -S(=O)2NRL-, - C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, C1-C30alkylene, C2-C30alkenylene, C2-C30alkynylene, C1-C30heteroalkylene, -(C1-C30alkylene)-O-, - O-(C1-C30alkylene)-, -(C1-C30alkylene)-NRL-, -NRL-(C1-C30alkylene)-, -(C1-C30alkylene)-N(RL)2+-, or -N(RL)2+-(C1-C30alkylene)-; wherein each cycloalkylene, heterocycloalkylene, arylene, heteroarylene, alkylene, alkenylene, alkynylene, and heteroalkylene is optionally independently substituted with one or more R; each RLis independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; k is 1-20; each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo.

[0417] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker LAhas a structure of Formula (L-1)Formula (L-1), wherein: each L0is independently -O-, -NRL-, -C(=O)-, -OC(=O)-, -C(=O)NRL-, -NRLC(=O)-, cycloalkylene, heterocycloalkylene, C1-C30alkylene, -(C1-C30alkylene)-O-, or -O-(C1-C30alkylene)-; wherein each cycloalkylene, heterocycloalkylene, and alkylene is optionally independently substituted with one or more R; each RLis independently hydrogen or C1-C4alkyl; k is 1-20; and R is independently -C(=O)OH.

[0418] In some embodiments of a compound of Formula (L-1), each L0is independently -O-, -NRL-, - C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRL-, -NRLC(=O)-, cycloalkylene, heterocycloalkylene, C1- C30alkylene, C1-C30heteroalkylene, -(C1-C30alkylene)-O-, -O-(C1-C30alkylene)-, -(C1-C30alkylene)-NRL-, or -NRL-(C1-C30alkylene)-; wherein each cycloalkylene, heterocycloalkylene, alkylene, and heteroalkylene is optionally independently substituted with one or more R.

[0419] In some embodiments of a compound of Formula (L-1), each L0is independently -O-, -NRL-, - C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRL-, -NRLC(=O)-, heterocycloalkylene, C1-C30alkylene, C1- C30heteroalkylene, -(C1-C30alkylene)-O-, or -O-(C1-C30alkylene)-; wherein each heterocycloalkylene, alkylene, and heteroalkylene is optionally independently substituted with one or more R.

[0420] In some embodiments of a compound of Formula (L-1), each L0is independently -O-, -NRL-, - C(=O)-, -OC(=O)-, -NRLC(=O)-, heterocycloalkylene, C1-C30alkylene, C1-C30heteroalkylene, or -O-(C1- C30alkylene)-; wherein each heterocycloalkylene, alkylene, and heteroalkylene is optionally independently substituted with one or more R.

[0421] In some embodiments of a compound of Formula (L-1), each L0is independently -O-, -NRL-, - C(=O)-, -OC(=O)-, -NRLC(=O)-, heterocycloalkylene, C1-C6alkylene, C1-C6heteroalkylene, or -O-(C1- C6alkylene)-; wherein each heterocycloalkylene, alkylene, and heteroalkylene is optionally independently substituted with one or more R.

[0422] In some embodiments of a compound of Formula (L-1), each L0is independently -O-, -NRL-, - C(=O)-, -OC(=O)-, -NRLC(=O)-, heterocycloalkylene, C1-C4alkylene, C1-C4heteroalkylene, or -O-(C1- C4alkylene)-; wherein each heterocycloalkylene, alkylene, and heteroalkylene is optionally independently substituted with one or more R.

[0423] In some embodiments of a compound of Formula (L-1), each RLis independently hydrogen or C1-C4alkyl. In some embodiments of a compound of Formula (L-1), each RLis hydrogen.

[0424] In some embodiments of a compound of Formula (L-1), k is 1-15. In some embodiments of a compound of Formula (L-1), k is 1-14. In some embodiments of a compound of Formula (L-1), k is 1-13. In some embodiments of a compound of Formula (L-1), k is 1-12. In some embodiments of a compound of Formula (L-1), k is 1-11. In some embodiments of a compound of Formula (L-1), k is 1-10. In some embodiments of a compound of Formula (L-1), k is 1-9. In some embodiments of a compound of Formula (L-1), k is 1-8. In some embodiments of a compound of Formula (L-1), k is 1-7. In some embodiments of a compound of Formula (L-1), k is 1-6. In some embodiments of a compound of Formula (L-1), k is 1-5. In some embodiments of a compound of Formula (L-1), k is 1-4. In some embodiments of a compound of Formula (L-1), k is 1-3. In some embodiments of a compound of Formula (L-1), k is 1 or 2.

[0425] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker LAhas a structure of Formula (L-1a),Formula (L-1a); wherein: L1is absent, -O-, -NRL-, -N(RL)2+-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, - C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, or -S(=O)2NRLC(=O)-;L2is1-8, C1-C10alkylene, or heterocycloalkylene optionally substituted with one or more R; L3is absent or C1-C10alkylene; and L4is absent, -O-, -NRL-, -N(RL)2+-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, - C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, or -S(=O)2NRLC(=O)-.

[0426] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker LAhas a structure of Formula (L-1a),Formula (L-1a); wherein: L1is absent, -O-, or -NRL-;L2, C1-C10alkylene, or heterocycloalkylene optionally substituted with one or more R; L3is absent or C1-C10alkylene; and L4is absent, -O-, -NRL-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRL-, or -NRLC(=O)-.

[0427] In some embodiments of a compound of Formula (L-1a), L1is absent, -O-, -NRL-, -C(=O)-, - C(=O)O-, -OC(=O)-, -C(=O)NRL-, or -NRLC(=O)-. In some embodiments of a compound of Formula (L- 1a), L1is absent, -O-, or -NRL-. In some embodiments of a compound of Formula (L-1a), L1is absent or - NRL-. In some embodiments of a compound of Formula (L-1a), L1is absent or -NH-.

[0428] In some embodiments of a compound of Formula (L-1a), L2is1-8, C1- C6alkylene, or heterocycloalkylene optionally substituted with one or more R. In some embodiments of acompound of Formula (L-1a), L2is1-8, C1-C4alkylene, or heterocycloalkylene optionally substituted with one or more R. In some embodiments of a compound of Formula (L-1a), L2is O 1-8or heterocycloalkylene optionally substituted with one or more R. O

[0429] In some embodiments of a compound of Formula (L-1a), L2is1-8. In some O embodiments of a compound of Formula (L-1a), L2is1-2. In some embodiments of a compound of Formula (L-1a), L2is. In some embodiments of a compound of Formula (L-1a),.

[0430] In some embodiments of a compound of Formula (L-1a), L2is C1-C10alkylene. In some embodiments of a compound of Formula (L-1a), L2is C1-C6alkylene. In some embodiments of a compound of Formula (L-1a), L2is C1-C4alkylene.

[0431] In some embodiments of a compound of Formula (L-1a), L2is heterocycloalkylene optionally substituted with one or more R. In some embodiments of a compound of Formula (L-1a), L2is monocyclic heterocycloalkylene optionally substituted with one or more R. In some embodiments of a compound of Formula (L-1a), L2is bicyclic heterocycloalkylene optionally substituted with one or moreR. In some embodiments of a compound of Formula (L-1a), L2is piperidinylene, azetidinylene, or diazaspiroheptanylene; each optionally substituted with one or more R.

[0432] In some embodiments of a compound of Formula (L-1a), L3is absent. In some embodiments of a compound of Formula (L-1a), L3is -CH2-.

[0433] In some embodiments of a compound of Formula (L-1a), L4is absent, -O-, -NRL-, -C(=O)-, - C(=O)O-, -OC(=O)-, -C(=O)NRL-, or -NRLC(=O)-. In some embodiments of a compound of Formula (L- 1a), L4is absent, -C(=O)-, -OC(=O)-, or -NRLC(=O)-. In some embodiments of a compound of Formula (L-1a), L4is absent, -C(=O)-, -OC(=O)-, or -NHC(=O)-.

[0434] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker LAis.

[0435] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker LAhas the structure of Formula (L-2):Formula (L-2); wherein: each L1, L2, and L3is independently -O-, -NRL-, -N(RL)2+-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, - NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, -S(=O)2NRL-, - C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, C3-C15cycloalkylene, C1-C12heterocycloalkylene, arylene,heteroarylene, C1-C30alkylene, C2-C30alkenylene, C2-C30alkynylene, C1-C30heteroalkylene, -(C1- C30alkylene)-O-, -O-(C1-C30alkylene)-, -(C1-C30alkylene)-NRL-, -NRL-(C1-C30alkylene)-, -(C1- C30alkylene)-N(RL)2+-, or -N(RL)2+-(C1-C30alkylene)-; wherein each cycloalkylene, heterocycloalkylene, arylene, heteroarylene, alkylene, alkenylene, alkynylene, and heteroalkylene is optionally independently substituted with one or more R; RHis a hydrophobic moiety; Y is N or CRL; each RLis independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; k1 is 0-20; k2 is 0-15; k3 is 0-15; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo.

[0436] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker LAhas the structure of Formula (L-2):Formula (L-2); wherein: each L1, L2, and L3is independently -O-, -NRL-, or -C(=O)-; RHis a hydrophobic moiety; Y is N or CRL; each RLis independently hydrogen or C1-C4alkyl; k1 is 0-20; k2 is 0-15; and k3 is 0-15.

[0437] In some embodiments of a compound of Formula (L-2), each L2and L3is independently -O-, -NRL-, -N(RL)2+-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, - C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-O-(CH2CH2) -O- (CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R;RLis hydrogen or C1-C4alkyl; k2 is 1-5; and k3 is 1-5.

[0438] In some embodiments of a compound of Formula (L-2), each L1is independently -O-, -NRL-, -N(RL)2+-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL- , -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R; RLis hydrogen or C1-C4alkyl; k1 is 1-15; and k2 is 1-15.

[0439] In some embodiments of a compound of Formula (L-2), each L2and L3is independently -O-, - NRL-, -N(RL)2+-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R.

[0440] In some embodiments of a compound of Formula (L-2), each L2and L3is independently -O-, - NRL-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRL-, -NRLC(=O)-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R.

[0441] In some embodiments of a compound of Formula (L-2), each L2and L3is independently -O-, - NRL-, -C(=O)-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R.

[0442] In some embodiments of a compound of Formula (L-2), each L2and L3is independently -O-, - NRL-, or -C(=O)-.

[0443] In some embodiments of a compound of Formula (L-2), each L2and L3is independently -NH- or -C(=O)-.

[0444] In some embodiments of a compound of Formula (L-2), each L1is independently -O-, -NRL-, - N(RL)2+-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, - NRLC(=O)O-, -NRLC(=O)NRL-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R.

[0445] In some embodiments of a compound of Formula (L-2), each L1is independently -O-, -NRL-, - C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRL-, -NRLC(=O)-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R;

[0446] In some embodiments of a compound of Formula (L-2), each L1is independently -C(=O)NRL-, -NRLC(=O)-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R;

[0447] In some embodiments of a compound of Formula (L-2), each L1is independently -C(=O)NH-, -NHC(=O)-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R.

[0448] In some embodiments of a compound of Formula (L-2), RLis hydrogen or C1-C4alkyl. In some embodiments of a compound of Formula (L-2), RLis hydrogen.

[0449] In some embodiments of a compound of Formula (L-2), k1 is 1-19. In some embodiments of a compound of Formula (L-2), k1 is 1-18. In some embodiments of a compound of Formula (L-2), k1 is 1-17. In some embodiments of a compound of Formula (L-2), k1 is 1-16. In some embodiments of a compound of Formula (L-2), k1 is 1-15. In some embodiments of a compound of Formula (L-2), k1 is 1- 14. In some embodiments of a compound of Formula (L-2), k1 is 1-13. In some embodiments of a compound of Formula (L-2), k1 is 1-12. In some embodiments of a compound of Formula (L-2), k1 is 1- 11. In some embodiments of a compound of Formula (L-2), k1 is 1-10. In some embodiments of a compound of Formula (L-2), k1 is 1-9. In some embodiments of a compound of Formula (L-2), k1 is 1-8. In some embodiments of a compound of Formula (L-2), k1 is 1-7. In some embodiments of a compound of Formula (L-2), k1 is 1-6. In some embodiments of a compound of Formula (L-2), k1 is 1-5. In some embodiments of a compound of Formula (L-2), k1 is 1-4. In some embodiments of a compound of Formula (L-2), k1 is 1-3. In some embodiments of a compound of Formula (L-2), k1 is 1 or 2.

[0450] In some embodiments of a compound of Formula (L-2), k2 is 1-14. In some embodiments of a compound of Formula (L-2), k2 is 1-13. In some embodiments of a compound of Formula (L-2), k2 is 1- 12. In some embodiments of a compound of Formula (L-2), k2 is 1-11. In some embodiments of a compound of Formula (L-2), k2 is 1-10. In some embodiments of a compound of Formula (L-2), k2 is 1- 9. In some embodiments of a compound of Formula (L-2), k2 is 1-8. In some embodiments of a compound of Formula (L-2), k2 is 1-7. In some embodiments of a compound of Formula (L-2), k2 is 1-6. In some embodiments of a compound of Formula (L-2), k2 is 1-5. In some embodiments of a compound of Formula (L-2), k2 is 1-4. In some embodiments of a compound of Formula (L-2), k2 is 1-3. In some embodiments of a compound of Formula (L-2), k2 is 1 or 2.

[0451] In some embodiments of a compound of Formula (L-2), k3 is 1-14. In some embodiments of a compound of Formula (L-2), k3 is 1-13. In some embodiments of a compound of Formula (L-2), k3 is 1- 12. In some embodiments of a compound of Formula (L-2), k3 is 1-11. In some embodiments of a compound of Formula (L-2), k3 is 1-10. In some embodiments of a compound of Formula (L-2), k3 is 1- 9. In some embodiments of a compound of Formula (L-2), k3 is 1-8. In some embodiments of a compound of Formula (L-2), k3 is 1-7. In some embodiments of a compound of Formula (L-2), k3 is 1-6. In some embodiments of a compound of Formula (L-2), k3 is 1-5. In some embodiments of a compound of Formula (L-2), k3 is 1-4. In some embodiments of a compound of Formula (L-2), k3 is 1-3. In some embodiments of a compound of Formula (L-2), k3 is 1 or 2.

[0452] In some embodiments of a compound of Formula (L-2), RHis a fatty acid chain, a C6-C10alkyl chain, a sterol, an aryl, or a heteroaryl; wherein the aryl and heteroaryl is optionally substituted with one or more R; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl.

[0453] In some embodiments of a compound of Formula (L-2), RHis phenyl substituted with a halogen or a C1-C3alkyl.

[0454] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker

[0455] In some embodiments of a compound of Formula (A), (B), (C), (AC), (BC), or (CC), the linker.

[0456] In some embodiments of a compound of Formula (A’), (B’), (C’), (AC’), (BC’), or (CC’), the linker LBhas the structure of Formula (L-3):Formula (L-3); wherein:each L1, L2, and L3is independently -O-, -NRL-, -N(RL)2+-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, - NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, -S(=O)2NRL-, - C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, C3-C15cycloalkylene, C1-C12heterocycloalkylene, arylene, heteroarylene, C1-C30alkylene, C2-C30alkenylene, C2-C30alkynylene, C1-C30heteroalkylene, -(C1- C30alkylene)-O-, -O-(C1-C30alkylene)-, -(C1-C30alkylene)-NRL-, -NRL-(C1-C30alkylene)-, -(C1- C30alkylene)-N(RL)2+-, or -N(RL)2+-(C1-C30alkylene)-; wherein each cycloalkylene, heterocycloalkylene, arylene, heteroarylene, alkylene, alkenylene, alkynylene, and heteroalkylene is optionally independently substituted with one or more R; Y is N or CRL; each RLis independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; k1 is 0-15; k2 is 0-15; k3 is 0-15; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo.

[0457] In some embodiments of a compound of Formula (A’), (B’), (C’), (AC’), (BC’), or (CC’), the linker LBhas the structure of Formula (L-3):Formula (L-3); wherein: each L1, L2, and L3is independently -O-, -NRL-, -C(=O)-, C1-C30alkylene, -(C1-C30alkylene)-O-, or -O- (C1-C30alkylene)-; Y is N or CRL; each RLis independently hydrogen or C1-C4alkyl; k1 is 0-15; k2 is 0-15; and k3 is 0-15.

[0458] In some embodiments of a compound of Formula (L-3), each L2and L3is independently -O-, - NRL-, -N(RL)2+-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R.

[0459] In some embodiments of a compound of Formula (L-3), each L2and L3is independently -O-, - NRL-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRL-, -NRLC(=O)-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R.

[0460] In some embodiments of a compound of Formula (L-3), each L2and L3is independently -O-, - NRL-, -C(=O)-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R.

[0461] In some embodiments of a compound of Formula (L-3), each L2and L3is independently - C(=O)-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R.

[0462] In some embodiments of a compound of Formula (L-3), each L2and L3is independently - C(=O)-, -O-(CH2CH2), or C1-C6alkylene.

[0463] In some embodiments of a compound of Formula (L-3), each L2and L3is independently - C(=O)- or C1-C6alkylene.

[0464] In some embodiments of a compound of Formula (L-3), each L1is independently -O-, -NRL-, - N(RL)2+-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, - NRLC(=O)O-, -NRLC(=O)NRL-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R.

[0465] In some embodiments of a compound of Formula (L-3), each L1is independently -O-, -NRL-, - C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRL-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R.

[0466] In some embodiments of a compound of Formula (L-3), each L1is independently -O-, -NRL-, - C(=O)-, -O-(CH2CH2), or C1-C6alkylene optionally independently substituted with one or more R.

[0467] In some embodiments of a compound of Formula (L-3), each L1is independently -NRL-, - C(=O)-, or C1-C6alkylene optionally independently substituted with one or more R.

[0468] In some embodiments of a compound of Formula (L-3), each L1is independently -NRL-.

[0469] In some embodiments of a compound of Formula (L-3), Y is N or CRL. In some embodiments of a compound of Formula (L-3), Y is N. In some embodiments of a compound of Formula (L-3), Y is CRL. In some embodiments of a compound of Formula (L-3), Y is CH.

[0470] In some embodiments of a compound of Formula (L-3), k1 is 1-15. In some embodiments of a compound of Formula (L-3), k1 is 1-14. In some embodiments of a compound of Formula (L-3), k1 is 1- 13. In some embodiments of a compound of Formula (L-3), k1 is 1-12. In some embodiments of a compound of Formula (L-3), k1 is 1-11. In some embodiments of a compound of Formula (L-3), k1 is 1- 10. In some embodiments of a compound of Formula (L-3), k1 is 1-9. In some embodiments of a compound of Formula (L-3), k1 is 1-8. In some embodiments of a compound of Formula (L-3), k1 is 1-7. In some embodiments of a compound of Formula (L-3), k1 is 1-6. In some embodiments of a compound of Formula (L-3), k1 is 1-5. In some embodiments of a compound of Formula (L-3), k1 is 1-4. In someembodiments of a compound of Formula (L-3), k1 is 1-3. In some embodiments of a compound of Formula (L-3), k1 is 1 or 2. In some embodiments of a compound of Formula (L-3), k1 is 0-2. In some embodiments of a compound of Formula (L-3), k1 is 0 or 1. In some embodiments of a compound of Formula (L-3), k1 is 0. In some embodiments of a compound of Formula (L-3), k1 is 1. In some embodiments of a compound of Formula (L-3), k1 is 2. In some embodiments of a compound of Formula (L-3), k1 is 3. In some embodiments of a compound of Formula (L-3), k1 is 4.

[0471] In some embodiments of a compound of Formula (L-3), k2 is 1-14. In some embodiments of a compound of Formula (L-3), k2 is 1-13. In some embodiments of a compound of Formula (L-3), k2 is 1- 12. In some embodiments of a compound of Formula (L-3), k2 is 1-11. In some embodiments of a compound of Formula (L-3), k2 is 1-10. In some embodiments of a compound of Formula (L-3), k2 is 1- 9. In some embodiments of a compound of Formula (L-3), k2 is 1-8. In some embodiments of a compound of Formula (L-3), k2 is 1-7. In some embodiments of a compound of Formula (L-3), k2 is 1-6. In some embodiments of a compound of Formula (L-3), k2 is 1-5. In some embodiments of a compound of Formula (L-3), k2 is 1-4. In some embodiments of a compound of Formula (L-3), k2 is 1-3. In some embodiments of a compound of Formula (L-3), k2 is 1 or 2.

[0472] In some embodiments of a compound of Formula (L-3), k3 is 1-14. In some embodiments of a compound of Formula (L-3), k3 is 1-13. In some embodiments of a compound of Formula (L-3), k3 is 1- 12. In some embodiments of a compound of Formula (L-3), k3 is 1-11. In some embodiments of a compound of Formula (L-3), k3 is 1-10. In some embodiments of a compound of Formula (L-3), k3 is 1- 9. In some embodiments of a compound of Formula (L-3), k3 is 1-8. In some embodiments of a compound of Formula (L-3), k3 is 1-7. In some embodiments of a compound of Formula (L-3), k3 is 1-6. In some embodiments of a compound of Formula (L-3), k3 is 1-5. In some embodiments of a compound of Formula (L-3), k3 is 1-4. In some embodiments of a compound of Formula (L-3), k3 is 1-3. In some embodiments of a compound of Formula (L-3), k3 is 1 or 2.

[0473] In some embodiments of a compound of Formula (A’), (B’), (C’), (AC’), (BC’), or (CC’), the linker LBis.

[0474] In some embodiments of a compound of Formula (A’), (B’), (C’), (AC’), (BC’), or (CC’), the linker LBis,

[0475] In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L-cycloalkyl, or -L- heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl or C1-C6haloalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1- C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6haloalkyl.

[0476] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L-cycloalkyl, or -L- heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl or C1-C6haloalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rbis hydrogen. In some embodiments of a compound disclosed herein, each Rbis independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis independently C1-C6haloalkyl.

[0477] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L-cycloalkyl, or -L- heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more R. In some embodiments of a compound disclosed herein, Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rcand Rdare each independently hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rcand Rdare each independently hydrogen, C1-C6alkyl or C1-C6haloalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rcand Rdare each independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, Rcand Rdare each independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, Rcand Rdare each independently hydrogen or C1- C6haloalkyl. In some embodiments of a compound disclosed herein, Rcand Rdare each hydrogen. In some embodiments of a compound disclosed herein, Rcand Rdare each independently C1-C6alkyl. In some embodiments of a compound disclosed herein, Rcand Rdare each independently C1-C6haloalkyl.

[0478] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.

[0479] In some embodiments of a compound disclosed herein, L is absent or C1-C3alkylene. In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is C1-C3alkylene. In some embodiments of a compound disclosed herein, L is -CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2CH2-.

[0480] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -SF5, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, - C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1- C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6- membered heterocycloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -SF5, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1-C3alkyl, C1- C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3- C6cycloalkyl, or 3- to 6-membered heterocycloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -SF5, -NH2, -C(=O)C1-C3alkyl, -C(=O)OH, - C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3- C6cycloalkyl, or 3- to 6-membered heterocycloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1- C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6- membered heterocycloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, or C1-C3haloalkoxy. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, - C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -C(=O)OH, -C(=O)OC1- C3alkyl, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -C(=O)OH, -C(=O)OC1-C3alkyl, or C1-C3alkyl.

[0481] In some embodiments, disclosed herein is a radiopharmaceutical conjugate comprising a covalently bound radioisotope. In some embodiments of Formula (AC), (AC’), (BC), (BC’), (CC), or (CC’), R30comprises the covalently bound radioisotope. In some embodiments of Formula (AC), (BC), or (CC), TL1comprises the covalently bound radioisotope. In some embodiments of Formula (AC), (BC), or (CC), TL2comprises the covalently bound radioisotope. In some embodiments of Formula (AC), (BC), or (CC), LAcomprises the covalently bound radioisotope. In some embodiments of Formula (AC’), (BC’), or (CC’), one or both of the TL1groups comprise the covalently bound radioisotope. In some embodiments of Formula (AC’), (BC’), or (CC’), one or both of the TL2groups comprise the covalently bound radioisotope. In some embodiments of Formula (AC’), (BC’), or (CC’), LBcomprises the covalently bound radioisotope. In some embodiments of Formula (BC), (BC’), (CC), or (CC’), X comprises the covalently bound radioisotope.

[0482] In some embodiments of Formula (AC), (AC’), (BC), (BC’), (CC), or (CC’), R30is an albumin binding moiety.

[0483] In some embodiments of Formula (AC), (AC’), (BC), (BC’), (CC), or (CC’), R30is a payload moiety. In some embodiments, the payload moiety comprises a payload and a linker connecting the payload to group LAor LB. In some embodiments, the payload moiety is a payload having cytotoxic, therapeutic, or diagnostic properties. In some embodiments, the payload moiety comprises a radioisotope. In some embodiments, the payload moiety comprises a covalently bound radioisotope. In some embodiments, the payload moiety comprises a chelator. In some embodiments, the payload moiety comprises a chelator and a radioisotope bound to the chelator. In some embodiments, payload is a toxin. In some embodiments, payload is a therapeutic agent. In some embodiments, the payload moiety comprises a cleavable linker and a toxin (e.g., an auristatin, such as auristatin E or a derivative thereof). Exemplary cleavable linkers can be found in, e.g., U.S. Pat. No. 9962454B2.

[0484] In some embodiments, the toxin is a taxane, a topoisomerase inhibitor, a vinca alkaloid, or the like.

[0485] In some embodiments, the toxin can be selected from, for example, DNA minor groove binders (e.g., enediynes and lexitropsins, a CBI compound; see also U.S. Pat. No. 6,130,237), duocarmycins, taxanes (e.g., paclitaxel and docetaxel), puromycins, and vinca alkaloids. Other cytotoxic agents include, for example, CC-1065, SN-38, topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholino- doxorubicin, echinomycin, combretastatin, netropsin, epothilone A and B, estramustine, cryptophysins, cemadotin, maytansinoids, discodermolide, eleutherobin, and mitoxantrone.

[0486] In some embodiments, the toxin is an anti-tubulin agent. Examples of anti-tubulin agents include, auristatins, taxanes (e.g., Taxol® (paclitaxel), Taxotere® (docetaxel)), T67 (Tularik) and vinca alkyloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine). Examples of anti-tubulin agents further include, for example, baccatin derivatives, taxane analogs (e.g., epothilone A and B), nocodazole, colchicine and colcimid, estramustine, cryptophycins, cemadotin, maytansinoids, combretastatins, discodermolide, and eleutherobin.

[0487] In some embodiments, the toxin is a maytansinoid, another group of anti-tubulin agents. For example, in some embodiments, the maytansinoid is maytansine or DM-1.

[0488] In some embodiments, the toxin is a dolastatin. In some embodiments, the toxin is of the auristatin class. In some embodiments, the toxin is MMAE. In some embodiments, the toxin is AFP.

[0489] In some embodiments of Formula (AC), (AC’), (BC), (BC’), (CC), or (CC’), R30is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted (e.g., with one or more R). In some embodiments of Formula (AC), (AC’), (BC), (BC’), (CC), or (CC’), R30is hydrogen.

[0490] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. Metal Chelator

[0491] In one aspect, described herein are conjugates that comprise a metal chelator, e.g., as represented by CL in the formulas described herein.

[0492] In some embodiments, the metal chelator binds with a radionuclide. In some embodiments, the conjugate described herein comprises two or more independent metal chelators, e.g., 2, 3, 4, 5, or more metal chelators. In some embodiments, the conjugate described herein comprises two metal chelators, which can be the same or different. In some embodiments, the conjugate described herein comprises two or more metal chelators. In some embodiments, the conjugate comprises two radionuclides bound to the metal chelators.

[0493] In some embodiments, the metal chelator is capable of binding a radioactive atom. The binding can be direct, e.g., the metal chelator can make hydrogen bonds or electrostatic interactions with the radioactive atom. The binding can also be indirect, e.g., the metal chelator binds to a molecule that comprises a radioactive atom. In some embodiments, the metal chelator comprises, or is, a macrocycle. In some embodiments, the metal chelator comprises, 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 someembodiments, the metal chelator comprises a macrocycle, e.g., a macrocycle comprising 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.

[0494] In some embodiments, the metal chelator comprises a plurality of amines. In some embodiments, the metal chelator includes 4 or more nitrogen atoms, 4 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator does not comprise S. In some embodiments, the metal chelator comprises a ring. In some embodiments, the ring comprises an oxygen atom and / or a nitrogen atom. In some embodiments, the metal chelator is a ring that includes 3 or more nitrogen atom, 3 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator is polydentate.

[0495] In some embodiments, the metal chelator (or CL) described herein is 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, p-SCN-Bn-NOTA, 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.

[0496] In some embodiments, the metal chelator (or CL) described herein comprises a cyclic chelating agent. Exemplary cyclic chelating agents include, but are not limited to, 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, 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-DTPA, 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, H3L1, H3L4, H2azapa, H5decapa, bispa2, H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4octapa, p-SCN-Bn-H4octapa, TTHA, p-NO2-Bn- neunpa, H4octox, H2macropa, H2bispa2, H4phospa, H6phospa, p-SCN-Bn-H6phospa, TETA, p-NO2-Bn- TETA, TRAP, TPA, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL, Bis-thioseminarabazones, p-SCN-NOTA, nNOTA, 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, motexafin, NTA, NOC, 3p-C-NETA, p- NH2-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C- NE3TA-NCS, NODASA, NETA-monoamide, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DFO-ChX- Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD, BAPEN, TACHPYR, NEC-SP, Lpy, L1, L2, L3, and EuK-106. In some embodiments, the metal chelator is 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 chelator described herein comprises an acyclic chelating agent. Exemplary acyclic chelating agents include, but are not limited to, DTA, CyEDTA, EDTMP, DTPMP, DTPA, CyDTPA, Cy2DTPA, DTPA-MA, DTPA-BA, and BOPA. In some embodiments, the metal chelator described herein comprises 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 chelator described herein comprises H4pypa, H4octox, H4octapa, p-NO2-Bn-neunpa, p-SCN-Bn-H4neunpa, TTHA,tBu4pypa-C7- NHS, H4neunpa, H2macropa, HP-DO3A, BT-DO3A, DO3A-Nprop, DO3AP, DO2A2P, DOA3P, DOTP, DOTPMB, DOTAMAE, DOTAMAP, DO3AMBu, DOTMA, TCE-DOTA, DEPA, PCTA, p-NO2-Bn- PCTA, p-NO2-Bn-DOTA, symPC2APA, symPCA2PA, asymPC2APA, asymPCA2PA, TRAP, AAZTA, DATAm, THP, HEHA, or HBED.

[0497] In some embodiments, the metal chelator (or CL) is DO3A. In some embodiments, the metal chelator is PEPA. In some embodiments, the metal chelator is EDTA. In some embodiments, the metal chelator is CHX-A″-DTPA. In some embodiments, the metal chelator is HEHA. In some embodiments, the metal chelator is DOTMP. In some embodiments, the metal chelator is t-Bu-calix[4]arene- tetracarboxylic acid. In some embodiments, the metal chelator is macropa. In some embodiments, the metal chelator is macropa-NCS. In some embodiments, the metal chelator is H4pypa. In some embodiments, the metal chelator is H4octapa. In some embodiments, the metal chelator is H4CHXoctapa. In some embodiments, the metal chelator is DOTP. In some embodiments, the metal chelator is crown.

[0498] Exemplary metal chelators 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 by reference in its entirety.

[0499] In some embodiments, the metal chelator (or CL) is DOTA. In some embodiments, the metal chelator is a chiral derivative of DOTA. In some embodiments, the metal chelator 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.

[0500] In some embodiments, the metal chelator (orwherein each Reis 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. In some embodiments, the metal chelator iswherein each Reis 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.tetra-(S,S,S,S)-Me-DOTA,tetra-(S,S,S,S)-Et-DOTA, ortetra-(S,S,S,S)-iBu-DOTA. In some embodiments, ,NH2-DOTA ,NH2-DOTA-GA,p-NCS-Bn-DOTA-GA, orp-NH2-Bn-oxo-DO3A. Insome embodiments, the metal chelatorembodiments, the metal chelatorsome embodiments, the metal chelator is. In some embodiments, the metal chelator is, , ,some embodiments, the metal chelator (or CL) isp-SCN-Bn-HEHA . In some embodiments, the metal chelator isH2-MACROPA-NCS,.

[0502] Exemplary metal chelators are also illustrated in FIG. 1 to FIG. 19.

[0503] 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

[0504] In some embodiments the conjugate disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is one of the compounds in Table 2. TABLE 2Further Forms of Compounds Disclosed Herein Isomers / Stereoisomers

[0505] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compoundsdescribed 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 diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. Isotopically enriched compounds

[0506] Unless otherwise stated, compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted1H (protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.

[0507] For example, the compounds described herein may be artificially enriched in one or more particular isotopes. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). In some embodiments, the compounds described herein are artificially enriched in one or more isotopes selected from2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br,131I, and125I. In some embodiments, the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar.

[0508] In some embodiments, the compound is deuterated in at least one position. In some embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms.

[0509] The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997, and the following synthetic methods. For example, deuterium substituted compounds may be synthesized using various methods such 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 ofRadiolabeled 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.

[0510] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co. Pharmaceutically acceptable salts

[0511] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0512] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0513] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0514] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as 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, tartaricacid, 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- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-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 sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0515] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4alkyl)4, and the like.

[0516] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Tautomers

[0517] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Radiopharmaceutical Conjugates

[0518] Disclosed herein are radiopharmaceutical conjugate comprising a conjugate disclosed herein bound to a radionuclide. Generally, the type of radionuclide used in a therapeutic radiopharmaceutical can be tailored to the specific type of cancer, the type of targeting moiety (e.g., binding peptide), etc. Radionuclides that undergo α-decay produce particles composed of two neutrons and two protons, and radionuclides that undergo β-decay emit energetic electrons from their nuclei. Some radionuclides can also undergo electron capture and emit Auger electrons. In some embodiments, the conjugate comprises an alpha particle-emitting radionuclide. Alpha radiation can cause direct, irreparable double-strand DNA breaks compared with gamma and beta radiation, which can cause single-stranded breaks via indirectDNA damage. The range of these particles in tissue and the half-life of the radionuclide can also be considered in designing the radiopharmaceutical conjugate. Tables 3 below illustrates some properties of exemplary radionuclides. Table 3. Exemplary radionuclides

[0519] In some embodiments, the radiopharmaceutical conjugate described herein comprises a radionuclide selected from Table 3. In some embodiments, disclosed herein are conjugates comprising a compound of Table 1, or a salt or stereoisomer thereof, complexed with a radionuclide selected from Table 3. In some embodiments, disclosed herein are compositions comprising a compound of Table 1, or a salt or stereoisomer thereof, complexed with a radionuclide selected from Table 3. In some embodiments, disclosed herein are conjugates comprising a compound of Table 2, or a salt or stereoisomer thereof, complexed with a radionuclide selected from Table 3. In some embodiments, disclosed herein are compositions comprising a compound of Table 2, or a salt or stereoisomer thereof, complexed with a radionuclide selected from Table 3.

[0520] 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, each of the one or more radionuclides is bound to the metal chelator of the radiopharmaceutical conjugate. In some embodiments, two radionuclides of the radiopharmaceutical conjugate are bound to the same metal chelator. In some embodiments, two radionuclides of the radiopharmaceutical conjugate are bound to two independent metal chelators. In some embodiments, each of the one or more radionuclides is an alpha particle-emitting radionuclide.

[0521] In some embodiments, the radiopharmaceutical conjugate described herein comprises an alpha particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises an alpha-particle emitting radionuclide bound to the metal chelator. In some embodiments, the alpha particle-emitting radionuclide is actinium-225 (225Ac), radium-223 (223Ra), radium-224 (224Ra), bismuth- 209 (209Bi), bismuth-213 (213Bi), gadolinium-148 (148Gd), terbium-149 (149Tb), polonium-213 (213Po), francium-223 (223Fr), thorium-227 (227Th), thorium-229 (229Th), or lead-212 (212Pb). In some embodiments, the alpha particle-emitting radionuclide is selected from225Ac,223Ra,209Bi,213Bi,148Gd,149Tb,213Po,223Fr,227Th,229Th, and212Pb. In some embodiments, the alpha particle-emitting radionuclide is225Ac. In some embodiments, the alpha particle-emitting radionuclide is213Bi. In some embodiments, the alpha particle-emitting radionuclide is212Bi. In some embodiments, the alpha particle-emitting radionuclide is212Pb. In some embodiments, the alpha particle-emitting radionuclide is224Ra. In some embodiments, the alpha particle-emitting radionuclide is223Ra. In some embodiments, the alpha particle- emitting radionuclide is227Th. In some embodiments, the alpha particle-emitting radionuclide is149Tb.

[0522] In some embodiments, the radiopharmaceutical conjugate described herein comprises a radionuclide selected from62Cu,64Cu,67Cu,90Y,109Pd,111Ag,134Ce,149Pm,153Sm,166Ho,99mTc,67Ga,68Ga,111In,90Y,177Lu,186Re,188Re,197Au,198Au,199Au,105Rh,165Ho,161Tb,149Pm,153Pm,44Sc,47Sc,213Po,212Pb,209Bi,212Bi,213Bi,225Ac,117mSn,67Ga,149Tb,152Tb,167Tm,175Yb,223Ra,223Fr,227Th,229Th,201Tl,148Gd,160Gd,148Nd,89Sr, and89Zr. In some embodiments, the radionuclide is selected from62Cu,64Cu,67Cu,68Ga,89Zr,90Y,99mTc,105Rh,111In,134Ce,148Gd,149Tb,152Tb,153Pm,167Tm,175Yb,177Lu,209Bi,212Pb,213Po,213Bi,223Ra,223Fr,227Th,225Ac, and229Th. In some embodiments, the radionuclide is225Ac. In some embodiments, the radionuclide is a decay daughter of225Ac such as221Fr,217At,213Bi,213Po,209Tl,209Pb, or209Bi. In some embodiments, the radiopharmaceutical conjugate comprises two225Ac radionuclides. In some embodiments, the radionuclide is177Lu. In some embodiments, the radiopharmaceutical conjugate comprises two177Lu radionuclides. In some embodiments, the radionuclide is no-carrier added (i.e., non- carrier-added or n.c.a.)177Lu. In some embodiments, the radionuclide is no-carrier added (i.e., non- carrier-added or n.c.a.)225Ac. In some embodiments, the radionuclide is177Lu free of long-lived radioactive contaminants and byproducts. In some embodiments, the radionuclide is a non-carrier-added radionuclide. In some embodiments, the radionuclide is a pseudo-radiometal. In some embodiments, the pseudo-radiometal is aluminum -[18F]fluoride ([18F]AlF) complex.

[0523] In some embodiments, the radiopharmaceutical conjugate described herein comprises a beta particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a beta particle-emitting radionuclide bound to the metal chelator. In some embodiments, the beta 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 beta particle emitting radionuclide is copper-67, yttrium-90, samarium-153, or lutetium-177. In some embodiments, the beta particle emitting radionuclide is lutetium-177.

[0524] 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 the metal chelator. In some embodiments, the gamma particle-emitting radionuclide is indium-111 or tin-117m.

[0525] In some embodiments, the radiopharmaceutical conjugate described herein comprises a positron particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a positron particle-emitting radionuclide bound to the metal chelator. 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.

[0526] In some embodiments, a conjugate described herein comprises a radionuclide suitable for imaging or diagnostic purposes. In some embodiments, the radionuclide suitable for imaging is selected from62Cu,64Cu,89Zr,134Ce,152Tb,68Ga,111In, and99mTc. In some embodiments, the radionuclide is suitable PET imaging. In some embodiments, the radionuclide suitable for PET imaging is selected from62Cu,64Cu,89Zr,134Ce,152Tb, and68Ga. In some embodiments, the radionuclide is suitable for SPECTimaging. In some embodiments, the radionuclide suitable for SPECT imaging is selected from111In and99mTc.

[0527] In some embodiments, radiopharmaceutical conjugates described herein do not contain any hot radionuclide, i.e., a cold conjugate. For example, in some cases, a radionuclide can be replaced with a surrogate (e.g.,225Ac replaced with lanthanum) for testing and experimental purposes. In some embodiments, hot lutetium (Lu-177) is replaced with a cold Lutetium (Lu-175).

[0528] A metal chelator such as DOTA can interact with a radionuclide (e.g.,177Lu or225Ac) via one or more functional groups and / or atoms. For example, the metal chelator can interact with a radionuclide via a nitrogen and / or an oxygen atom. As another example, the metal chelator can interact with a radionuclide via carbonyl, carboxylic acid, amino, and / or amide groups of the metal chelator. In some embodiments, the interaction of the metal chelator and a radionuclide of the conjugates disclosed herein can be illustratedsome embodiments, the interaction of the metal chelator and a radionuclide of the conjugates disclosed herein can be illustratedsome embodiments, the interaction of the metal chelator and a radionuclide of the conjugates disclosedsome embodiments, the interaction of the metal chelator and a radionuclide of the conjugates disclosed herein can be illustrated assome embodiments, the interaction of the metal chelator and a radionuclide of the conjugates disclosed herein are illustrated. In some embodiments, the interaction of the metal chelator and a radionuclide of the conjugates disclosed herein are illustratedsome embodiments, the radionuclide exists in a positive oxidation state e.g.,225Ac3+,177Lu3+. In some embodiments, for example in certain aqueous conditions, the radionuclide exists in a salt form, e.g., as225Ac3+,177Lu3+. In some embodiments, for example in certain acidic aqueous conditions, the radionuclide exists in a salt form, e.g., as225Ac3+,177Lu3+. In some embodiments, the conjugate is in a salt form. In some embodiments, one or more of the carboxylic acid groups of the conjugate may exist as carboxylate anions. In some embodiments, one or more of the carboxylate anions of the conjugate may coordinate to the radionuclide. A person of ordinary skill would appreciate that the dissociation of an acid depends on the pH value of the environment and its pK value. Accordingly, in some embodiments, the conjugate described herein can exist in a completely ionized, partially ionized, or non-ionized form.

[0529] In some embodiments, the radiopharmaceutical conjugate is selected from a conjugate found in table 4a or 4b.* The radionuclide of Table 4a and Table 4b is bound to the chelator of the corresponding compound.

[0530] In some embodiments, the radiopharmaceutical conjugate is selected from a conjugate found in table 5a or 5b.* The radionuclide of Table 5a and Table 5b is bound to the chelator of the corresponding compound.

[0531] In some embodiments, disclosed herein is a radiopharmaceutical conjugate comprising a covalently bound radioisotope. In some embodiments of Formula (AC), (AC’), (BC), (BC’), (CC), or (CC’), R30comprises the covalently bound radioisotope. In some embodiments of Formula (AC), (BC), or (CC), TL1 comprises the covalently bound radioisotope. In some embodiments of Formula (AC), (BC), or (CC), TL2comprises the covalently bound radioisotope. In some embodiments of Formula (AC), (BC), or (CC), LAcomprises the covalently bound radioisotope. In some embodiments of Formula (AC’), (BC’), or (CC’), one or both of the TL1groups comprise the covalently bound radioisotope. In some embodiments of Formula (AC’), (BC’), or (CC’), one or both of the TL2groups comprise the covalently bound radioisotope. In some embodiments of Formula (AC’), (BC’), or (CC’), LBcomprises the covalently bound radioisotope. In some embodiments of Formula (BC), (BC’), (CC), or (CC’), X comprises the covalently bound radioisotope. In some embodiments, the covalently bound radioisotope is selected from11C,13N,15O,18F,70As,71As,72As,73As,74As,76As,77As,76Br,123I,124I,125I,131I, and211At. In some embodiments, the covalently bound radioisotope is131I. In some embodiments, the covalently bound radioisotope is211At. In some embodiments, the covalently bound radioisotope is18F.

[0532] In some embodiments, a compound of Formula (AC), (AC’), (BC), (BC’), (CC), or (CC’), or a pharmaceutically acceptable salt or a stereoisomer thereof comprises a covalently bound radioisotope (designated as R*), and wherein the compound comprises a structure represented in Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), or Formula (Ve):wherein, R* is a covalently bound radioisotope (e.g., such as fluorine-18 (18F), iodine-131 (131I), iodine-123 (123I), iodine-124 (124I), iodine-125 (125I), or astatine-211 (211At)); andRbis hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C9heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted (e.g., optionally substituted with one or more R as described herein).

[0533] In some embodiments of Formula (AC), (AC’), (BC), (BC’), (CC), or (CC’), R30comprises a structure represented in Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), or Formula (Ve).

[0534] In some embodiments of Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), or Formula (Ve), the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are independently optionally substituted by one or more halogen, amino, -OH, -NO2, oxo, -CN, C1-3alkoxyl, C1-3alkyl and C1-3haloalkyl. In some embodiments, Rbis hydrogen. In some embodiments, Rbis C1-C4alkyl. In some embodiments, Rbis C1-C4cycloalkyl. In some embodiments, R* is131I.

[0535] In some embodiments, a structure represented in Formula (Va), Formula (Vb), Formula (Vc),

[0536] In some embodiments, radiopharmaceutical conjugates comprising covalently bound radionuclides described herein can be synthesized from a boronic acid, boronate, or stannane precursor. Boronic acid, boronate, and stannane precursors can be formed according to the following general reaction:

[0537] Reaction 1:X = Cl, Br, IM = -B(OR)2, -B(OH)2, -SnR3Y = C6-C10 aryl or 5-12 membered heteroaryl , where R is a variable chemical moiety, for example alkyl or hydrogen. A halogen on ring Y, for example chloro, bromo, or iodo, can undergo a palladium mediated coupling reaction with a boronic acid,boronate, or stannane compound to form an intermediate compound wherein group M has replaced halogen X.

[0538] A radioisotope, for example R*, such as fluorine-18 (18F), iodine-131 (131I), iodine-123 (123I), iodine-124 (124I), iodine-125 (125I), or astatine-211 (211At), or any other radioisotope of Table 5A and Table 5B can be formed, for example, from the intermediate compound according to the following general reactions:

[0539] Reaction 2:,

[0540] Reaction 3: NaR* Cu(pyridine)4(OTf)2 1,1-phenanthroline MeOH or H2O or MeCNM = -B(OR)2, -B(OH)2, -SnR3Y= C6-C10 aryl or 5-12 membered heteroaryl

[0541] Reaction 4: NaR*M = -B(OR)2, -B(OH)2, -SnR3Y= C6-C10 aryl or 5-12 membered heteroarylwhere R is a variable chemical moiety, for example alkyl or hydrogen.

[0542] In some embodiments, radiolabeled conjugates described herein can be synthesized from a chloro, bromo, or iodio precursor according to the following general reaction:X = Cl, Br, I Y = C6-C10 aryl or 5-12 membered heteroaryl , where R* is a radioisotope, for example, fluorine-18 (18F), iodine-131 (131I), iodine-123 (123I), iodine-124 (124I), iodine-125 (125I), astatine-211 (211At), or a radioisotope of Table 5A and Table 5B.

[0543] The radiolabeling reactions depicted above are used as example procedures in the synthesis of radiolabeled conjugates described herein. Additional reactions, including nucleophilic substitution, electrophilic substitution, isotopic exchanges, bromine-radioiodine exchange, radioiododestannylation, radioiododeboronation, and transition metal mediated halogen exchange are contemplated andprocedures 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 by reference herein in their entirety. Method of Treatment

[0544] Disclosed herein are methods of treating a CA-IX-mediated disease or disorder in a subject in need thereof, the method comprising administering to the subject a radiopharmaceutical conjugate disclosed herein. In some embodiments, the CA-IX-mediated disease or disorder is cancer.

[0545] Disclosed herein are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject a radiopharmaceutical conjugate disclosed herein.

[0546] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is hypoxic.

[0547] In some embodiments, the cancer includes any of various malignant neoplasms characterized by the proliferation of anaplastic cells that tend to invade surrounding tissue and metastasize to new body sites. Non-limiting examples of cancers suitable for treatment using the radiopharmaceutical conjugate disclosed herein include anal cancer, appendix cancer, bile duct cancer, bladder cancer, bone cancer, breast cancer, cancer of the central nervous system, cervical cancer, choriocarcinomas, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gall bladder cancer, gastrointestinal carcinoid tumors, glioma, head and neck cancers, leukemia (e.g., acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, or hairy cell leukemia), liver cancer, lung cancer, lymphoma (e.g., non-Hodgkin's lymphoma, Hodgkin's lymphoma, B-cell lymphoma, or Burkitt's lymphoma), multiple myeloma, neuroblastoma, oral squamous cell carcinoma, osteogenic sarcomas, ovarian cancer, pancreatic cancer, pleural cancer, prostate cancer, rectal cancer, renal cancer (e.g., renal cell carcinoma), skin cancer (e.g., melanoma) small intestine cancer, stomach (gastric) cancer, testicular cancer, and thyroid cancer.

[0548] 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 carcinoma, oral squamous cell carcinoma, pancreatic cancer, breast cancer, ovarian cancer, glioblastoma, head and neck cancer, or lung cancer. In some embodiments, the cancer is clear cell renal cell carcinoma (ccRCC). In some embodiments, the lung cancer is squamous cell lung cancer or non-cell small lung cancer. In some embodiments, the pancreatic cancer is ductal carcinoma. In some embodiments, the lung cancer is squamous cell lung cancer.

[0549] In some embodiments, provided herein are methods for killing a cell comprising contacting the cell with a radiopharmaceutical conjugate or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the cell expresses a CA-IX receptor. In some embodiments, theradiopharmaceutical conjugate or a pharmaceutically acceptable salt or stereoisomer thereof releases a number of alpha particles by natural radioactive decay. In some embodiments, the radiopharmaceutical conjugate or a pharmaceutically acceptable salt or stereoisomer thereof releases a number of beta particles, gamma rays, and / or Auger electrons by natural radioactive decay. The radiopharmaceutical conjugate described herein can kill a cell by radiation. In some embodiments, the radiopharmaceutical conjugate kills the cell directly by radiation. In some embodiments, the radiopharmaceutical conjugate kills the cell by inducing double-stranded DNA breaks. In some embodiments, the cell is a cancer cell. In some embodiments, the method comprises killing a cell with an alpha-particle emitting radionuclide. After contacting a cell, the radiopharmaceutical conjugate described herein can be internalized by the cell. The internalization can be mediated by cell receptors, cell membrane endocytosis, etc. In some embodiments, the radiopharmaceutical conjugate or a pharmaceutically acceptable salt or stereoisomer thereof is configured to treat cancer by ablating tumor cells.

[0550] In addition to the methods of treatment described above, the radiopharmaceutical conjugates and compositions described herein can be used to image, and / or as part of a treatment for diseases. Conjugates for imaging applications, e.g., single-photon emission computed tomography (SPECT) and positron emission tomography (PET), can comprise a radionuclide suitable for use as imaging isotopes (e.g., Dx in Table 3) such as the isotopes in Table 3. Accordingly, the radiopharmaceutical conjugate can be administered as a companion diagnostic.

[0551] In one aspect, described herein is a method of treatments that comprises administering a first radiopharmaceutical conjugate and a second radiopharmaceutical conjugate. The first radiopharmaceutical conjugate can be used as companion diagnostics and the second radiopharmaceutical conjugate can be used for therapeutics. 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 comprises a gamma particle emitting radionuclide. In some embodiments, the first radiopharmaceutical conjugate comprises a radionuclide marked Dx of Table 3. In some embodiments, the first radiopharmaceutical conjugate comprises a radionuclide selected from Lu-177, In-111, Ga-68, Cu-64, and Zr-89. In some embodiments, the second radiopharmaceutical conjugate comprises an alpha or beta-particle emitting radionuclide. In some embodiments, the second radiopharmaceutical conjugate comprises a radionuclide marked Tx of Table 3. In some embodiments, the second radiopharmaceutical conjugate comprises Ac- 225. In some embodiments, the method comprises administering (i) a first radiopharmaceutical conjugate comprising a radionuclide configured for companion diagnostic (such as PET imaging) and (ii) a second radiopharmaceutical conjugate comprising a radionuclide selected from an alpha or beta-particle emitter, wherein the first and the second radiopharmaceutical conjugate have the same structure except for the radionuclide.

[0552] In one aspect, described herein is a method of diagnosing or imaging a cancer in a subject in need thereof, comprising administering to the subject a radiopharmaceutical conjugate or a pharmaceutical composition described herein.

[0553] In some embodiments, the subject is 1 to 100 years old. In some embodiments, the subject 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 to 65, 15 to 75, 18 to 25, 18 to 35, 18 to 45, 18 to 55, 18 to 65, 18 to 75, 25 to 35, 25 to 45, 25 to 55, 25 to 65, 25 to 75, 35 to 45, 35 to 55, 35 to 65, 35 to 75, 45 to 55, 45 to 65, 45 to 75, 55 to 65, 55 to 75, or 65 to 75 years old. In some embodiments, the subject is at least 5, 10, 15, 18, 25, 35, 45, 55, or 65 years old. In some embodiments, the subject is at most 10, 15, 18, 25, 35, 45, 55, 65, or 75 years old. Dosing

[0554] In certain embodiments, the compositions containing the radiopharmaceutical conjugates described herein are administered for therapeutic treatments. In certain therapeutic applications, the radiopharmaceutical conjugates described herein are administered to a patient already suffering from a disease or disorder, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or disorder. Amounts effective for this use depend on the severity and course of the disease or disorder, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. The amount of radiopharmaceutical conjugates described herein or a pharmaceutically acceptable salt or stereoisomer thereof and / or pharmaceutical compositions administered can be sufficient to deliver a therapeutically effective dose of the particular subject. In some embodiments, radiopharmaceutical conjugate dosages can be between about 0.1 pg and about 50 mg per kilogram of body weight. In some embodiments, the dose of the radiopharmaceutical conjugate or a pharmaceutically acceptable salt or stereoisomer thereof described herein for the described methods is about 0.001 mg to about 1000 mg per dose for the subject being treated.

[0555] In some cases, the elimination profile of the conjugate can be adjusted by a reversible binding between the conjugate and a plasma protein such as albumin. A suitable affinity between the conjugate and the plasma protein can utilize the plasma protein as a reservoir for the conjugates, attaching and preserving the conjugates at high concentration and releasing the conjugates at a lower concentration, thereby improving elimination profile. In some embodiments, a dissociation constant (Kd) between the conjugate and human serum albumin is at most 500 µM, as determined at room temperature in human serum condition. In some embodiments, the Kd is from about 0.1 nM to about 1000 µM. In some embodiments, the Kd is at most 100 µM. In some embodiments, the Kd is at most 15 µM. In some embodiments, the Kd is from about 1 nM to about 10 µM. In some embodiments, the Kd is from about 10 nM to about 10 µM. In some embodiments, the Kd is from about 50 nM to about 1 µM. In some embodiments, the Kd is from about 100 nM to about 10 µM. Routes of Administration

[0556] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections. Pharmaceutical Compositions / Formulations

[0557] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0558] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, 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, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. EXAMPLES A: Synthesis of the Compounds General Information

[0559] 1H NMR spectra were recorded on either a Bruker Avance III 400 (400 MHz), or Bruker Avance 300 (400 MHz) spectrometer. Chemical shifts are reported in ppm with solvent resonance as the internal standard (CDCl3:7.27 ppm, DMSO-d6: 2.50 ppm, CD3OD: 3.31 ppm). Data are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet), and coupling constants (Hz).

[0560] Liquid chromatography was performed using forced flow (flash chromatography) on silica gel (SiO2, 1000 mesh) or by column chromatography (silica gel, 1000 mesh). Thin layer chromatography (TLC) was performed on 20-25 μm silica gel glass backed plates. Preparative TLC was performed on a 40-45μm silica gel glass backed plates. Visualization was performed using ultraviolet light (254 nm), iodide, or KMnO4in water. A1. Synthesis of Intermediate 1 Scheme A1.1.1 Preparation of compound 1B

[0561] A solution 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) in THF (20 mL), MeOH (20 mL) and H2O (20 mL) was stirred at 20°C for 1h. The reaction mixture was concentrated under reduced pressure to remove organics and the aqueous phase adjusted to pH = 5 by the addition of 1 M HCl. White solid precipitated and was filtered. The filter cake collected and dried under reduced pressure to give compound 1B (5.4 g, 92% yield) as a white solid; LCMS [M+H]: 137.1;1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1 H), 3.12 (s, 1 H), 2.21 (s, 6 H). 1.2 Preparation of Intermediate 1

[0562] 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 (40 mL) and DIEA (44.8 mL, 257 mmol, 5 eq) was added dropwise a solution of T3P (36.7 mL, 61.7 mmol, 50% w / w solution in EtOAc, 1.2 eq) in THF (4 mL) at 20°C. The mixture was stirred at 20°C for 2h. The mixture was diluted with H2O (40 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was triturated with H2O (20 mL), filtered, and concentrated under reduced pressure to give Intermediate 1 (6.0 g, 39% yield) as a white solid; LCMS [M+H]: 299.0;1H NMR (400 MHz, DMSO-d6) δ 13.17 (br s, 1H), 8.32 (s, 2H), 3.19 (s, 1H), 2.40 (s, 6H). A2. Synthesis of Intermediate 2 Scheme A2.1.3. Preparation of compound 2B

[0563] To a solution of compound 2A (3.5 g, 19.0 mmol, 1 eq) in THF (50 mL) was added 1M BH3.THF (17.1 mL, 0.9 eq) at -20°C. The mixture was stirred at 0 °C for 0.5 h, quenched by addition ofMeOH (20 mL) at 0 °C and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc) to give 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). 1.4. Preparation of compound 2C

[0564] To a solution of compound 2B (3.1 g, 18.2 mmol, 1 eq) in DCM (30 mL) was added 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). The mixture was stirred at 25 °C for 16h. The residue was diluted with H2O (50 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give crude compound 2C (3.0 g, 98% yield) as a yellow oil which was used directly in the next reaction. 1.5. Preparation of compound 2D

[0565] To a solution of compound 2C (3.0 g, 17.8 mmol, 1 eq) and Bestmann reagent (4.11 g, 21.4 mmol, 1.2 eq) in MeOH (30 mL) was added K2CO3(4.93 g, 35.7 mmol, 2 eq) at 0°C. The mixture was stirred at 25 °C for 2h. The reaction mixture was partitioned between MTBE (150 mL) and H2O (300 mL). The organic phase was separated, washed with brine (3 × 50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc) to give compound 2D (1.7 g, 58% yield) as a white oil;1H 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). 1.6. Preparation of compound 2E

[0566] To a solution of compound 2D (1.6 g, 9.74 mmol, 1 eq) in 2:2:1 THF:MeOH:H2O (10 mL) was added LiOH.H2O (818 mg, 19.5 mmol, 2 eq). The mixture was stirred at 25 °C for 4h. The reaction mixture was concentrated under reduced pressure, the residue diluted with H2O (8 mL) and acidified with 1M HCl (150 mL). White solids precipitated, the suspension filtered and the filtrate concentrated under reduced pressure to give compound 2E (1.6 g, 98% yield, 90% purity) as a white solid;1H 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). 1.7. Preparation of Intermediate 2

[0567] To a solution of compound 2E (1.0 g, 6.7 mmol, 1 eq) in DCM (5 mL) was added oxalyl dichloride (991 μL, 11.3 mmol, 1.7 eq) at 0°C. The mixture was stirred at 25 °C for 1h. The mixture was quenched with the addition of MeOH and concentrated under reduced pressure. The yellow oil was taken up in THF (10 mL) and added 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) at 0°C. The solution was stirred at 15°C for 1h and concentrated under reduced pressure. The residue was triturated with H2O (120 ml) at 15°C for 20 min to give 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). A3. Synthesis of Intermediate 3 Scheme A3.1.8 Preparation of compound 3B

[0568] To a solution of compound 3A (9.0 g, 24.4 mmol, 1 eq) and TEA (68 mL, 244 mmol, 10 eq) in DCM (100 mL) was added 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 min then 30°C for 16 h. The mixture was diluted with DCM (100 mL) and extracted with H2O (10 × 50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give crude compound 3B (3.8 g) as colorless oil. 1.9 Preparation of compound 3C

[0569] To 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) in MeOH (90 mL) was added K2CO3 (12.9 g, 46.7 mmol, 2 eq) at 0°C. The mixture was stirred at 25°C for 2h. The mixture was diluted with MTBE (80 mL) and extracted with H2O (3 × 50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc) to give compound 3C (7.3 g, 88% yield) as a white solid. 1.10 Preparation of compound 3D

[0570] To a solution of compound 3C (7.3 g, 20.5 mmol, 1 eq) in 2:2:1THF:MeOH:H2O (25 mL) was added LiOH.H2O (2.58 g, 30.7 mmol, 1.5 eq). The mixture was stirred at 30°C for 4h and concentrated under reduced pressure. The residue was diluted with H2O (8 mL) and acidified with 1M HCl (150 mL). White solids precipitated, the suspension filtered, and the filtrate concentrated under reduced pressure to give compound 3D (6.1 g, 91% yield) as a white solid. 1.11 Preparation of Intermediate 3

[0571] To a solution of compound 3D (6.10 g, 18.6 mmol, 1 eq) in 2-MeTHF (30 mL) was added DMF (286 µL, 1.86 mmol, 0.1 eq) and SOCl2(5.38 mL, 37.2 mmol, 2 eq) at 0°C. The mixture was stirred at 25°C for 1h and concentrated under reduced pressure. The residue in DMF (20 mL) 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 DMF (20 mL) at 0°C. The solution was stirred at 15°C for 1h and the reaction mixture concentrated under reduced pressure. The residue was triturated with H2O (120 ml) at 15oC for 20 min to give Intermediate 3 (10.3 g, 85% yield) as a white solid; LCMS [M+H]: 327.0;1H 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).A4. Synthesis of Intermediate 4 Scheme A4.1.12 Preparation of compound 4B

[0572] To a mixture of compound 4A (2.0 g, 10.2 mmol, 1 eq) and Bestmann reagent (2.35 g, 12.2 mmol, 1.2 eq) in MeOH (50 mL) and K2CO3 (2.82 g, 20.4 mmol, 2 eq) was added at 0°C. The mixture was stirred at 0°C for 2 h, and then stirred at 20°C for 1h. The reaction mixture diluted with water (50 mL) and extracted with MTBE (3 × 50 mL). The combined organic layer was washed with brine (25 mL), dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc) to give compound 4B (1.82 g, 93% yield) as a white solid;1H NMR (400 MHz, CHLOROFORM-d) δ 3.64 (s, 3H), 2.09 (s, 1H), 1.80 (s, 12H). 1.13 Preparation of compound 4C

[0573] To a solution of compound 4B (1.82 g, 9.47 mmol, 1 eq) in 1:1:1 THF:MeOH:H2O (60 mL) was added LiOH.H2O (1.39 g, 33.1 mmol, 3.5 eq). The mixture was stirred at 15°C for 3h. The reaction mixture was washed with 1M HCl (43 mL), filtered and concentrated under reduced pressure to give compound 4C (1.58 g, 94% yield) as a white solid;1H NMR (400 MHz, CHLOROFORM-d) δ 7.27 (s, 1H), 2.10 (s, 1H), 1.85 - 1.80 (m, 12H). 1.14 Preparation of Intermediate 4

[0574] 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 h, diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was triturated with EtOAc at 15oC for 5 min to give Intermediate 4 (131 mg, 14% yield) as a white solid; LCMS [M+H]: 341.1. A5. Synthesis of Intermediate 5 Scheme A5.1.15 Preparation of compound 5B

[0575] To a solution of compound 5A (2.0 g, 12.0 mmol, 1 eq) in THF (10 mL) and H2O (10 mL) was added LiOH.H2O (656 mg, 15.6 mmol, 1.3 eq). The mixture was stirred at 20°C for 2h and 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 concentrated under reduced pressure. The residue was recrystallization from H2O to give compound 5B (1.72 g, 94% yield) as a white solid; LCMS [M+H]: 153.1;1H 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). 1.16 Preparation of Intermediate 5

[0576] To a solution of compound 5B (1.52 g, 9.99 mmol, 1 eq) in DCM (5 mL) was added DMF (77 µL, 999 µmol, 0.1 eq) and oxalyl chloride (870 µL, 9.99 mmol, 1 eq) at 0oC. The reaction mixture was stirred at 20°C for 30 min and concentrated under reduced pressure. The oil was taken up in 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 h, diluted with EtOAc (100 mL) and extracted with H2O (3 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was further purified by recrystallization from H2O (10 mL) to give Intermediate 5 (3.03 g, 97% yield) as a white solid; LCMS [M+H]: 315.1;1H 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, 4 H). A6. Synthesis of Intermediate 6 Scheme A6.,1.17 Preparation of compound 6B

[0577] To a solution of compound 6A (12.5 g, 79.0 mmol, 1 eq) in THF (250 mL) was added NaH (3.79 g, 94.8 mmol, 60% purity, 1.2 eq) at 0°C under a nitrogen atmosphere. 3-Bromoprop-1-yne (17 mL, 158 mmol, 80% purity, 2 eq) was added dropwise and the reaction stirred at 15°C for 12h. Themixture was purified by column chromatography (SiO2, petroleum ether:EtOAc) to give compound 6B (2.5 g, 8.1% yield) as a yellow oil. 1.18 Preparation of compound 6C

[0578] To a solution of compound 6B (2.5 g, 12.7 mmol, 1.0 eq) in 1:1:1 THF:MeOH:H2O (15 mL) was added LiOH.H2O (535 mg, 12.74 mmol, 1 eq) at 15°C under a nitrogen atmosphere. The mixture was stirred at 15°C for 12h. The reaction was concentrated under reduced pressure. The residue was adjusted pH to 5-6 with 1M HCl (15 mL) and filtered. The filter cake was dried under vacuum to give compound 6C (1.4 g, 30% yield) as yellow solid;1H 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). 1.19 Preparation of Intermediate 6

[0579] Oxalyl chloride (576 µL, 6.59 mmol, 1 eq) was added dropwise 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) at 0°C. The mixture was stirred at 20°C for 0.5h and concentrated under reduced pressure. The yellow oil was taken up in DCM (8 mL) and added 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) at 0°C. The mixture was stirred at 20°C for 1h, poured into H2O (50 mL), stirred at 20oC for 10 min, filtered and the filter cake dried under reduced pressure. The crude product was triturated with 1:1 petroleum ether:MTBE (20 mL) at 20oC for 20 min to give Intermediate 6 (1.3 g, 51% yield, 88% purity) as a yellow solid;1H 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). A7. Synthesis of Intermediate 7 Scheme A7.1.20 Preparation of compound 7B

[0580] 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 stirred at 10°C for 3h. 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 stirred at 0°C for 0.5h and then warmed to 10°C for 1 h. The reaction mixture was quenched by addition of 1M HCI (30 mL) at 0°C and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether:EtOAc) to give compound 7B(372 mg, 83% yield) as a white solid;1H NMR (400 MHz, METHANOL-d4) δ 4.44 - 4.35 (m, 2H), 2.51 (s, 1H), 2.34 (s, 6H). 1.21 Preparation of Intermediate 7

[0581] 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 24h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was triturated with EtOAc at 10°C for 10 min to give 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 0.5h under a nitrogen atmosphere, the reaction mixture cooled to room temperature, filtered and the filtrate concentrated under reduced pressure. The residue was triturated with H2O at 15°C for 10 min to give Intermediate 7 (183 mg, 62% yield) as a white solid;1H NMR (400 MHz, METHANOL-d4) δ 7.88 (s, 1H), 2.48 (s, 1H), 2.35 (s, 6H).

[0582] Intermediates in table 7.1 were prepared by procedures depicted in scheme A7. Table 7.1.

[0583] A8. Synthesis of Intermediate 8 Scheme A8.1.22 Preparation of Intermediate 8

[0584] 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 stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure and taken up in 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 stirred at 50°C for 12 h. The crude product was triturated with H2O at 15°C for 10 min and triturated with EtOAc at 15°C for 10 min to give crude Intermediate 8 (4.2 g) as a yellow solid; LCMS [M+H]: 309.0;1H 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).

[0585] Intermediates in table 6.1 were prepared by procedures depicted in scheme A8. Table 6.1.A9. Synthesis of Intermediate 9 Scheme A9.1.23 Preparation of compound 9B

[0586] To a solution of compound 9A (2.50 g, 11.6 mmol, 1 eq) in DCM (50 mL) was added (COCl)2(5.09 mL, 58.1 mmol, 5 eq) and DMF (1.5 mL) at 0°C and the mixture was stirred at 25°C for 2 h. The reaction was repeated. The two reactions were combined and concentrated under reduced pressure to give crude compound 9B (5.4 g) as a yellow oil that was used directly in the next reaction. 1.24 Preparation of compound 9C

[0587] To a solution of 5-amino-1,3,4-thiadiazole-2-sulfonamide (2.97 g, 16.5 mmol, 1 eq) in DMF (54 mL) was added pyridine (1.33 mL, 16.5 mmol, 1 eq). A solution of compound 9B (2.69 g, 11.5 mmol, 0.7 eq) in DMF (10 mL) was added at 0°C and the mixture stirred at 25°C for 2 h. The reaction was repeated and combined. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4),filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm, 15 um); mobile phase: [H2O (0.1%TFA)-ACN];gradient:24%-54% B over 28.0 min) to give compound 9C (3.0 g, 24% yield) as white solid; LCMS [M+2H]: 379.0. 1.25 Preparation of compound 9D

[0588] To a solution of compound 9C (1.2 g, 3.18 mmol, 1 eq) in THF (24 mL) was added 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). The mixture stirred at 80°C for 12h. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, Petroleum ether:EtOAc) to give compound 9D (2.4 g, 83% yield, 87% purity) as yellow solid; LCMS [M+H]: 395.2. 1.26 Preparation of Intermediate 9

[0589] To a solution of compound 9D (2.0 g, 5.07 mmol, 1 eq) in MeOH (40 mL) was added K2CO3(1.05 g, 7.60 mmol, 1.5 eq) at 50°C, and the mixture was stirred at 50°C for 2 h. The mixture was adjusted to pH=3 with 1M HCl, the solid filtered and the filter cake concentrated to give intermediate 9 (1.4 g, 86% yield) as a yellow solid that was used directly in the next reaction; LCMS [M+H]: 323.1;1H 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).

[0590] Intermediates in table 6.2 were prepared by procedures depicted in scheme A9. Table 6.2.A10. Synthesis of Intermediate 10 Scheme A10.10 1. 27 Preparation of compound 10B

[0591] To a solution of compound 10A (10 g, 99.9 mmol, 1 eq) in DCM (100 mL) were added TEA (27.8 mL, 200 mmol, 2 eq) and MsCl (11.6 mL, 150 mmol, 1.5 eq) at 0°C under a nitrogen atmosphere. The mixture was stirred at 20°C for 1 h. The reaction mixture was washed with NaHCO3(50 mL), NH4Cl (50 ml), H2O (20ml) and brine (20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to give compound 10B (17.8 g, 100% yield) as a yellow oil;1H 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). 1.28 Preparation of compound 10C

[0592] To a solution of compound 10B (17.8 g, 99.9 mmol, 1 eq) in DMF (200 mL) was added potassium ethanethioate (22.8 g, 200 mmol, 2 eq) at 20°C under a nitrogen atmosphere. The mixture was stirred at 40°C for 2 h. The residue was dissolved in EtOAc (500 mL), washed with H2O (2 × 100 mL) and 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:EtOAc) to give compound 10C (9.2 g, 58% yield) as a light yellow liquid;1H 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). 1.29 Preparation of compound 10E

[0593] To a solution of compound 10C (7.11 g, 44.9 mmol, 1 eq) and compound 10D (11.1 g, 44.9 mmol, 1 eq) in EtOH (100 mL) was added K2CO3 (31.1 g, 225 mmol, 5 eq) at 20°C. The mixture was stirred at 40°C for 16h. The reaction mixture was diluted with H2O (160 mL) and extracted with EtOAc (3 × 400 mL). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether:EtOAc) to give compound 10E (6.4 g, 41% yield) as a white solid; LCMS [M+H]: 344.0.1H 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).1.30 Preparation of compound 10F

[0594] To a solution of compound 10E (2.0 g, 5.83 mmol, 1 eq) in MeOH (24 mL) and THF (8 mL) was added Oxone (14.3 g, 23.3 mmol, 4 eq) in H2O (16 mL) at 0°C. The mixture was stirred at 30°C for 16 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (2 × 50 mL). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether:EtOAc) to give compound 10F (1.4 g, 64% yield) as a white solid; LCMS [M-H]: 373.9;1H 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). 1.31 Preparation of Intermediate 10

[0595] To a solution of compound 10F (1.2 g, 3.20 mmol, 1 eq) in DMSO (12 mL) was added TEA (890 µL, 6.39 mmol, 2 eq) and (S)-1-cyclopropylethan-1-amine (408 mg, 4.80 mmol, 1.5 eq) under a nitrogen atmosphere. The mixture was stirred at 65°C for 3 h. The residue was diluted with H2O (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layer was washed with brine (2 × 10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, petroleum ether:EtOAc) to give Intermediate 10 (840 mg, 60% yield) as a yellow oil; LCMS [M-H]: 439.3;1H 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). Intermediates in table 6.3 were prepared by procedures depicted in Scheme A10. Table 6.3.A11. Synthesis of Intermediate 11 Scheme A11.1.32 Preparation of intermediate 11

[0596] To a solution of compound 11A (1.7 g, 4.95 mmol, 1 eq) in DMSO (17 mL) was added TEA (1.38 mL, 9.90 mmol, 2 eq) and cyclooctanamine (1.26 g, 9.90 mmol, 2 eq). The mixture was stirred at 60°C for 16h, diluted with H2O (40 mL) and extracted with EtOAc (2 × 40 mL). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether:EtOAc) to give intermediate 11 (1.4 g, 63% yield) as a yellow oil; LCMS [M-H]: 449.4;1H 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). A12. Synthesis of Intermediate 12 Scheme A12.1.33 Preparation of compound 12B

[0597] To a solution of compound 12A (4.0 g, 31.7 mmol, 1 eq) in acetone (160 mL) and H2O (2.8 mL) was added DBDMH (9.07 g, 31.7 mmol, 1 eq) and imidazolidine-2-thione (486 mg, 4.76 mmol, 0.15 eq) at 25 °C. The reaction was stirred at 45 °C for 12 h, filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether:EtOAc) to give compound 12B (3.8 g, 54% yield) as yellow solid;1H 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). 1.34 Preparation of Intermediate 12

[0598] To a solution of compound 12B (1.9 g, 8.52 mmol, 1 eq) in EtOH (19 mL) was added 5- amino-1,3,4-thiadiazole-2-sulfonamide (1.53 g, 8.52 mmol, 1 eq) and the mixture stirred at 80 °C for 12 h. The procedure was repeated. The two batches were combined and filtered. The filter cake was collected and purified by prep-HPLC (column: Phenomenex Titank C18 Bulk 250*70mm 10u; mobile phase: [H2O(0.1%TFA)-ACN]; gradient:25%-65% B over 20.0 min) to give Intermediate 12 (2.0 g, 39% yield) as yellow solid;1H 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). A13. Synthesis of Intermediate 13 Scheme A13.1.35 Preparation of compound 13B

[0599] 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) was added NH3.H2O (7.24 mL, 52.6 mmol, 28% purity, 5.6 eq) dropwise. NaClO (3.44 mL, 2.93 mmol, 5.3% purity) was added dropwise at 0°C and the resulting mixture stirred at 0-5 °C for 1 h. The mixture was filtered and the filter cake washed with H2O (3 mL) to give crude compound 13B (2.78 g) as a white solid; LCMS [M+H]: 227.0;1H 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). 1.36 Preparation of compound 13C

[0600] To a solution of compound 13B (2.78 g, 12.3 mmol, 1 eq) in acetone (60 mL) and H2O (60 mL) was added a solution of KMnO4(3.88 g, 24.6 mmol, 2 eq) in H2O (90 mL) dropwise at 0°C. The reaction mixture was stirred at 10 °C for 2h. The mixture was treated with activated carbon and 10 N NaOH (4 mL), stirred for 30 min, filtered, and washed with EtOAc (50 mL). To the filtrate was added H2O (50 mL), the mixture extracted with EtOAc (3 × 50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc) to give compound 13C (2.1 g, 66% yield) as a white solid; LCMS [M+H]: 259.0;1H 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). 1.37 Preparation of compound 13D

[0601] To a mixture of compound 13C (2.5 g, 9.68 mmol, 1 eq) in DCE (39 mL) was added AlCl3(2.38 mL, 43.6 mmol, 4.5 eq) and the mixture stirred at 25°C for 12h under a nitrogen atmosphere. The reaction was quenched with H2O (6 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc) to give compound 13D (2.13 g, 96% yield) as a white solid; LCMS [M+H]: 230.9;1H 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). 1.38 Preparation of compound 13E

[0602] To a solution of compound 13D (0.5 g, 2.17 mmol, 1 eq) in DMF (5 mL) was added DMF- DMA (1.91 mL, 14.4 mmol) at 20°C. The mixture was stirred at 40°C for 4 h. The mixture was concentrated, the residue dissolved in DMF (5 mL), NaH (130 mg, 3.26 mmol, 60% purity, 1.50 eq) added at 0°C and the mixture stirred at 0°C for 0.5 h.3-Bromoprop-1-yne (373 μL, 3.46 mmol, 1.59 eq) in DMF (0.5 mL) was added at 0°C, the mixture stirred at 20°C for 2h and the residue poured into a mixture of water (5 mL) and EtOAc (5 mL). The mixture was filtered, the filter cake collected, dissolved in DCM (10 mL), and washed with saturated aqueous NaHCO3(3 × 8 mL). The residue was purified by column chromatography (SiO2, DCM / MeOH) to give 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). 1.39 Preparation of Intermediate 13

[0603] To a solution of compound 13E (0.24 g, 742 μmol, 1 eq) in NH3 / MeOH (10 mL) was stirred at 20°C for 2 h. The mixture was adjusted to pH = 2 with conc. HCl and concentrated under reduced pressure. The solid was triturated with ice-water (5 mL), filtered and the filter cake was concentrated to give Intermediate 13 (0.16 g, 80% yield) as a yellow solid; LCMS [M+H]: 269.0. A14. Synthesis of Intermediate 14 Scheme A14.1.40 Preparation of compound 14B

[0604] To a solution of compound 14A (20 g, 74.3 mmol, 1 eq) in DCM (300 mL) was added Ghosez reagent (11.8 mL, 89.1 mmol, 1.2 eq), and the mixture stirred at 25 °C for 1h. The reaction mixture was concentrated under reduced pressure to give compound 14B (21 g, 98% yield) as a yellow oil that was used directly in the next reaction.1.41 Preparation of compound 14C

[0605] To a solution of 5-amino-1,3,4-thiadiazole-2-sulfonamide (12.5 g, 70 mmol, 1 eq) in THF (200 mL) was added pyridine (11.2 mL, 139 mmol, 2 eq). A solution of compound 14B (20 g, 69.5 mmol, 1 eq) in THF (20 mL) was added at 0°C and the mixture stirred at 25°C for 2h. The aqueous layer was extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with brine (300 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was triturated with petroleum ether:EtOAc (200 mL), stirred for 5 min, filtered and the filter cake collected to give compound 14C (24 g, 80% yield) as a white solid;1H 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). 1.42 Preparation of Intermediate 14

[0606] To a solution of compound 14C (25 g, 57.9 mmol, 1 eq) in DCM (500 mL) was added 4 M HCl:dioxane (579 mL, 40 eq), and the mixture stirred at 25°C for 1h. The reaction mixture was concentrated under reduced pressure to give crude Intermediate 14 (26 g) as a white solid; LCMS [M- H]: 330.2;1H NMR (400 MHz, DMSO-d6) δ 13.02 (br s, 1H), 9.15 - 8.86 (m, 2H), 3.48 - 3.34 (m, 1H), 3.05 - 2.81 (m, 4H), 2.21 - 1.97 (m, 4H), 1.86 - 1.62 (m, 4H). A15. Synthesis of Intermediate 15 Scheme A15.1.43 Preparation of compound 15B

[0607] To a solution of compound 15A (3.0 g, 9.8 mmol, 1 eq) and 5-amino-1,3,4-thiadiazole-2- sulfonamide (3.53 g, 19.6 mmol, 2 eq) in pyridine (12 mL) was added EDCI (3.75 g, 19.6 mmol, 2 eq). The mixture was stirred at 20°C for 1h and concentrated under reduced pressure. The solid was washed with MeOH (3 × 30 mL), the mixture filtered and the filter cake dried under reduced pressure to give compound 15B as a yellow solid; LCMS [M+H]: 469.2;1H NMR (400 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.31 (s, 2H), 8.07 (br d, J = 8.8 Hz, 2H), 7.04 (br d, J = 8.8 Hz, 2H), 3.53 - 3.30 (m, 8H), 1.42 (s, 9H). 1.44 Preparation of Intermediate 15

[0608] A solution of compound 15B (2.8 g, 5.98 mmol, 1 eq) in HCl / dioxane (28 mL) was stirred at 20°C for 1h and concentrated under reduced pressure. The residue was triturated with MTBE to give Intermediate 15 as a white sold; LCMS [M+H]: 369.2;1H NMR (400 MHz, DMSO-d6) δ 13.36 - 13.04(m, 1H), 9.49 (br s, 2H), 8.34 (s, 2H), 8.10 (br d, J = 8.8 Hz, 2H), 7.11 (br d, J = 9.0 Hz, 2H), 3.70 - 3.59 (m, 4H), 3.19 (br s, 4H). A16. Synthesis of Intermediate 16 Scheme A16.1.45 Preparation of compound 16B

[0609] Compound 16A (20 g, 94.2 mmol, 1 eq) was taken up in THF (200 mL). The mixture degassed and purged with nitrogen 3 times, cooled to 0°C, 10 M borane methylsulfanylmethane (23.6 mL, 2.5 eq) added dropwise for 15 minutes. The reaction was stirred at 20°C for 2 h. The reaction mixture was quenched by addition of MeOH (200 mL) at 20°C and concentrated under reduced pressure to give crude Compound 16B (18.7 g) as a colorless oil;1H NMR (400 MHz, DMSO-d6) δ 4.35 (t, J = 5.6 Hz, 1H), 3.55 (s, 3H), 3.02 (d, J = 5.4 Hz, 2H), 1.75 - 1.57 (m, 6H), 1.42 - 1.27 (m, 6H). 1.46 Preparation of compound 16C

[0610] To a solution of compound 16B (18.7 g, 94.2 mmol, 1 eq) in DCM (160 mL) was added TEA (131 mL, 942 mmol, 10 eq) at 20°C. Pyridine;sulfur trioxide (45 g, 283 mmol, 3 eq) was dissolved in DMSO (100 mL), stirred for 15 minutes at 20°C then added to the reaction mixture at 0°C. The mixture was stirred at 30°C for 16 h, diluted with DCM (200 mL). The combined organic layers were washed with H2O (3 × 200 mL) and brine (2 × 200 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give crude compound 16C (18.5 g) as a yellow oil;1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 3.58 (s, 3H), 1.80 - 1.68 (m, 6H), 1.64 - 1.54 (m, 6H). 1.47 Preparation of compound 16D

[0611] To a solution of compound 16C (18.5 g, 94.2 mmol, 1 eq) in MeOH (185 mL) was added K2CO3(26.0 g, 188 mmol, 2 eq) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (21.7 g, 113 mmol,1.2 eq) at 0°C then the mixture stirred at 0°C for 2 h. The reaction mixture was poured into H2O (150 mL) and extracted with MTBE (3 × 150 mL). The combined organic layers were washed with brine (150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether:EtOAc) to give compound 16D (14 g, 77% yield) as a white solid;1H NMR (400 MHz, DMSO-d6) δ 3.56 (s, 3H), 2.89 (s, 1H), 1.70 (s, 12H). 1.48 Preparation of compound 16E

[0612] Compound 16D (5.0 g, 26.0 mmol, 1 eq) was taken up in THF (500 mL). The suspension was degassed under reduced pressure and purged with nitrogen several times. The solution was cooled to below -65°C and 2.5 M n-BuLi (12.5 mL) was added dropwise over 30 min under a nitrogen atmosphere. The mixture was stirred at -65°C for 30 min then Boc2O (6.27 mL, 27.3 mmol) was added at -65°C. The mixture was warmed to 20°C and stirred for 16 h. The mixture was cooled to 0°C then NH4Cl (50 mL) was added and stirred at 0°C for 10 min. The mixture was stirred at 20°C for 30 min. The aqueous phase extracted with EtOAc (3 × 200 mL) and the combined organic phase was washed with brine (2 × 100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether:EtOAc) to give compound 16E (2.4 g, 32% yield) as a white solid;1H NMR (400 MHz, DMSO-d6) δ 3.57 (s, 3H), 1.80 - 1.66 (m, 12H), 1.41 (s, 9H). 1.49 Preparation of compound 16F

[0613] To a mixture of compound 16E (2.20 g, 7.52 mmol, 1 eq) in THF (20 mL) and H2O (5 mL) was added LiOH.H2O (316 mg, 7.52 mmol, 1 eq) at 20°C under a nitrogen atmosphere. The mixture was stirred at 20°C for 16 h. The reaction mixture was poured into water (50 mL) and the aqueous phase was extracted with EtOAc (150 mL). The aqueous phase adjusted with 1M HCl to pH = 4-5 and extracted with EtOAc (2 × 150 mL). The combined organic phase was washed with brine (2 × 100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give compound 16F (1.5 g, 72% yield) as a white solid; LCMS [M-H]: 277.1;1H NMR (400 MHz, DMSO-d6) δ 12.14 (br s, 1H), 1.72 (q, J = 9.6 Hz, 12H), 1.42 (s, 9H). 1.50 Preparation of compound 16G

[0614] To a mixture of compound 16F (650 mg, 2.34 mmol, 1 eq) in DCM (8 mL) was added oxalyl chloride (307 μL, 3.50 mmol, 1.5 eq) and DMF (18 μL, 234 μmol) at 20°C under a nitrogen atmosphere. The mixture was stirred at 20°C for 1h and concentrated under reduced pressure to give crude compound 16G (1.39 g) as a white solid. 1.51 Preparation of Intermediate 16

[0615] To a mixture of 5-amino-1,3,4-thiadiazole-2-sulfonamide (838 mg, 2.32 mmol, 1 eq) in NMP (8 mL) was added pyridine (375 μL, 4.65 mmol) and compound 16G (690 mg, 2.32 mmol, 1 eq) dropwise over 30 min at 0°C under a nitrogen atmosphere. The mixture was stirred at 20°C for 16 h, H2O (40 mL) added at 20°C, the mixture filtered and the filter cake dried under reduced pressure. The crude product was washed with MTBE (2 × 10 mL) to give crude Intermediate 16 (2.3 g) as a light brown solid; LCMS [M+H]: 441.1;1H NMR (400 MHz, DMSO-d6) δ 12.69 (br s, 1H), 8.30 (s, 2H), 1.91 - 1.74 (m, 12H), 1.49 - 1.33 (m, 9H).A17. Synthesis of Intermediate 17 Scheme A17.1.52 Preparation of compound 17B

[0616] To a solution of compound 17A (2.95 g, 21.7 mmol) in t-BuOH (50 mL) was added MgCl2(89 μL, 2.17 mmol) and Boc2O (5.97 mL, 26 mmol). The mixture was stirred at 45°C for 16 h, quenched by addition of NaHCO3 (20 mL) at 25°C, the combined organic layers washed with DCM (60 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, Petroleum ether:EtOAc) to give compound 17B (5.0 g, 60% yield) as a white solid;1H NMR (400 MHz, CDCl3) δ = 2.28 (s, 6H), 2.11 (s, 1H), 1.44 (s, 9H). 1.53 Preparation of compound 17C

[0617] 2M LDA (4.94 mL) was added slowly to a solution of compound 17B (1.0 g, 4.94 mmol) in THF (100 mL) and TMEDA (75 μL, 494 μmol) at -78℃ and stirred at -78℃ for 1h. Methyl carbonochloridate (382 μL, 4.94 mmol) was added at -78℃ and the mixture stirred at -78 °C for 1 h. The reaction mixture was quenched by addition of NH4Cl (100 mL) at 20°C for 30 min, and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, EtOAc:Petroleum ether) to give compound 17C (5.3 g, 86% yield) as a white solid;1H NMR (400 MHz, CDCl3) δ 3.77 (s, 3 H) 2.34 (s, 6 H) 1.43 (s, 9 H). 1.54 Preparation of compound 17D

[0618] A solution of compound 17C (3.0 g, 12 mmol) in DCM (15 mL) and TFA (15 mL) was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to give crude compound 17D (4.4 g, TFA) as a white solid that was used without further purification;1H NMR (400 MHz, CDCl3) δ 3.78 (s, 3 H) 2.44 (s, 6 H). 1.55 Preparation of compound 17E

[0619] To a solution of compound 17D (3.3 g, 17.0 mmol) in DCM (33 mL) was added DMF (131 μL 1.70 mmol). Oxalyl dichloride (1.79 mL, 20.4 mmol) was added at 0℃, the mixture stirred at 25°C for 1 h and concentrated under reduced pressure to give compound 17E (3.6 g, 99% yield) as a white solid. 1.56 Preparation of intermediate 5

[0620] To a solution of intermediate 17E (3.1 g, 16.9 mmol) in NMP (60 mL) was added Py (2.73 mL, 34 mmol). 5-Amino-1,3,4-thiadiazole-2-sulfonamide (3.6 g, 16.9 mmol) in NMP (60 mL) was added to the mixture under N2at 0℃. The mixture was stirred at 25°C for 1h, the crude product triturated with H2O at 25oC for 15 min and filtered. The filter cake was concentrated under reduced pressure to give intermediate 17 (4.0 g, 66% yield) as a white solid; LCMS [M+H]+= 357.2;1H NMR (400 MHz, DMSO-d6) δ 13.24 (br s, 1H), 8.34 (s, 2H), 3.71 (s, 3H), 2.52 (s, 6H). Intermediates in table 6.4 were prepared according to literature procedures. Table 6.4.B1. Synthesis of Intermediate 30 Scheme B1.2.1 Synthesis of compound 30C

[0621] To a mixture of 2-Cl-Trt-Cl resin (110 g, 110 mmol / g) in DCM (1000 mL) was added a solution of compound 30B (45.3 g, 110 mmol, 1 eq), DIEA (38.3 mL, 220 mmol, 2 eq) in DCM (500mL) at 15°C. The mixture was shaken at 15°C for 16h under a nitrogen atmosphere. The reaction mixture was filtered, the filter cake washed with DCM (3 × 1000 mL), DMF (2 × 1000 mL), MeOH (3 × 1000 mL) and DMF (2 × 1000 mL), the resin dried with nitrogen to give compound 30C that was used directly in the next reaction. 2.2 Synthesis of compound 30D

[0622] A mixture of compound 30C in piperidine (200 mL) and DMF (800 mL) was shaken at 15°C for 10 min under a nitrogen atmosphere and the mixture filtered. The procedure was repeated four times, the cake washed with DCM (2 × 1000 mL) and DMF (2 × 1000 mL), the resin dried with nitrogen to give compound 30D that was used directly in the next reaction. 2.3 Synthesis of compound 30F

[0623] A mixture of compound 30E (61.7 g, 150 mmol, 1.5 eq), HCTU (62.1 g, 150 mmol, 1.5 eq), HOBt (20.3 g, 150 mmol, 1.5 eq) and DIEA (29.6 mL, 170 mmol, 1.7 eq) in DMF (1000 mL) was stirred at 15°C for 30 min. The above mixture was added to a solution of Compound 30D in DMF (1000 mL) and the mixture shaken at 15°C for 2 h. The mixture was filtered, the cake washed with DMF (1000 mL), DCM (3 × 1000 mL) and DMF (2 × 1000 mL), the resin dried with nitrogen to give compound 30F that was used directly in the next reaction. 2.4 Synthesis of compound 30G

[0624] A mixture of compound 30F in piperidine (200 mL) and DMF (800 mL) was shaken at 15°C for 10 min under a nitrogen atmosphere and the mixture filtered. This procedure was repeated four times, the cake washed with DCM (2 × 1000 mL) and DMF (2 × 1000 mL), the resin dried with nitrogen to give compound 30G that was used directly in the next reaction. 2.5 Synthesis of compound 30J A mixture of compound 30H (43.0 g, 150 mmol, 1.5 eq), HCTU (62.1 g, 150 mmol, 1.5 eq), HOBt (20.3 g, 150 mmol, 1.5 eq), DIEA (29.6 mL, 1.7 eq) in DMF (1000 mL) was stirred at 15°C for 30 min. The mixture was added to a solution of compound 30G in DMF (1000 mL) and the mixture shaken at 15 °C for 2 h. The mixture was filtered, the cake washed with DMF (1000 mL), DCM (3 × 1000 mL) and DMF (2 × 1000 mL). The resin was dried with nitrogen to give compound 30J that was used directly in the next reaction. 2.6 Synthesis of compound 30

[0625] A solution of compound 30J in DCM (1000 mL), TFA (10 mL) and TIPS (10 mL) was shaken at 15°C for 10 min. This procedure was repeated three times to ensure completion of the cleavage. The resin was washed with THF (1000 mL), the mixture filtered, the combined organic layer washed with NaHCO3(34 g in 500 mL H2O), the organic layer dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc) to give compound 30 (50 g) as a yellow solid; LCMS [M+H]: 629.5.

[0626] Compounds in table 7.1 were prepared by procedures depicted in Scheme B1. Table 7.1.B2. Synthesis of Intermediate 31 Scheme B2.2.9 Synthesis of compound 31B

[0627] A mixture of compound 31A (8.59 g, 24.3 mmol, 1.5 eq), HOBt (3.28 g, 24.3 mmol, 1.5 eq), HCTU (10.1 g, 24.3 mmol, 1.5 eq) and DIEA (4.80 mL, 27.5 mmol, 1.7 eq) in DMF (50 mL) was stirredat 15°C for 30 min. The mixture was added to a solution of compound 30D in DMF (50 mL), and the mixture shaken at 15°C for 2 h. The mixture was filtered and the cake washed with DMF (100 mL), DCM (3 × 100 mL) and DMF (2 × 100 mL). The resin was dried with nitrogen to give compound 31B which was used directly in the next reaction. 2.10 Synthesis of compound 31C

[0628] A mixture of compound 31B in piperidine (20 mL) and DMF (80 mL) was shaken at 15°C for 10 min under a nitrogen atmosphere and the mixture filtered. The procedure was repeated four times. The cake was washed with DCM (2 × 100 mL) and DMF (2 × 100 mL), the resin dried with nitrogen to give compound 31C which was used directly in the next reaction. 2.11 Synthesis of compound 31E

[0629] To a mixture of compound 31C (3.1 g, 5.35 mmol, 1 eq) and compound 31D (2.41 g, 8.03 mmol, 1.5 eq) in DMF (50 mL) was added DIEA (1.59 mL, 9.10 mmol, 1.7 eq), HOBt (1.09 g, 8.03 mmol, 1.5 eq) and HCTU (3.32 g, 8.03 mmol, 1.5 eq). The mixture was shaken at 25°C for 1 h. The mixture was filtered. The cake was washed with DMF (100 mL), DCM (3 × 100 mL) and DMF (2 × 100 mL). The resin dried with nitrogen to give compound 31B which was used directly in the next reaction. 2.12 Synthesis of compound 31

[0630] To a solution of compound 31E (4.6 g, 5.34 mmol, 1 eq) in DCM (100 mL) was added TFA (1 mL) and TIPS (1 mL). The reaction was shaken for 10 min at 15°C and the mixture filtered. The procedure was repeated three times. THF (100 mL) was added and shaken for 10 min at 15°C. The mixture was filtered, washed with NaHCO3(3.4 g in 50 mL H2O), the organic layer dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc) to give compound 31 (1.4 g, 45% yield) as a yellow solid; LCMS [M+H]: 585.3.

[0631] Compounds in table 7.2 were prepared by procedures depicted in scheme B2. Table 7.2.B3. Synthesis of Intermediate 32 Scheme B3.2.13 Synthesis of compound 32C

[0632] To a mixture of compound 32B (2.59 g, 9.02 mmol, 1.0 eq) and compound 32A (2.0 g, 9.92 mmol, 1.1 eq) in DMF (30 mL) was added DIPEA (7.85 mL, 45.1 mmol, 5 eq) and T3P (10.7 mL, 18.0 mmol, 50% purity, 2 eq) at 20°C under a nitrogen atmosphere. The mixture was stirred at 20°C for 2 h. The reaction mixture was poured into water (60 mL). The aqueous phase was extracted with EtOAc (3 × 80 mL). The combined organic phase was washed with brine (2 × 80 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:EtOAc) to give compound 32C (4.0 g, 57% yield, 56% purity) as a colorless oil. 2.14 Synthesis of compound 32D

[0633] To a mixture of compound 32C (3.30 g, 7.60 mmol, 1 eq) in DCM (30 mL) was added TFA (10 mL) in one portion at 20°C under a nitrogen atmosphere. The mixture was stirred at 20°C for 16h and concentrated under reduced pressure to give crude compound 32D (2.5 g) as colorless oil;1H NMR(400 MHz, METHANOL-d4) δ 7.47 - 7.27 (m, 5H), 5.17 (s, 2H), 3.99 (s, 2H), 3.74 (s, 3H), 3.28 - 3.14 (m, 4H), 2.46 - 2.24 (m, 4H). 2.15 Synthesis of compound 32F

[0634] To a mixture of compound 32D (2.4 g, 7.18 mmol, 1 eq) and compound 32E (2.06 g, 7.18 mmol, 1 eq) in DCM (5 mL) was added DMAP (175 mg, 1.44 mmol, 0.2 eq), DIEA (5.00 mL, 28.7 mmol, 4 eq) and EDCI (2.06 g, 10.8 mmol, 1.5 eq) in one portion at 20°C under a nitrogen atmosphere. The mixture was stirred at 20°C for 6 h. The reaction mixture was poured into water (80 mL), the aqueous phase extracted with DCM (3 × 120 mL), the combined organic phase washed with brine (2 × 80 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Petroleum ether:EtOAc) to give compound 32F (3.6 g, 69% yield, 83% purity) as a white solid;1H NMR (400 MHz, METHANOL-d4) δ 7.40 - 7.19 (m, 5H), 7.08 - 6.97 (m, J = 8.6 Hz, 4H), 6.70 (d, J = 8.8 Hz, 4H), 5.13 (s, 2H), 4.58 (s, 2H), 3.95 (s, 2H), 3.68 (s, 3H), 3.55 - 3.40 (m, 2H), 3.11 (q, J = 4.8 Hz, 2H), 2.33 - 2.24 (m, 2H), 2.14 - 2.04 (m, 2H), 1.96 (br d, J = 4.4 Hz, 2H), 1.55 (s, 3H). 2.16 Synthesis of compound 32

[0635] To a solution of compound 32F (3.2 g, 5.31 mmol, 1 eq) in MeOH (35 mL) was added Pd / C (600 mg, 5.31 mmol, 10% purity, 1 eq) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen 3 times. The mixture was stirred under a hydrogen atmosphere (15 psi) at 20°C for 2h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give intermediate 32 (2.6 g, 96% yield) as a white solid;1H NMR (400 MHz, METHANOL- d4) δ 7.02 (d, J = 8.6 Hz, 4H), 6.69 (d, J = 8.4 Hz, 4H), 3.92 - 3.83 (m, 2H), 3.80 - 3.67 (m, 4H), 3.40 - 3.34 (m, 3H), 3.24 - 3.10 (m, 1H), 2.39 - 2.18 (m, 2H), 2.18 - 1.97 (m, 6H). B4. Synthesis of Intermediate 33 Scheme B4.2.17 Synthesis of compound 33B

[0636] To a solution of compound 33A (60 g, 209 mmol, 1 eq) in DMF (500 mL) was added HATU (83 g, 219 mmol, 1.1 eq) and DIEA (109 mL, 627 mmol, 3 eq). The mixture was stirred at 20°C for 0.5 h, NH3.H2O (34.5 mL, 251 mmol, 1.2 eq) added at 20°C and stirred at 20°C for 1 h. The reaction mixture was extracted with EtOAc (4 × 500 mL). The combined organic layers were washed with (3 × 200 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM:MeOH) to give compound 33B (60 g, 92% yield) as a white solid;1H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.14 (m, 2H), 3.65 (s, 3H), 3.52 - 3.39 (m, 2H), 3.10 (br s, 2H), 1.98 - 1.80 (m, 4H), 1.48 - 1.29 (m, 9H). 2.18 Synthesis of compound 33C

[0637] To a solution of compound 33B (50 g, 175 mmol, 1 eq) in THF (300 mL) and H2O (100 mL) was added LiOH.H2O (14.7 g, 349 mmol, 2 eq) at 20°C. The mixture was stirred at 20°C for 1h and concentrated under reduced pressure to remove organics. 1N HCl was added to adjust reaction mixture to pH=2-3, filtered and concentrated under reduced pressure to give crude compound 33C (57 g) as a white solid;1H NMR (400 MHz, DMSO-d6) δ 12.91 - 12.68 (m, 1H), 7.19 (s, 2H), 3.40 (ddd, J = 4.0, 6.2, 13.4 Hz, 2H), 3.15 (br d, J = 8.8 Hz, 2H), 1.96 - 1.78 (m, 4H), 1.38 (s, 9H). 2.19 Synthesis of compound 33D

[0638] To a solution of compound 33C (55 g, 101 mmol, 1 eq) and methyl glycinate (27.9 g, 111 mmol, 1.1 eq) in pyridine (400 mL) was added EDCI (46.5 g, 121 mmol, 1.2 eq) at 20°C. The mixture was stirred at 20°C for 2h and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM:MeOH) to give crude compound 33D (66.5 g) as a white solid;1H NMR (400 MHz, DMSO-d6) δ 8.13 (br t, J = 5.6 Hz, 1H), 7.30 - 6.99 (m, 2H), 3.82 (br d, J = 5.5 Hz, 2H), 3.62 (s, 3H), 3.50 - 3.37 (m, 2H), 3.16 (br s, 2H), 2.08 - 1.91 (m, 2H), 1.88 - 1.73 (m, 2H), 1.39 (s, 9H). 2.20 Synthesis of compound 33E

[0639] To a solution of compound 33D (60 g, 175 mmol, 1 eq) in DCM (300 mL) was added TFA (100 mL) at 20°C. The mixture was stirred at 20°C for 1h and concentrated under reduced pressure. The crude product was triturated with THF at 20°C for 10 min to give compound 33E (53 g, 82% yield, TFA) as a white solid;1H NMR (400 MHz, DMSO-d6) δ 8.51 - 8.37 (m, 2H), 7.52 - 7.11 (m, 2H), 3.85 (br d, J = 5.8 Hz, 2H), 3.64 (s, 3H), 3.11 (br s, 2H), 3.00 (br s, 2H), 2.24 (br d, J = 13.6 Hz, 2H), 2.11 - 1.99 (m, 2H). 2.21 Synthesis of compound 33F

[0640] To a solution of 5-oxohexanoic acid (92 mL, 768 mmol, 1 eq) in H2O (24.9 mL, 1.38 mol, 1.8 eq) was added phenol (135 mL, 1.54 mol, 2 eq), the mixture cooled to 0°C, H2SO4 (73.7 mL, 1.38 mol, 1.8 eq) was added dropwise for 15 min at 0°C, the reaction stirred at 50°C for 96 h, poured into water (2000 mL) and stirred for 10 minutes. The aqueous phase was extracted with EtOAc (3 × 2000 mL). The combined organic phase was washed with water (6 × 1000 mL), combined aqueous phase extracted with ethyl acetate (6 × 1000 mL), organics dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / EtOAc) and further purifiedby prep-HPLC (column: Phenomenex Titank C18 Bulk 250*150mm 10u; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:1%-25% B over 20.0 min) to give compound 33F (128 g, 18% yield) as a white solid; LCMS [M-H]: 299.0;1H NMR (400 MHz, DMSO-d6) δ 11.95 (br s, 1H), 9.13 (br s, 2H), 6.94 (d, J = 8.6 Hz, 4H), 6.64 (d, J = 8.6 Hz, 4H), 2.16 (br t, J = 7.4 Hz, 2H), 2.03 - 1.85 (m, 2H), 1.48 (s, 3H), 1.35 - 1.16 (m, 2H). 2.22 Synthesis of compound 33G

[0641] To a solution of compound 33E (40 g, 112 mmol, 1 eq, TFA) and compound 33F (33.6 g, 112 mmol, 1 eq) in DMF (300 mL) was added DIEA (58.5 mL, 336 mmol, 3 eq) and PYAOP (61.3 g, 118 mmol, 1.1 eq) at 20°C. The mixture was stirred at 20°C for 2h, H2O (600 mL) added and then the mixture extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (3 × 150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM:MeOH) to give compound 33G (60 g, 89% yield, 87% purity) as a white solid;1H NMR (400 MHz, DMSO-d6) δ 9.15 - 9.07 (m, 2H), 8.15 (t, J = 5.8 Hz, 1H), 7.26 - 7.04 (m, 2H), 6.97 - 6.89 (m, 4H), 6.63 (d, J = 8.6 Hz, 4H), 3.83 (d, J = 5.8 Hz, 2H), 3.62 (s, 3H), 3.47 - 3.39 (m, 1H), 3.29 - 3.22 (m, 1H), 3.17 (d, J = 5.3 Hz, 2H), 2.29 - 2.21 (m, 2H), 2.07 - 1.90 (m, 4H), 1.88 - 1.72 (m, 2H), 1.48 (s, 3H), 1.26 (d, J = 1.1 Hz, 2H). 2.23 Synthesis of intermediate 33

[0642] To a solution of compound 33G (40 g, 76.1 mmol, 1 eq) in THF (120 mL) and H2O (40 mL) was added LiOH.H2O (6.39 g, 152 mmol, 2 eq) at 20°C. The mixture was stirred at 20 °C for 2 h. LCMS showed Compound 33G was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove THF. The pH was adjusted to 2-3 with 1N HCl and concentrated under reduced pressure to give intermediate 33 (36 g, 92% yield) as a white solid;1H NMR (400 MHz, DMSO-d6) δ 12.07 - 13.19 (m, 1 H) 9.00 - 9.36 (m, 2 H) 8.09 (br t, J = 5.6 Hz, 1 H) 7.12 - 7.25 (m, 2 H) 6.93 (d, J = 8.6 Hz, 4 H) 6.63 (d, J = 8.6 Hz, 4 H) 3.74 (br d, J = 5.75 Hz, 2 H) 3.57 - 3.66 (m, 1 H) 3.45 (br s, 1 H) 3.19 - 3.29 (m, 2 H) 2.24 (br t, J = 7.2 Hz, 2 H) 1.89 - 2.06 (m, 4 H) 1.74 - 1.87 (m, 2 H) 1.47 (s, 3 H) 1.17 - 1.30 (m, 2 H).

[0643] Compounds in table 7.3 were prepared by procedures depicted in scheme B4. Table 7.3.B5. Synthesis of Intermediate 34 Scheme B5.2.24 Synthesis of compound 34A

[0644] To a solution of compound 33F (15.0 g, 52.4 mmol, 1 eq) in acetone (150 mL) was added K2CO3(43.4 g, 314 mmol, 6 eq) and bromomethylbenzene (37.3 mL, 314 mmol, 6 eq). Themixture was stirred at 60 °C for 16h. Additional bromomethylbenzene (37.3 mL, 314 mmol, 6 eq) was added and the mixture stirred at 60 °C for 14 h. The reaction mixture was quenched by addition of H2O (40 mL) at 15°C, diluted with H2O (50 mL) and extracted with EtOAc (2 × 120 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc) to give compound 34A (18.1 g, 62%) as a white solid;1H NMR (400 MHz, DMSO-d6) δ 7.48 - 7.27 (m, 15H), 7.07 (d, J = 8.9 Hz, 4H), 6.92 (d, J = 8.8 Hz, 4H), 5.08 - 5.00 (m, 6H), 2.37 - 2.29 (m, 2H), 2.15 - 2.05 (m, 2H), 1.51 (s, 3H). 2.25 Synthesis of compound 34B

[0645] To a solution of compound 34A (17 g, 31 mmol, 1 eq) in H2O (40 mL) was added KOH (9.42 g, 168 mmol, 5.5 eq) and EtOH (120 mL). The mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted with MTBE (150 mL) and extracted with MTBE (2 × 40 mL). To the mixture was added aqueous citric acid solution until the reaction mixture pH = 4. The combined organic layers were washed with brine (150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give compound 34B (14.3 g, 100% yield) as a colorless oil;1H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.30 (m, 9H), 7.14 - 7.04 (m, 4H), 6.91 (d, J = 8.8 Hz, 4H), 5.09 - 5.02 (m, 4H), 3.10 - 3.05 (m, 1H), 2.29 - 2.21 (m, 2H), 2.02 (br s, 3H), 1.56 - 1.44 (m, 3H). 2.26 Synthesis of compound 34C

[0646] To a solution of compound 34B (13.3 g, 28.5 mmol, 1 eq) in toluene (10 mL) was added TEA (11.9 mL, 85.4 mmol, 3 eq), BnOH (8.9 mL, 85.4 mmol, 3 eq) and DPPA (6.17 mL, 28.5 mmol, 1 eq). The mixture was stirred at 110 °C for 15 h. The reaction mixture was extracted with MTBE (2 × 100 mL), washed with 1M NaOH (2 × 150 mL), 0.5 M HCl (200 mL), brine (150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc) to give compound 34C (10.5 g, 65%) as a colorless oil. 2.27 Synthesis of compound 34D

[0647] A suspension of compound 34C (4.7 g, 8.22 mmol, 1 eq) in THF (100 mL) was degassed under vacuum and purged with nitrogen three times. Then Pd / C (2.5 g, 8.22 mmol, 10% purity, 1 eq) was added slowly. The suspension was degassed and purged with hydrogen 3 times and the mixture was stirred at 15 °C for 4 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give crude compound 34D (4.8 g) as a pink solid;1H NMR (400 MHz, DMSO-d6) δ 6.95 - 6.80 (m, 4H), 6.63 (br d, J = 8.5 Hz, 4H), 3.63 - 3.56 (m, 1H), 2.34 - 2.26 (m, 2H), 2.08 - 2.00 (m, 2H), 1.80 - 1.71 (m, 1H), 1.47 (s, 3H). 2.28 Synthesis of compound 34E

[0648] A suspension of compound 34D (4.3 g, 16.7 mmol, 1 eq), 2-chloropyrimidine-5-carboxylic acid (2.65 g, 16.7 mmol, 1 eq), DIEA (14.6 mL, 83.6 mmol, 5 eq) and DMF (40 mL) was degassed under reduced pressure and purged with nitrogen three times. Then T3P (14.9 mL, 25.1 mmol, 50% purity, 1.5 eq) was added slowly and the mixture stirred at 15°C for 2 h. The reaction mixture was quenched by addition of H2O (15 mL) at 20°C, diluted with H2O (30 mL) and extracted with EtOAc (100 mL). Thecombined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether:EtOAc) to give compound 34E (3.33 g, 50% yield) as a colorless oil;1H NMR (400 MHz, DMSO- d6) δ 9.20 - 9.15 (m, 2H), 9.05 (s, 2H), 8.75 (t, J = 5.3 Hz, 1H), 6.99 (d, J = 8.7 Hz, 4H), 6.66 (d, J = 8.7 Hz, 4H), 3.12 - 2.98 (m, 2H), 2.30 - 2.18 (m, 2H), 1.56 (s, 3H). 2.29 Synthesis of compound 34F

[0649] To a solution of compound 34E (2.93 g, 7.36 mmol, 1 eq) in DMA (30 mL) was added DIEA (3.21 mL, 18.4 mmol, 2.5 eq) and 4-(tert-butyl) 1-methyl L-aspartate HCl (1.94 g, 8.10 mmol, 1.1 eq). The mixture was stirred at 110°C for 16 h. The reaction mixture was quenched by addition of H2O (5 mL) at 15°C. The residue was purified by column chromatography (SiO2, Petroleum ether:EtOAc) to give compound 34F (2.88 g, 69%) as a yellow oil;1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 2H), 8.68 (s, 2H), 8.25 (t, J = 5.3 Hz, 1H), 8.04 - 7.99 (m, 1H), 6.99 (d, J = 8.6 Hz, 4H), 6.66 (d, J = 8.6 Hz, 4H), 4.91 (dt, J = 6.1, 8.0 Hz, 1H), 3.61 (s, 3H), 3.01 (td, J = 5.4, 10.4 Hz, 2H), 2.85 - 2.77 (m, 1H), 2.75 - 2.68 (m, 1H), 2.24 - 2.15 (m, 2H), 1.55 (s, 3H), 1.36 (s, 9H). 2.30 Synthesis of compound 34

[0650] To a solution of compound 34F (2.5 g, 4.43 mmol, 1 eq) in DCM (18 mL) was added TIPS (18.2 mL, 88.6 mmol, 20 eq) and TFA (6.0 mL, 81.0 mmol). The mixture was stirred at 15°C for 5 h. The reaction mixture was concentrated under reduced pressure, washed with H2O (2 × 25 mL), extracted with EtOAc (2 × 75 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give compound 34 (2.4 g, crude) as a yellow solid;1H NMR (400 MHz, DMSO-d6) δ 12.54 - 12.34 (m, 1H), 9.21 - 9.11 (m, 2H), 8.68 (br s, 2H), 8.25 (br s, 1H), 8.03 (br d, J = 8.0 Hz, 1H), 6.99 (br d, J = 8.4 Hz, 4H), 6.66 (br d, J = 8.3 Hz, 4H), 4.93 - 4.82 (m, 1H), 3.61 (s, 3H), 3.00 (br s, 2H), 2.89 - 2.69 (m, 2H), 2.25 - 2.15 (m, 2H), 1.55 (br s, 3H), 1.06 - 0.93 (m, 1H). B6. Synthesis of Intermediate 35 Scheme B62.31 Synthesis of compound 35B

[0651] To a solution of compound 35A (10 g, 29.8 mmol, 1.0 eq) in DCM (100 mL) was added 2-Cl- Trt-Cl resin (9.34 g, 29.8 mmol, 1.0 eq), and DIEA (41.6 mL, 239 mmol, 8 eq). The mixture was stirred at 20°C for 36 hours under a nitrogen atmosphere. The reaction mixture was filtered, the cake washed with DCM (3 × 200 mL), DMF (2 × 200 mL), MeOH (3 × 200 mL) and DMF (200 mL), the resin dried with nitrogen to give compound 35B which was used directly in the next reaction. 2.32 Synthesis of compound 35C

[0652] A mixture of compound 35B (5.0 g, 14.9 mmol, 1.0 eq) in piperidine (20 mL) and DMF (100 mL) was shaken at 20°C for 10 minutes under a nitrogen atmosphere, and the mixture filtered. The procedure was repeated four times. The cake was washed with DCM (2 × 100 mL), DMF (2 × 100 mL), the resin dried with nitrogen to give compound 35C which was used directly in the next reaction. 2.33 Synthesis of compound 35D

[0653] To a solution of (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4- oxobutanoic acid (9.22 g, 22.4 mmol, 1.5 eq) in DMF (50 mL) was added HCTU (9.27 g, 22.4 mmol, 1.5 eq), HOBt (3.03 g, 22.4 mmol, 1.5 eq) and DIEA (7.81 mL, 44.8 mmol, 3 eq). The mixture stirred at 20°C for 0.5 h. Compound 35C (1.69 g, 14.9 mmol, 1 eq) was added and the mixture stirred at 20°C for 1h under a nitrogen atmosphere. The mixture was filtered, the cake washed with DMF (3 × 100 mL), DCM (5 × 100 mL), and DMF (100 mL). The resin was dried with nitrogen to give compound 35D which was used directly in the next reaction. 2.34 Synthesis of compound 35E

[0654] A mixture of compound 35D (7.57 g, 14.9 mmol, 1.0 eq) in piperidine (20 mL) and DMF (100 mL) was shaken at 20°C for 10 minutes under a nitrogen atmosphere, and the mixture filtered. The procedure was repeated four times. The cake was washed with DCM (2 × 100 mL) and DMF (2 × 100mL), the resin was dried with nitrogen to give compound 35E which was used directly in the next reaction. 2.35 Synthesis of compound 35F

[0655] To a solution of 4,4-bis(4-hydroxyphenyl)pentanoic acid (4.08 g, 15.0 mmol, 1 eq) in DMF (50 mL) was added HCTU (5.89 g, 15 mmol, 1 eq), HOBt (1.92 mg, 15 mmol, 1 eq) and DIEA (2.98 mL, 17.09 mmol, 1.2 eq). To the mixture was added compound 35F (4.25 g, 14.95 mmol, 1 eq) and the mixture stirred at 20°C for 1h under a nitrogen atmosphere. The mixture was filtered, the cake washed with DMF (3 × 100 mL) and DCM (5 × 100 mL), the resin dried with nitrogen to give compound 35F which was used directly in the next reaction. 2.36 Synthesis of Intermediate 35

[0656] A solution of compound 35F (13.2 g, 23.8 mmol, 1 eq) in DCM (100 mL), TFA (1 mL) and TIPS (2.5 mL) was stirred at 20°C for 10 minutes. The procedure was repeated three times. THF (100 mL) was added and stirred at 20°C for 10 min. The mixture was filtered, washed with NaHCO3 until the reaction mixture pH=7, the organic layer dried (Na2SO4), filtered and concentrated under reduced pressure to give crude Intermediate 35 (3.24 g); LCMS [M+H]: 553.4;1H NMR (400 MHz, DMSO-d6) δ 12.89 (br s, 1H), 9.15 (s, 2H), 8.28 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.6 Hz, 4H), 6.64 (d, J = 8.6 Hz, 4H), 4.44 - 4.30 (m, 2H), 2.80 (t, J = 2.4 Hz, 1H), 2.54 (br t, J = 4.8 Hz, 4H), 2.21 - 2.12 (m, 2H), 1.91 - 1.80 (m, 2H), 1.46 (s, 3H), 1.36 (s, 9H). B7. Synthesis of Intermediate 36 Scheme B7.36 2.37 Preparation of compound 36B

[0657] To a solution of compound 36A (30 g, 72.9 mmol, 1.0 eq) in DCM (300 mL) was added 2-Cl- Trt-Cl resin (22.8 g, 72.9 mmol, 1 eq), and DIEA (25.4 mL, 146 mmol, 2 eq). The mixture was stirred at 20 °C for 48h under a nitrogen atmosphere. The reaction mixture was filtered and the cake washed with DCM (3 × 300 mL), DMF (2 × 300 mL), MeOH (3 × 300 mL) and DMF (300 mL). The resin was dried with nitrogen to give compound 36B which was used directly in the next reaction. 2.38 Preparation of compound 36C

[0658] A mixture of compound 36B (30 g, 72.9 mmol, 1.0 eq) in piperidine (20 mL) and DMF (100 mL) was shaken at 20°C for 10 min under a nitrogen atmosphere and the mixture filtered. A sample ofthe filtrate (0.1 mL) was added to water (0.5 mL) and the mixture turned to a white suspension. This procedure was repeated four times until the mixture of the filtrate and water was a transparent liquid. The cake was then washed with DCM (2 × 300 mL), DMF (2 × 300 mL), the resin dried with nitrogen to give compound 36C which was used directly in the next reaction. 2.39 Preparation of compound 36D

[0659] To a solution of (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4- oxobutanoic acid (45.0 g, 109 mmol, 1.5 eq) in DMF (240 mL) was added HCTU (45 g, 109 mmol, 1.5 eq), HOBt (14.8 g, 109 mmol, 1.5 eq) and DIEA (25.4 mL, 146 mmol, 2 eq). The mixture was stirred at 20°C for 0.5 h, compound 36C (13.8 g, 72.9 mmol, 1 eq) added and the mixture stirred at 20°C for 1h under a nitrogen atmosphere. The mixture was filtered, the cake washed with DMF (3 × 300 mL), DCM (5 × 300 mL), and DMF (300 mL), the resin dried with nitrogen to give compound 36D which was used directly in the next reaction. 2.40 Preparation of Intermediate 36

[0660] To a solution of compound 36D (42.5 g, 72.9 mmol, 1.0 eq) in DCM (100 mL) and TFA (1 mL) was stirred at 20°C for 10 min. This procedure was repeated three times to ensure completion of the cleavage. DCM (300 mL) was added to the reaction mixture and the reaction stirred at 20°C for 10 min. The mixture was filtered, the filtrate diluted with MeOH and washed with saturated NaHCO3 solution (pH = 7), the organic layer dried (Na2SO4), filtered and concentrated to give Intermediate 36 (40 g) as a white solid; LCMS [M+H]: 583.4;1H NMR (400 MHz, DMSO-d6) δ 8.06 (br d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.47 (br d, J = 7.2 Hz, 2H), 7.27 (br d, J = 8.4 Hz, 1H), 7.22 - 7.15 (m, 2H), 7.13 - 7.06 (m, 2H), 4.29 - 4.20 (m, 1H), 4.12 - 3.93 (m, 4H), 2.40 - 2.30 (m, 4H), 1.14 (br d, J = 2.8 Hz, 18H). B8. Synthesis of Compound 37 Scheme B8.2.41 Synthesis of compound 37B

[0661] To a solution of compound 37A (10.0 g, 34.8 mmol, 1 eq) and Boc2O (20 mL, 87.1 mmol, 2.50 eq) in t-BuOH (20 mL) was added DMAP (1.28 g, 10.4 mmol, 0.3 eq) at 15°C under a nitrogen atmosphere. The mixture was stirred at 80°C for 12 h then concentrated under reduced pressure andpurified by chromatography column (SiO2, petroleum ether:EtOAc) to give compound 37B (11 g, 92% yield) as a white solid. 2.42 Synthesis of compound 37C

[0662] To a solution of compound 37B (11 g, 32.0 mmol, 1 eq) in MeOH (12 mL) was added 3M NaOH (10.7 mL, 1 eq) at 15°C under a nitrogen atmosphere. The mixture was stirred at 80°C for 3h and concentrated under reduced pressure. The aqueous solution was adjusted to pH=2 with 1M HCl (30 mL), filtered and the filter cake concentrated under reduced pressure to give compound 37C (10 g, 95% yield) as a white solid that was used directly in the next reaction;1H NMR (400 MHz, CHLOROFORM-d) δ 3.56 - 3.36 (m, 4H), 2.13 - 1.97 (m, 4H), 1.47 (d, J = 3.9 Hz, 18H). 2.43 Synthesis of compound 37D

[0663] To a solution of compound 37C (8.8 g, 26.7 mmol, 1 eq) and methyl glycinate hydrochloride (8.39 g, 67 mmol, 2.5 eq, HCl) in DMF (9 mL) were added T3P (31.8 mL, 53.4 mmol, 50% purity, 2 eq) and DIEA (27.9 mL, 160 mmol, 6 eq) at 15°C under a nitrogen atmosphere. The mixture was stirred at 15°C for 12h and concentrated under reduced pressure. Brine (60 mL) was added. The reaction was extracted with DCM (3 × 60 mL), the organics dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography column (SiO2, petroleum ether:EtOAc) to give compound 37D (10 g...

Claims

CLAIMS WHAT IS CLAIMED:

1. A conjugate of Formula (A), or a pharmaceutically acceptable salt or stereoisomer thereof:wherein: TL1represents a 1sttargeting moiety that binds to carbonic anhydrase IX; TL2represents a 2ndtargeting moiety that binds to carbonic anhydrase IX; LArepresents a linker; s is 0 or 1; Ring A is an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and CL represents a metal chelator.

2. A conjugate of Formula (A’), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (A’); wherein: each TL1independently represents a 1sttargeting moiety that binds to carbonic anhydrase IX; each TL2 independently represents a 2ndtargeting moiety that binds to carbonic anhydrase IX; LBrepresents a linker; and each Ring A is independently an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and CL represents a metal chelator.

3. The conjugate of claim 1 or 2, wherein: Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo. *.

6. The conjugate of any one of claims 1-5, wherein TL1is of Formula (IA):Formula (IA); wherein: W1is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR11-, -C(=O)-, -C(=O)NR11-, -NR11C(=O)-, -S(=O)2NR11-, or -NR11S(=O)2; X1is C1-C10alkylene optionally substituted with one or more R and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR11-; A1is absent, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R; T1is absent or C1-C3alkylene optionally substituted with one or more R and wherein one carbon atom of the C1-C3alkylene is optionally replaced with -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -O-, or -NR11-; B1is absent, C1-C10alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R, and wherein one, two, three, or four carbon atoms in the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, -NR11-;S1is absent or C1-C3alkylene optionally substituted with one or more R and wherein one or two carbon atoms of the C1-C3alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or -NR11-; Y1is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR11-, -C(=O)-, -C(=O)NR11-, -NR11C(=O)-, -S(=O)2NR11-, or -NR11S(=O)2; R11is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring C1is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R12is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; n is 0, 1, 2, 3, 4, 5, or 6; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3alkylene optionally substituted with one or more R; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo; or two R on the same or different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

7. The conjugate of claim 6, wherein W1is absent, -C(=O)-, or -C(=O)NR11-.

8. The conjugate of claim 6 or 7, wherein X1is C1-C4alkylene.W1X1. The conjugate of claim 6, wherein, ,10. The conjugate of claim 6 or 9, wherein.

11. The conjugate of any one of claims 6-10, whereinwherein R’ is hydrogen or R.

12. The conjugate of any one of claims 6-11, wherein T1is absent or C1-C3alkylene.

13. The conjugate of any one of claims 6-12, wherein B1is C1-C6alkylene.

14. The conjugate of any one of claims 6-12, wherein B1is cycloalkyl optionally substitued with one or more R.

15. The conjugate of any one of claims 6-12, wherein B1is a bicyclic cycloalkyl optionally substitued with one or more R.

16. The conjugate of any one of claims 6-12, wherein B1is bicyclo[1.1.1]pentanyl.

17. The conjugate of any one of claims 6-16, wherein S1is absent.

18. The conjugate of any one of claims 12-17 wherein19. The conjugate of any one of claims 12-18 wherein20. The conjugate of any one of claims 12-19, wherein. . The conjugate of any one of claims 6-20, wherein Y1is absent, -O-, -S-, -S(=O)2-, -C(=O)NR11-, or -NR11C(=O)-.

22. The conjugate of any one of claims 6-21, wherein Ring C1is heteroaryl or phenyl.

23. The conjugate of any one of claims 6-21, wherein Ring C1is monocyclic heteroaryl.

24. The conjugate of any one of claims 6-21, wherein Ring C1is bicyclic heteroaryl. . The conjugate of any one of claims 6-21, whereinwherein each Z1is independently -N- or -CR12’-; Z2is -O-, -S-, or -NR12’’-; each R12’is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; and R12’’is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1- C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. . The conjugate of any one of claims 6-21, wherein.

27. The conjugate of any one of claims 6-21, wherein.

28. The conjugate of any one of claims 6-21, wherein.

29. The conjugate of any one of claims 1-28, wherein TL2is of Formula (IIA):Formula (IIA);wherein: W2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; X2is absent or C1-C10alkylene optionally substituted with one or more R, and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR21-; Y2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; A2is absent, C1-C10alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R22; each R22is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; S2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; T2is absent or C1-C10alkylene optionally substituted with one or more R, and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR21-; R21is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; (i) B2is absent; or (ii) B2is -N(R23)2; each R23is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or (iii) B2is -CF3; or (iv) B2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R24; each R24is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; orRing C2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R25is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; m is 0, 1, 2, 3, or 4; R26is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring D2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R27is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; p is 0, 1, 2, 3, or 4; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;L is absent or C1-C3alkylene optionally substituted with one or more R; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo; or two R on the same or different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

30. The conjugate of claim 29, wherein W2is absent, -C(=O)-, or -NR21C(=O)-.

31. The conjugate of claim 29 or 30, wherein X2is C1-C4alkylene optionally substituted with one or more R.

32. The conjugate of any one of claims 29-31, wherein X2is -CH2-.

33. The conjugate of any one of claims 29-32, wherein Y2is absent, -NR21-, or -NR21C(=O)-.

34. The conjugate of any one of claims 29-33, wherein Y2is -NR21C(=O)-..

36. The conjugate of claim 29, wherein,37. The conjugate of any one of claims 29-36, wherein A2is C1-C6alkylene optionally substitued with one or more R22.

38. The conjugate of any one of claims 29-36, wherein A2is heterocycloalkyl optionally substitued with one or more R22.

39. The conjugate of any one of claims 29-36, wherein A2is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substitued with one or more R22.

40. The conjugate of any one of claims 29-36, wherein A2is piperidinyl optionally substitued with one or more R22.

41. The conjugate of any one of claims 29-36, whereinoptionally substitued with one or more R22.

42. The conjugate of any one of claims 29-36, wherein.

43. The conjugate of any one of claims 29-42, wherein each R22is independently -C(=O)ORbor - C(=O)NRcRd.

44. The conjugate of any one of claims 29-43, wherein each R22is independently -C(=O)NRcRd.

45. The conjugate of any one of claims 29-44, wherein S2is absent, -NR21-, -C(=O)-, or - NR21C(=O)-.

46. The conjugate of any one of claims 29-45, wherein T2is absent or C1-C6alkylene optionally substituted with one or more R.

47. The conjugate of claim 45 or 46, wherein,,48. The conjugate of any one of claims 45-47, wherein49. The conjugate of any one of claims 29-48, wherein B2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R24.

50. The conjugate of any one of claims 29-49, wherein each R24is independently halogen, -OH, C1- C6alkyl, or C1-C6haloalkyl.

51. The conjugate of any one of claims 29-48, whereinwherein: Ring C2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R25is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; m is 0, 1, 2, 3, or 4; R26is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring D2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R27is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; and p is 0, 1, 2, 3, or 4.

52. The conjugate of any one of claims 29-48, wherein.

53. A conjugate of Formula (B), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (B); wherein: LArepresents a linker; s is 0 or 1; CL represents a metal chelator; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1is of Formula (IB):Formula (IB); wherein: W1is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR11-, -C(=O)-, -C(=O)NR11-, -NR11C(=O)-, -S(=O)2NR11-, or -NR11S(=O)2; X1is C1-C10alkylene optionally substituted with one or more R and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR11-; A1is absent, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R; T1is absent or C1-C3alkylene optionally substituted with one or more R and wherein one carbon atom of the C1-C3alkylene is optionally replaced with -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -O-, -NR11-; B1is cycloalkyl, heterocycloalkyl, or aryl, wherein the cycloalkyl, heterocycloalkyl, and aryl is optionally substitued with one or more R; or B1is heteroaryl substituted with one or more R; S1is absent or C1-C3alkylene optionally substituted with one or more R and wherein one or two carbon atoms of the C1-C3alkylene are optionally replaced with -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -O-, or - NR11-; Y1is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR11-, -C(=O)-, -C(=O)NR11-, -NR11C(=O)-, -S(=O)2NR11-, or -NR11S(=O)2; R11is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring C1is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R12is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl,C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; n is 0, 1, 2, 3, 4, 5, or 6; TL2is of Formula (IIB):Formula (IIB); wherein: W2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; X2is absent or C1-C10alkylene optionally substituted with one or more R, and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR21-; Y2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; A2is absent, C1-C10alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R22; each R22is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; S2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; T2is absent or C1-C10alkylene optionally substituted with one or more R, and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR21-; R21is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; (i) B2is absent; or (ii) B2is -N(R23)2; each R23is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or(iii) B2is -CF3; or (iv) B2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R24; each R24is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; orRing C2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R25is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; m is 0, 1, 2, 3, or 4; R26is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring D2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R27is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; p is 0, 1, 2, 3, or 4; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3alkylene optionally substituted with one or more R; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo; or two R on the same or different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

54. The conjugate of claim 53, wherein T1is absent or C1-C3alkylene.

55. The conjugate of claim 53 or 54, wherein B1is cycloalkyl optionally substitued with one or more R.

56. The conjugate of any one of claims 53-55, wherein B1is bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.1.1]hexanyl.

57. The conjugate of any one of claims 53-55, wherein B1is bicyclo[1.1.1]pentanyl.

58. The conjugate of any one of claims 53-57, wherein S1is absent..

60. The conjugate of claim 53, wherein.

61. The conjugate of claim 53, wherein.

62. The conjugate of any one of claims 53-61, wherein A2is C1-C6alkylene optionally substitued with one or more R22.

63. The conjugate of any one of claims 53-61, wherein A2is heterocycloalkyl optionally substitued with one or more R22.

64. The conjugate of any one of claims 53-61, wherein A2is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substitued with one or more R22.

65. The conjugate of any one of claims 53-61, wherein A2is piperidinyl optionally substitued with one or more R22.

66. The conjugate of any one of claims 53-61, wherein A2isoptionally substitued with one or more R22.

67. The conjugate of any one of claims 53-66, wherein each R22is independently -C(=O)ORbor - C(=O)NRcRd.

68. The conjugate of any one of claims 53-67, wherein each R22is independently -C(=O)NRcRd.

69. A conjugate of Formula (C), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (C); wherein: LArepresents a linker; s is 0 or 1; CL represents a metal chelator; X is N, optionally substituted CH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; TL1is of Formula (IC):Formula (IC); wherein: W1is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR11-, -C(=O)-, -C(=O)NR11-, -NR11C(=O)-, -S(=O)2NR11-, or -NR11S(=O)2; X1is C1-C10alkylene optionally substituted with one or more R and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR11-; A1is absent, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R; T1is absent or C1-C3alkylene optionally substituted with one or more R and wherein one carbon atom of the C1-C3alkylene is optionally replaced with -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -O-, -NR11-; B1is absent, C1-C10alkylene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R, and wherein one, two, three, or four carbon atoms in the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, -NR11-; S1is absent or C1-C3alkylene optionally substituted with one or more R and wherein one or two carbon atoms of the C1-C3alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or -NR11-; Y1is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR11-, -C(=O)-, -C(=O)NR11-, -NR11C(=O)-, -S(=O)2NR11-, or -NR11S(=O)2; R11is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring C1is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R12is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; n is 0, 1, 2, 3, 4, 5, or 6; TL2is of Formula (IIC):Formula (IIC); wherein: W2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2;X2is absent or C1-C10alkylene optionally substituted with one or more R, and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR21-; Y2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; A2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R22; each R22is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; S2is absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NR21-, -C(=O)-, -C(=O)NR21-, -NR21C(=O)-, -S(=O)2NR21-, or -NR21S(=O)2; T2is absent or C1-C10alkylene optionally substituted with one or more R, and wherein one, two, three, or four carbon atoms of the C1-C10alkylene are optionally replaced with -S-, -S(=O)-, -S(=O)2-, -O-, or - NR21-; R21is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; (i) B2is absent; or (ii) B2is -N(R23)2; each R23is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or (iii) B2is -CF3; or (iv) B2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R24; each R24is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; orRing C2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R25is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; m is 0, 1, 2, 3, or 4; R26is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring D2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R27is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; p is 0, 1, 2, 3, or 4; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3alkylene optionally substituted with one or more R; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo; or two R on the same or different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

70. The conjugate of claim 69, wherein T1is absent.

71. The conjugate of claim 69 or 70, wherein B1is C1-C6alkylene.

72. The conjugate of any one of claims 69-71, wherein B1is cycloalkyl optionally substitued with one or more R.

73. The conjugate of any one of claims 69-71, wherein B1is a monocyclic cycloalkyl optionally substitued with one or more R.

74. The conjugate of any one of claims 69-71, wherein B1is a bicyclic cycloalkyl optionally substitued with one or more R.

75. The conjugate of any one of claims 69-71, wherein B1is bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.1.1]hexanyl.

76. The conjugate of any one of claims 69-71, wherein B1is bicyclo[1.1.1]pentanyl.

77. The conjugate of any one of claims 69-76, wherein S1is absent. 78.,79..

80. The conjugate of claim 69,.

81. The conjugate of any one of claims 69-80, wherein A2is heterocycloalkyl optionally substitued with one or more R22.

82. The conjugate of any one of claims 69-80, wherein A2is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substitued with one or more R22.

83. The conjugate of any one of claims 69-80, wherein A2is piperidinyl optionally substitued with one or more R22.

84. The conjugate of any one of claims 69-80, whereinoptionally substitued with one or more R22.

85. The conjugate of any one of claims 69-80, wherein.

86. The conjugate of any one of claims 69-85, wherein each R22is independently -C(=O)ORbor - C(=O)NRcRd.

87. The conjugate of any one of claims 69-86, wherein each R22is independently -C(=O)NRcRd.

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

89. The conjugate of any one of claims 53-87, wherein X is optionally substituted heterocycloalkyl.

90. The conjugate of any one of claims 53-89, wherein W1is absent, -C(=O)-, or -C(=O)NR11-.

91. The conjugate of any one of claims 53-90, wherein X1is C1-C4alkylene.

93. The conjugate of any one of claims 53-92, wherein.

94. The conjugate of any one of claims 53-93, wherein A1is heteroaryl optionally substitued with one or more R.

95. The conjugate of any one of claims 53-93, wherein A1is triazolyl optionally substitued with one or more R.

96. The conjugate of any one of claims 53-92,wherein R’ is hydrogen or R.

97. The conjugate of any one of claims 53-96, wherein T1is absent or C1-C3alkylene.

98. The conjugate of any one of claims 53-97, wherein Y1is absent, -O-, -S-, -S(=O)2-, - C(=O)NR11-, or -NR11C(=O)-.

99. The conjugate of any one of claims 53-98, wherein Ring C1is heteroaryl or phenyl.

100. The conjugate of any one of claims 53-98, wherein Ring C1is monocyclic heteroaryl.

101. The conjugate of any one of claims 53-98, wherein Ring C1is bicyclic heteroaryl.

102. The conjugate of any one of claims 53-98, whereinwherein each Z1is independently -N- or -CR12’-; Z2is -O-, -S-, or -NR12’’-; each R12’is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; and R12’’is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1- C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl.

103. The conjugate of any one of claims 53-98, wherein.

104. The conjugate of any one of claims 53-98, wherein.

105. The conjugate of any one of claims 53-98, wherein.

106. The conjugate of any one of claims 53-105, wherein W2is absent, -C(=O)-, or -NR21C(=O)-.

107. The conjugate of any one of claims 53-106, wherein X2is C1-C4alkylene optionally substituted with one or more R.

108. The conjugate of any one of claims 53-107, wherein X2is -CH2-.

109. The conjugate of any one of claims 53-108, wherein Y2is absent, -NR21-, or -NR21C(=O)-.

110. The conjugate of any one of claims 53-109, wherein Y2is -NR21C(=O)-.

111. The conjugate of any one of claims 53-110, whereinis,112. The conjugate of any one of claims 53-111, wherein S2is absent, -NR21-, -C(=O)-, or - NR21C(=O)-.

113. The conjugate of any one of claims 53-112, wherein T2is absent or C1-C6alkylene optionally substituted with one or more R.

116. The conjugate of any one of claims 53-115, wherein B2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substitued with one or more R24.

117. The conjugate of any one of claims 53-116, wherein each R24is independently halogen, -OH, C1- C6alkyl, or C1-C6haloalkyl.

118. The conjugate of any one of claims 53-115, whereinwherein: Ring C2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R25is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; m is 0, 1, 2, 3, or 4; R26is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; Ring D2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R27is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; and p is 0, 1, 2, 3, or 4.

119. The conjugate of any one of claims 53-115, wherein.

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

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

122. The conjugate of any one of claims 1-119 or 121, wherein the linker LAhas a structure of Formula (L-1)Formula (L-1), wherein: each L0is independently -O-, -NRL-, -N(RL)2+-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)- , -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, - NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, -S(=O)2NRL-, - C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, C1-C30alkylene, C2-C30alkenylene, C2-C30alkynylene, C1-C30heteroalkylene, -(C1-C30alkylene)-O-, - O-(C1-C30alkylene)-, -(C1-C30alkylene)-NRL-, -NRL-(C1-C30alkylene)-, -(C1-C30alkylene)-N(RL)2+-, or -N(RL)2+-(C1-C30alkylene)-; wherein each cycloalkylene, heterocycloalkylene, arylene, heteroarylene, alkylene, alkenylene, alkynylene, and heteroalkylene is optionally independently substituted with one or more R;each RLis independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; k is 1-20; and each 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-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo.

123. The conjugate of claim 122, wherein the linker LAhas a structure of Formula (L-1a),Formula (L-1a); wherein: L1is absent, -O-, -NRL-, -N(RL)2+-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, - C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, or -S(=O)2NRLC(=O)-;L2is1-8, C1-C10alkylene, or heterocycloalkylene optionally substituted with one or more R; L3is absent or C1-C10alkylene; and L4is absent, -O-, -NRL-, -N(RL)2+-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, - C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, or -S(=O)2NRLC(=O)-.

124. The conjugate of any one of claims 1-119 or 121-123, wherein the linker LAis ,, , , ,.

125. The conjugate of claim 124, wherein the metal chelator ior.

126. The conjugate of any one of claims 1-125, wherein the conjugate is found in table 1.

127. The conjugate of any one of claims 1-126, further comprising a radionuclide bound to the metal chelator to form a radiopharmaceutical conjugate.

128. The radiopharmaceutical conjugate of claim 127, wherein the radionuclide is an alpha particle- emitting radionuclide.

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

130. The radiopharmaceutical conjugate of claim 127, wherein the radionuclide is a beta particle- emitting radionuclide.

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

132. The radiopharmaceutical conjugate of claim 127, wherein the radionuclide is a positron-emitting radionuclide.

133. A conjugate having a structure of Formula (AC), (AC’), (BC), (BC’), (CC), or (CC’), wherein each of the formula is described herein.

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

135. A method of diagnosing or imaging a disease or disorder in a subject in need thereof, the method comprising administering to the subject the radiopharmaceutical conjugate of any one of claims 128-133, or the pharmaceutical composition of claim 134.

136. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject the radiopharmaceutical conjugate of any one of claims 128-133, or the pharmaceutical composition of claim 134.

137. The method of claim 135 or 136, wherein the disease or disorder is a cancer.

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

139. The method of any one of claim 137 or 138, wherein the cancer is cell renal cell carcinoma (ccRCC).

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