Compounds and compositions for conjugation to bioligands for imaging and radiopharmaceutical applications

Abstract

The present disclosure relates to radiolabeled prosthetic groups, which can be used to prepare bioactive ligands containing PET, SPECT, alpha- or beta-emitting radioisotopes, and their use in treating and / or imaging diseases, e.g, cancer.

Description

704.101.419COMPOUNDS AND COMPOSITIONS FOR CONJUGATION TO BIOLIGANDS FOR IMAGING AND RADIOPHARMACEUTICAL APPLICATIONSRELATED APPLICATION DATA

[0001] The present application claims priority pursuant to Article 8 of the Patent Cooperation Treaty to United States Provisional Patent Application Serial Number 63 / 667,419 filed July 3, 2024 which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] Among other things, the disclosure relates to compounds and compositions (e.g., prosthetic groups) that are useful for preparation of theranostic agents. In some embodiments, the present disclosure relates to compounds and compositions (e.g., prosthetic groups) that can be used in conjugation to ligands for various uses, e.g., PET / SPECT imaging, alpha- or beta- particle therapy for the diagnosis and treatment of various diseases, e.g., cancer.SEQUENCE LISTINGThe instant application contains a Sequence Listing which has been submitted via Patent Center and is hereby incorporated by reference in its entirety. Said.xml copy, created on July 01, 2025, is named 060024-00132(24-0058), and is 16,840 bytes in size.BACKGROUND

[0003] Conjugation of bioactive ligands with radiolabeled prosthetic groups is an important strategy to construct radio-imaging and radio-therapeutic agents under mild conditions.

[0004] Radio-imaging agents comprising radionuclides are useful in diagnosing and monitoring the progression of diseases. Prosthetic groups comprising radio-imaging isotopes (e.g., fluorine-18) can be conjugated with bioactive ligands for imaging, such as positron emission tomography (PET) imaging. However, preparation of stable radiolabeled prosthetic groups can be intricate, often requiring multi-step radiosynthesis under harsh conditions. Thus, there is an unmet need to identify and prepare compounds and compositions (e.g., radiolabeled prosthetic groups) that can be used in radio-imaging for the diagnosis and monitor various diseases.

[0005] Targeted radiotherapy is a modality for the treatment of otherwise intractable diseases, e.g., cancers. This modality relies on the incorporation of destructive alpha- or beta-emitting704.101.419isotopes into targeting ligands (e.g., small molecules, peptides, or other biomolecules) to target cancer cells selectively for elimination. Prosthetic groups offer a simple and mild means for the incorporation of radiotherapeutic isotopes, e.g., alpha- and beta-emitting radioisotopes such as

[0211] At and

[0131] I, to furnish radiolabeled prosthetic groups which can be conjugated to the targeting ligand of choice. Hence, there remains a need to identify and prepare compounds and compositions (e.g., radiolabeled prosthetic groups) that can be used in radiotherapy for treating various diseases.

[0006] Compounds with radiolabeled halogen atoms are widely used as diagnostic and therapeutic agents. However, the stability of the carbon-halogen bond decreases with increasing halogen size and increasing carbon hybridization state. Amaouch el al., Mol. Phys. 2016, 114, 1326-1333. This contributes to the instability of radiolabeled compounds especially those containing heavy halogens such as iodine and astatine. For example, it was reported that while the astatine radiolabeling process was robust, the resulting [21 l]At radiolabeled proteins were unstable, leading to fast release of astatine from the protein. Aaij etal., hit. J. Appl. Radial. Isol.1975, 26, 25-30.SUMMARY

[0007] in some embodiments, the present disclosure provides compounds that are well-matched prosthetic theranostic agents. In some embodiments, a provided compound is a diagnostic prosthetic group. In some embodiments, a provided compound comprises

[0018] F. In some embodiments, a provided compound is a therapeutic prosthetic group. In some embodiments, a provided compound comprises [123 / 131]! or

[0211] At. In some embodiments, the present disclosure provides a method of conjugating a provided compound under mild conditions to furnish the theranostic targeting agents.

[0008] In some embodiments, the present disclosure provides a prosthetic group. In some embodiments, the present disclosure provides a radiolabeled prosthetic group. In some embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R3O)n704.101.419Formula (I),wherein each variable is independently as described herein.

[0009] In some embodiments, the present disclosure provides compounds comprising hypervalent iodine or astatine atom. In some embodiments, a hypervalent iodine atom has an oxidation state of +3. In some embodiments, a hypervalent astatine atom has an oxidation state of +3. In some embodiments, a hypervalent iodine atom is a radioisotope of iodine. In some embodiments, a hypervalent astatine atom is a radioisotope of astatine. In some embodiments, compounds comprising hypervalent iodine or astatine atoms demonstrate improved stability.

[0010] In some embodiments, the present disclosure provides a compound of Formula (Hyper-R*), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R2)mFormula (Hyper-R*),wherein each variable is independently as described herein.

[0011] In some embodiments, the present disclosure provides methods for the preparation of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R3O)nR1—CA7L^QR^ I(R2)mFormula (I),the method comprising:(a) obtaining a compound of Formula (INT-a) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R3O)nr5—Cajl^qR^ l(R2)mFormul (INT-a),704.101.419(b) contacting the compound of Formula (INT-a) with a radioisotope source for

[0076] Br,

[0077] Br,

[0082] Br,

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, or

[0211] At in the presence of an oxidant to obtain the compound of Formula (I);wherein each variable is independently as described herein.

[0012] In some embodiments, the present disclosure provides a method of making radiolabeled bioactive ligands by employing a provided compound (e.g., radiolabeled prosthetic group). In some embodiments, the present disclosure provides a method of making radiolabeled bioactive ligand, comprising:(a) obtaining a bioactive ligand; and(b) contacting the bioactive ligand with a provided compound containing at least one radioisotope to form radiolabeled bioactive ligands.

[0013] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound (e.g., a radiolabeled bioactive ligand) as described herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier(s).

[0014] In some embodiments, the present disclosure provides a method of treating a disease, disorder, and / or condition, comprising administering to the patient in need thereof a compound as described herein, e.g., a radiolabeled bioactive ligand prepared from compound of Formula (I), or a pharm ceutically acceptable salt thereof.

[0015] In some embodiments, the present disclosure provides a method of treating a disease, disorder, and / or condition that is treatable by modulation of amino acid metabolism or by utilization of an amino acid transport mechanism, comprising administering to a subject in need thereof a therapeutically effective amount of a compound (e.g., a radiolabeled bioactive ligand), a prodrug, or a composition as disclosed herein In some embodiments, a disease, disorder, or condition is cancer. In some embodiments, a cancer is pancreatic cancer, breast cancer or brain cancer.

[0016] In some embodiments, the present disclosure provides a method of imaging a subject for diagnosing a disease or assessing efficacy of a treatment, the method comprising administering to the subject in need thereof an effective amount of a compound (e.g., a radiolabeled bioactive ligand), a prodrug, or a composition as disclosed herein.BRIEF DESCRIPTION OF THE DRAWINGS704.101.419

[0017] FIG. 1 shows HPLC isolation of (((LS)-5-(2-((fert-butoxycarbonyl)amino)-3-(3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl)propanamido)-l-carboxypentyl)carbamoyl)~£-glutamic acid by HPLC condition 1.

[0018] FIG. 2 provides HPLC analysis of product diastereomers of Examples 55 and 56 by HPLC condition 2.

[0019] FIG. 3 shows HPLC isolation of the first eluting isomer of Examples 55 and 66 by HPLC condition 3.

[0020] FIG. 4 show HPLC isolation of the second eluting isomer of Examples 55 and 66 by HPLC condition 3.

[0021] FIG. 5 shows UV-Vis HPLC (212 nm / 254 nm) and RadioHPLC analysis of (((S)-5-((S)-2-amino-3-(3-(dimethylcarbamoyl)-5-fluoro-2-(iodo-1317)phenyl)propanamido)-l-carboxypentyl)carbamoyl)-L-glutamic acid by using HPLC condition 3.

[0022] FIG. 6 shows quality control, according to UV-Vis HPLC (212 nm / 254 nm) and RadioHPLC analyses of ((( ’)-5-((5')-2-amino-3-(3-(dimethylcarbamoyl)-5-fluoro-2-(iodo-1317)phenyl)propanamido)-l-carboxypentyl)carbamoyl)-Z-glutamic acid by using HPLC condition 3.

[0023] FIG. 7 provides 1-131 imaging, biodistribution for (((5)-5-((V)-2-amino-3-(3-(dimethylcarbamoyl)-5-fluoro-2-(iodo-1317)phenyl)propanamido)-l-carboxypentyl)carbamoyl)-£-glutamic acid.DETAILED DESCRIPTION

[0024] Radiolabeled prosthetic groups are useful in constructing radio-imaging and radio-therapeutic agents under mild conditions. As described herein, in some embodiments, a radiolabeled prosthetic group comprises a radioisotope (e g., radio-imaging isotope, radiotherapeutic isotope) and a highly reactive functional group that can be coupled to bioactive ligands efficiently.

[0025] An ideal radiolabeled prosthetic group should present both high reactivity on its coupling site, and high chemical and radiochemical stability on other parts of the molecule. However, many existing radiolabeled prosthetic groups are plagued by their instability in physiological environments. For example, stability of alkyl [18F] -fluorides can be compromised in physiological environments by both substitution reactions with biological nucleophiles, as well as many enzymatic metabolic pathways. These facile in vivo defluorination processes are704.101.419oftentimes responsible for high bone uptake in the subsequent imaging studies (e.g., PET imaging).

[0026] Among other things, the present disclosure provides radiolabeled arenes / heteroarenes, e.g., [18F]-arenes, [18F] -heteroarenes with higher in vivo stabilities and are useful in constructing diagnostic ligands for in radio-imaging.

[0027] Radiotherapy, e.g., targeted radiotherapy (TRT), is a promising modality for the treatment of various cancers via the incorporation of either alpha- or beta-emitting radioisotopes on targeting ligands such as peptides and small biomolecules. Halogen-based alpha- or betaemitting radionuclides such as [21 l]At or

[0131] I have shown preliminary promise as TRT agents given their properties (e.g. ideal half-life, ease of production, readily available precursors, etc.) and their ready incorporation into organic molecules. However, the instability of radiolabeled compounds that comprise heavy halogen atoms (e.g., iodine and astatine) has impeded the development of useful prosthetic groups for radio-imaging and radiotherapy.

[0028] Among other things, the present disclosure recognizes the instability of radiolabeled iodine and astatine compounds and provides solutions for improving the stability of compounds comprising radioisotopes of halogens, e.g., those comprising radioisotopes of I and At. Among other things, the present disclosure provides compounds comprising a halogen atom and a stabilizing group. In some embodiments, a compound comprising a halogen atom and a stabilizing group (e.g., that is adjacent to the halogen atom) demonstrates improved stability compared to an otherwise identical compound that does not have such a stabilizing group.Without wishing to be bound by any particular theory, the present disclosure provides an insight that radiolabeled compounds with halogen atoms at higher oxidation state demonstrate improved stability than those with halogen atoms at a lower oxidation state due to the fact that the halogen is bonded to more atoms when in a higher oxidation state. In some embodiments, the present disclosure recognizes that hypervalent astatine at +3 oxidation state shows improved stability than astatine at +1 oxidation state, hi some embodiments, the present disclosure recognizes that compounds comprising halogen atoms can show improved stability when there is a stabilizing group in proximity to the halogen atom, e.g., radioisotopes of 1 or At. In some embodiments, a stabilizing group stabilizes a compound comprising halogen atoms by forming a hypervalent halogen species. In some embodiments, a hypervalent halogen has an oxidation state of +3. In some embodiments, a halogen atom has an oxidation state of +1 in a compound that comprises a704.101.419halogen atom but does not comprise a stabilizing group. In some embodiments, a compound comprising a halogen atom in +3 oxidation state and a stabilizing group demonstrates improved stability compared to an otherwise identical compound that does not comprise such stabilizing group and the halogen atom is in +1 oxidation state. In some embodiments, a hypervalent halogen species is formed in situ. In some embodiments, a hypervalent halogen species is formed in vivo. In some embodiments, the present disclosure encompasses an insight that radiolabeled compounds comprising halogen atoms and a stabilizing group can demonstrate improved stability due to inductive effects of such stabilizing group. In some embodiments, radiolabeled compounds comprising halogen atoms and a stabilizing group demonstrate improved stability due to electron-withdrawing effects of such stabilizing group. In some embodiments, radiolabeled compounds comprising halogen atoms and a stabilizing group demonstrate improved stability due to electron-donating effects of such stabilizing group. In some embodiments, a stabilizing group is an electron-withdrawing group. In some embodiments, a stabilizing group is an electron-donating group. In some embodiments, a stabilizing group is F. In some embodiments, a stabilizing group is -OMe. In some embodiments, a F is ortho to a halogen atom in an aromatic system. In some embodiments, a F is para to a halogen atom an aromatic system. In some embodiments, -OMe is ortho to a halogen atom in an aromatic system. In some embodiments, -OMe is para to a halogen atom in an aromatic system. In some embodiments, a halogen atom is a radioisotope of halogen. In some embodiments, ahalogen atom is

[0076] Br,

[0077] Br,

[0082] Br,

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, and

[0211] At.

[0029] In some embodiments, a provided compound comprises a stabilizing group as described herein and a radioisotope of halogen (e.g.,

[0076] Br,

[0077] Br,

[0082] Br,

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, and [21 l]At). In some embodiments, a stabilizing group is in close proximity to a radioisotope of halogen. In some embodiments, a stabilizing group is ortho to a radioisotope of halogen. In some embodiments, a stabilizing group is meta to a radioisotope of halogen. In some embodiments, a stabilizing group is para to a radioisotope of halogen. In some embodiments, a stabilizing group is ortho to a radioisotope of iodine. In some embodiments, a stabilizing group is ortho to a radioisotope of astatine. Without wishing to be bound by any particular theory, the present disclosure recognizes that when a stabilizing group is in close704.101.419proximity to a halogen atom at +1 oxidation state, such compound demonstrates improved stability due to formation of hypervalent halogen species (e.g., +3 oxidation state).

[0030] In some embodiments, a hypervalent halogen species comprises bonding between a halogen atom (e g., a radioisotope of halogen atom) and a stabilizing group. In some embodiments, a radiolabeled hypervalent halogen compound comprises a radioisotope of iodine or astatine in a 5 membered or 6 membered ring. In some embodiments, a radioisotope of iodine or astatine having +3 oxidation state is part of a 5 membered or 6 membered ring that is formed with a stabilizing group.

[0031] In some embodiments, a compound as described herein (e.g., a prosthetic group) can lead to a “theranostic pair” of radiolabeled prosthetic groups, depending on the radiolabeling patterns of such compound. For example, if a compound comprising both fluorine atom and iodine atom is radiolabeled at fluorine site (e.g., replacing

[0019] F with

[0018] F), such compound can be used as a diagnostic prosthetic group for constructing imaging agents. On the other hand, if such compound is radiolabeled at the iodine site (e.g., replacing

[0127] I with

[0131] !), such compound can be used as a therapeutic prosthetic group to construct a therapeutic agent to deliver beta-particles (beta particle therapy). In both scenarios, the chemical connectivity of such compound remains the same; however, it can serve at least two purposes (e.g., diagnostic or therapeutic) depending on how it is radiolabeled. Due to the dual purpose of compounds described herein, in some embodiments, a compound described herein is a theranostic agent. In some embodiments, a theranostic agent disclosed herein comprises at least two halogen atoms Despite the promise of various radioisotopes of halogens, such as

[0018] F,

[0131] I and [21 l]At, few truly structurally matched theranostic agents have been prepared and evaluated in the context of cancer treatments.

[0032] Among other things, the present disclosure provides a true theranostic pair that can be generated to both diagnose and treat otherwise intractable forms of cancer. Without wishing to be bound by any theory, the present disclosure recognizes that a true theranostic pair offers an opportunity to use diagnostic and therapeutic agents that act on the same specific biological target and provide more accurate patient selection and selective delivery of radiation to desired target. In some embodiments, the present disclosure provides therapeutic agents comprising

[0131] I and [21 l]At with companion

[0018] F diagnostic agents to form true theranostic pairs. In some embodiments, the present disclosure provides therapeutic agent (e.g., therapeutic prosthetic704.101.419group) identically matched with a companion diagnostic agent (e g., diagnostic prosthetic group) that is useful for radio-imaging (e.g., PET or SPECT).

[0033] Among other things, the present disclosure provides methods of preparing radiolabeled compounds (e.g., poly halogenated radiolabeled prosthetic groups) that demonstrate improved efficiency, suitability for large scale production, reduced environmental impacts, etc. In some embodiments, the present disclosure provides a photoredox method for preparing radiofluorinated compounds for diagnosis (e.g., imaging), which not only allows easy conversion of traditional drug molecules to PET / SPECT agents, but also could be used to produce established agents on a large scale that were previously complicated to synthesize. Unlike existing radiolabeling reactions, photoredox methods described herein utilize mild labeling conditions and metal-free catalyst system, thus offering various benefits such as eliminating the need to analyze residual metal contaminants In some embodiments, methods described herein provide easy access to a unique library of amino acid derivatives for fast screening based on PET imaging. In some embodiments, the methods described herein allows for the development of theranostic agent (e.g., poly halogenated radiolabeled prosthetic groups) that can be used for cancer prognosis (e.g., based on

[0018] F) and radionuclide-based therapy (e.g., based on

[0131] I and

[0211] At), all of which can impact the care of cancer patients. In some embodiments,

[0131] I based agents and the corresponding

[0018] F imaging agents possess the same atom connectivity as their non-radioactive (

[0127] V

[0019] F) isotope-bearing counterparts, making them a true theranostic pair.Definitions

[0034] The terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approxi mations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein and that each value is also herein disclosed as “about” that704.101.419particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed Further, unless specified by the term “integer,” the number specified includes fractions or numbers with decimals. For example, the range of “from about 1 to about 5” includes numbers such as 1, 1.1, 1.5, 2.0, 2.2, and so on. As used herein, the term “integer’’ refers to a number that is a whole number, and not a fraction.

[0035] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denote the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5 and are present in such ratio regardless of whether additional components are contained in the compositions.

[0036] In the following description, certain specific details are set forth in order 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 embodim ents. 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.

[0037] 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 dictates otherwise. It should also be noted that704.101.419the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0038] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0039] “Oxo” refers to =0. As will be understood by those skilled in the art, a C=O moiety may be represented as C(O) or CO depending on the context, e.g., -COOH refers to -C(=O)OH, -COOMe refers to -C(=O)OMe, -COH refers to -C(=O)H, etc. Similarly, a S=O moiety may be represented as S(O) or SO. A S(=O)2 moiety may be represented as S(O)2 or SO2.

[0040] “Amino” refers to -NH2.

[0041] “Hydroxy” refers to -OH.

[0042] “Carboxyl” refers to -C( =0)011.

[0043] “Administration” and “administering” refer to the act of giving a drug, prodrug, or other agent, or therapeutic treatment to a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs. Exemplary’ routes of administration to the human body can be through space under the arachnoid membrane of the brain or spinal cord (intrathecal), the eyes (ophthalmic), mouth (oral), skin (topical or transdermal), nose (nasal), lungs (inhalant), oral mucosa (buccal), ear, rectal, vaginal, by injection (e.g., intravenously, subcutaneously, intratumorally, intraperitoneally, etc.) and the like.

[0044] “Aliphatic” refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is completely saturated or that contains one or more units of unsaturation, or combinations thereof. Unless otherwise specified, aliphatic groups contain 1-100 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-20 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-9 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-7 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic704.101.419groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof.

[0045] “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-l -propyl, 2-methyl- 1 -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl- 2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, secbutyl, 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 “Ci-Ce alkyl,” 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 Ci-Cio alkyl. In some embodiments, the alkyl is a C1-C6 alkyl, a C1- alkyl, a C1-C4 alkyl, or a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, - NH2, or -NO2. In some embodiments, the alkyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is independently optionally substituted with halogen.

[0046] “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 or Z or E conformation about the double bond(s) and should be understood to include both isomers.Examples include, but are not limited to, ethenyl f-CH^CEh), 1 -propenyl (-CFhCH^CFh), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range, such as “C2-C6 alkenyl,” 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 is704.101.419designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -Nib, or -NO2. In some embodiments, the alkenyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is independently optionally substituted with halogen.

[0047] “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-C6 alkynyl,” 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 one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is independently optionally substituted with halogen.

[0048] “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 one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. hi some embodiments, the alkylene is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is independently optionally substituted with halogen.704.101.419

[0049] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally- substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is independently optionally substituted with one or more halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is independently optionally substituted with halogen.

[0050] “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 includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0051] “Anticancer agent” or “anti neoplastic agent,” refers to a therapeutic agent that is useful for treating or controlling the growth of cancerous cells.

[0052] “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, anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triph enylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH, or -NO2. In some embodiments, the aryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is independently optionally substituted with halogen704.101.419

[0053] “Carriers” as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Non-limiting examples of physiologically acceptable earners include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, dextrin or cyclodextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium, potassium, calcium, and magnesium; and / or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™ In certain embodiments, the pharmaceutically acceptable carrier is a non-naturally occurring pharmaceutically acceptable carrier.

[0054] “Co-administration” and “co-administering” refer to the administration of at least two agent(s) (e.g., cell cycle checkpoint inhibitor and one or more additional therapeutics) or therapies to a subject. In some embodiments, the co-administration of two or more agents or therapies is concurrent. In other embodiments, a first agent / therapy is administered prior to a second agent / therapy. Those of skill in the art understand that the pharmaceutical compositions and / or routes of administration of the various agents or therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art. In some embodiments, when agents or therapies are co-administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent(s), and / or when co-administration of two or more agents results in sensitization of a subject to beneficial effects of one of the agents via co-administration of the other agent.

[0055] “Cycloalkyl” refers to a partial! y 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, and / 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-C15 fully saturated704.101.419cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cisdecalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3 2]decyl, bicyclo[l.l.l]pentyl, bicyclo[3.1,0]hexyl, bicyclo[3.1.1 jheptyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is independently optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, - OMe, -NH?, or -NO2 In some embodiments, a cycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is independently optionally substituted with halogen.

[0056] “Diastereomers” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers may separate under high-resolution analytical procedures such as electrophoresis and chromatography.704.101.419

[0057] The term “electron-withdrawing group” is recognized in the art and denotes the tendency of a substituent to attract valence electrons from neighboring atoms, i.e., the substituent is electronegative with respect to neighboring atoms. A quantification of the level of electron¬ withdrawing capability is given by the Hammett sigma (G) constant. This well-known constant is described in many references, for instance, J. March, Advanced Organic Chemistry, McGraw Hill Book Company, New York, (1977 edition) pp. 251-259. The Hammett constant values are generally negative for electron donating groups (o[P] = -0.66 for NH2), o[P] indicating para substitution. Exemplary electron-withdrawing groups include nitro, acyl, formyl, sulfonyl, trifluoromethyl, cyano, chloride, and the like.

[0058] “Enantiomers” refers to two stereoisomers of a compound which arenon-superimposable mirror images of one another. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw -Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wiley, S., “Stereochemistry' of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Mixtures of stereoisomers may separate under high-resolution analytical procedures such as electrophoresis, chiral salt formation and chromatography.

[0059] Halo” or “halogen” refers to bromo, chloro, fluoro, iodo, or astato. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. In some embodiments, halogen is chloro.

[0060] “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,tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0061] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0062] “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 includes.704.101.419for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0063] “Heteroaliphatic” is given its ordinary meaning in the art and refers to aliphatic groups as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like). In some embodiments, one or more units selected from C, CH, CH2, and CH3 are independently replaced by one or more heteroatoms (including oxidized and / or substituted forms thereof). In some embodiments, a heteroaliphatic group is heteroalkyl. In some embodiments, a heteroaliphatic group is heteroalkenyl.

[0064] “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, 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 Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur 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)OCH, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is independently optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, a heteroalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the heteroalkyl is independently optionally substituted with halogen.

[0065] “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 group704.101.419consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is a 3- to 8-membered partially or fully saturated ring comprising one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is a 3- to 6-membered partially or fully saturated ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is a 3- to 6-membered fully saturated ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. 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 nonaromatic 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 heterocycloalkyl s include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), 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- Cs fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[ 1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl,704.101.419isothiazolidinyl, 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 -di hydroisobenzofuran- 1 -yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,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 is independently optionally substituted, for example, with one or more 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 independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is independently optionally substituted with halogen.704.101.419

[0066] “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 is a 5- to 10-membered ring comprising one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6- membered ring comprising one or two 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 of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen 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. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. 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 comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6- membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzofb] [ 1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazol yl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,704.101.419oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl -IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is independently optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is independently optionally substituted with halogen. In some embodiments, the heteroaryl is independently optionally substituted with on oxo to form an N-oxide.

[0067] “Increase,” “increases,” “increased,” “increasing,” “improve,” “enhance,” and similar terms indicate an elevation in the specified parameter of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500%, or more.

[0068] “Inhibit,” “inhibition,” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0069] Leaving Group / LG: refers to an atom or group of atoms that detaches from the main or residual part of a substrate during a reaction or elementary step of a reaction. In some embodiments, LG is a halogen. In some embodiments, LG is -Cl. In some embodiments, LG is -OH.

[0070] “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),704.101.419mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFIICIIF?, etc.).

[0071] “One or more” when referring to an optional substituent means that the subject group is independently optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is independently optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is independently optionally substituted with one, two, or three substituents. In some embodiments, the subject group is independently optionally substituted with one or two substituents. In some embodiments, the subject group is independently optionally substituted with one substituent In some embodiments, the subject group is independently optionally substituted with two substituents. In some embodiments, the subject group is independently optionally substituted with three substituents.

[0072] “Pharmaceutical composition or formulation” refers to the combination of an active agent with a carrier, inert or active, making the composition or formulation especially suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.

[0073] “Pharmaceutically acceptable” or “pharmacologically acceptable,” as used herein, refer to compositions that do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject.

[0074] “Pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of skill in the art, “salts” of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.704.101.419

[0075] “Prevent,” “preventing,” or “prevention” of any disease, disorder, and / or condition refers to the prophylactic treatment of the disease, disorder, and / or condition; or delaying the onset or progression of the disease, disorder, and / or condition.

[0076] “Protecting group” or “PG” as used herein, is well known in the art and includes those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999 (“Greene”), the entirety of which is incorporated herein by reference. Suitable amino-protecting groups include methyl carbamate, ethyl carbamante, 9 -fluorenylmethyl carbamate (Fmoc), 9- (2-sulfo) fluorenylmethyl carbamate, 9- (2, 7-dibromo) fluoroenylmethyl carbamate, 2, 7-di-t-butyl- [9- (10, 10-dioxo-10, 10, 10, 10- tetrahydrothioxanthyl) ] methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2, 2, 2-trichloroethyl carbamate (Troc), 2-trimethylsilyl ethyl carbamate (Teoc), 2- phenylethyl carbamate (hZ), 1- (1-adamantyl) -1 -methylethyl carbamate (Adpoc), 1, 1 — dimethyl-2-haloethyl carbamate, 1, l-dimethyl-2, 2-dibromoethyl carbamate (DB-t-BOC), 1, 1-dimethyl-2, 2, 2-trichloroethyl carbamate (TCBOC), 1-methyl-l- (4-biphenylyl) ethyl carbamate (Bpoc), 1- (3, 5-di-t-butylphenyl) -1-methylethyl carbamate (t-Bumeoc), 2- (2’-and 4’-pyridyl) ethyl carbamate (Pyoc), 2- (N, N-dicyclohexylcarboxamido) ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-m ethoxybenzyl carbamate (Moz), p- nitobenzyl carbamate, p bromobenzyl carbamate, p chlorobenzyl carbamate, 2, 4 dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methyl sulfonyl ethyl carbamate, 2- (p-toluenesulfonyl) ethyl carbamate, [2- (1, 3-dithianyl) ] methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2, 4— di methyl thiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1, 1- dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl) benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2- (trifluoromethyl) -6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3, 5-dimethoxybenzyl carbamate, o -nitrobenzyl carbamate, 3, 4 -dimethoxy-6-nitrobenzyl carbamate, phenyl (o- nitrophenyl) methyl carbamate, phenothiazinyl- (10) -carbonyl derivative, N’-p-704.101.419toluenesulfonylaminocarbonyl derivative, N’-phenylaminothiocarbonyl derivative, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyl oxy benzyl carbamate, 2, 2-dimethoxycarbonylvinyl carbamate, o- (N, N-dimethylcarboxamido) benzyl carbamate, 1, 1 -di methyl -3 - (N, N-dimethylcarboxamido) propyl carbamate, 1, 1 -dimethylpropynyl carbamate, di (2— pyridyl) methyl carbamate, 2-furanyl methyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p - (p’-~ m ethoxyphenyl azo) benzyl carbamate, 1 -methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1-methyl-l-cyclopropylmethyl carbamate, 1-methyl-l- (3, 5-dimethoxyphenyl) ethyl carbamate, 1-methyl-l- (p-phenyl zophenyl) ethyl carbamate, 1-methyl-l-phenylethyl carbamate, 1-methyl-l- (4-pyridyl) ethyl carbamate, phenyl carbamate, p- (phenylazo) benzyl carbamate, 2, 4, 6-tri-t-butyl phenyl carbamate, 4- (trimethylammonium) benzyl carbamate, 2, 4, 6-trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, tri fluoroacetamide, phenyl acetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenyl acetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’- dithiobenzyloxycarbonylamino) acetamide, 3- (p-hydroxyphenyl) propanamide, 3- (o- nitrophenyl) propanamide, 2-methyl-2- (o-nitrophenoxy) propanamide, 2-methyl-2- (o-phenyl azophenoxy) propanamide, 4-chlorobutanamide, 3-methyl-3~nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, o- (benzoyloxymethyl) benzamide, 4, 5 diphenyl 3 oxazolin 2 one, N phthalimide, N dithiasuccinimide (Dts), N-2, 3-diphenylmal eimide, N-2, 5-dimethylpyrrole, N-l, 1, 4, 4-tetramethyl disilylazacyclopentane adduct (STABASE), 5-substituted 1, 3 -dimethyl -1, 3, 5-triazacyclohexan-2-one, 5-substituted 1, 3-dibenzyl-l, 3, 5-triazacyclohexan-2-one, 1 -substituted 3, 5-dinitro-4-pyridone, N-methylamine, N-allylamine, N- [2- (trimethylsilyl) ethoxy] methylamine (SEM), N-3- acetoxypropylamine, N- (l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl) amine, quaternary ammonium salts, N-benzylamine, N-di (4-methoxyphenyl) methylamine, N-5- dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [ (4-methoxyphenyl) diphenylmethyl] amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2, 7-dichloro-9-fluorenyl methyleneamine, N -ferrocenylmethyl amino (Fem), N-2--picolylamino N’ -oxide, N-l, 1 -dimethylthiomethyleneamine, N-benzyli den earn ine, N-p-methoxybenzylideneamine, N-704.101.419diphenylmethyleneamine, N- [ (2-pyridyl) mesityl] methyleneamine, N- (N’, N’- di m ethyl am inom ethylene) amine, N, N’-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N- (5-chloro-2-hydroxyphenyl) phenylmethyleneamine, N-cyclohexylideneamine, N- (5, 5-dimethyl-3-oxo-l-cyclohexenyl) amine, N-borane derivative, N-diphenylborinic acid derivative, N- [phenyl (pentacarbonylchromium-or tungsten) carbonyl] amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphorami date, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2, 4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,tri phenyl m ethyl sul fen ami de, 3-nitropyridinesulfenamide (Npys), p-toluenesulfonamide (Ts), benzenesulfonamide, 2, 3, 6, -trimethyl-4-m ethoxybenzenesulfonamide (Mtr), 2, 4, 6-trimethoxybenzenesulfonamide (Mtb), 2, 6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2, 3, 5, 6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2, 4, 6-trimethylbenzenesulfonamide (Mts), 2, 6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2, 2, 5, 7, 8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4’, 8’-dimethoxynaphthylmethyl) benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethyl sulfonamide, and phenacyl sulfonamide.Suitably protected carboxylic acids further include, but are not limited to, silyl, alkyl, alkenyl- and-, and arylalkyl-protected carboxylic acids. Examples of suitable silyl groups include trimethylsilyl, tri ethyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and the like. Examples of suitable alkyl groups include methyl, benzyl, p-methoxybenzyl, 3, 4-di methoxybenzyl, trityl, t-butyl, tetrahydropyran-2-yl. Examples of suitable alkenyl groups include allyl. Examples of suitable aryl groups include optionally substituted phenyl, biphenyl, or naphthyl. Examples of suitable arylalkyl groups include optionally substituted benzyl (e.g., p- methoxybenzyl (MPM), 3, 4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2, 6— di chlorobenzyl, p-cyanobenzyl), and 2-and 4-picolyl.

[0077] Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiom ethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM),704.101.419benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy) methyl (p-AOM), guaiacol methyl (GUM), t-but oxy methyl, 4-pentenyloxym ethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2, 2, 2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 ---methoxycyclohexyl, 4 -methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S - dioxide, 1 - [ (2 -chloro -4 -methyl) phenyl] -4 - methoxypiperidin-4-yl (CTMP), 1, 4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2, 3, 3a, 4, 5, 6, 7, 7a-octahydro-7, 8, 8-trimethyl-4, 7-methanobenzofuran-2-yl, 1 -ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-l-methoxyethyl, 1-methyl-l-benzyloxyethyl, 1-methyl- l-benz.yloxy-2-fluoroethyl, 2, 2, 2-trichloroethyl, 2-trimethylsilyl ethyl, 2- (phenyl sei enyl) ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2, 4-di nitrophenyl, benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2, 6-dichlorobenzyl, p -cyanobenzyl, p -phenylbenzyl, 2 -picolyl, 4 - picolyl, 3 -methyl -2 -picolyl N--oxido, diphenylmethyl, p, p’-dinitrobenzhydryl, 5-dibenzosuberyl, tri phenyl methyl, a-naphthyl diphenylmethyl, p -methoxyphenyl diphenylmethyl, di (p -methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4’-bromophenacyloxyphenyl) diphenylmethyl, 4, 4’, 4”-tris (4, 5-dichlorophthalimidophenyl) methyl, 4, 4’, 4”-tris (levulinoyl oxyphenyl) methyl, 4, 4’, 4”-tris (benzoyloxyphenyl) methyl, 3- (imidazol-l-yl) bis (4’, 4”-dimeth oxy phenyl) methyl, 1, 1— bis (4-m ethoxyphenyl) -l’-pyrenylmethyl, 9-anthryl, 9 (9 phenyl) xanthenyl, 9 - (9 phenyl 10 oxo) anthryl, I, 3 benzodithiolan 2 -yl, benzisothiazolyl S, S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexyl silyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri— p— xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, di chloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4, 4- (ethyl enedithio) pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2, 4, 6 -trimethyl benzoate (mesitoate), alkyl methyl carbonate, 9 - fluorenyl methyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2, 2, 2-tri chloroethyl carbonate704.101.419(Troc), 2- (trimethylsilyl) ethyl carbonate (TMSEC), 2- (phenyl sulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p- methoxybenzyl carbonate, alkyl 3, 4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p --nitrobenzyl carbonate, alkyl S -benzyl thiocarbonate, 4 -ethoxy -1 -napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2 --formylbenzenesulfonate, 2 -- (methylthiomethoxy) ethyl, 4 - (methylthiomethoxy) butyrate, 2- (methylthiomethoxymethyl) benzoate, 2, 6-dichloro-4-methylphenoxyacetate, 2, 6-dichloro-4- (1, 1, 3, 3-tetramethylbutyl) phenoxyacetate, 2, 4— bis (1, 1 -dimethylpropyl) phenoxy acetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E) -2-methyl-2-butenoate, o- (methoxy carbonyl) benzoate, a-naphthoate, nitrate, alkyl N, N, N’, N’-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2, 4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzyl sulfonate, and tosylate (Ts). For protecting 1, 2-or 1, 3 -diols, the protecting groups include methylene acetal, ethylidene acetal, 1-t-butylethylidene ketal, 1-phenylethylidene ketal, (4-methoxyphenyl) ethylidene acetal, 2, 2, 2 --trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 2, 4-dimethoxybenzylidene ketal, 3, 4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1- methoxyethylidene ortho ester, 1 -ethoxyethylidine ortho ester, 1, 2-di ethoxyethylidene ortho ester, a methoxybenzylidene ortho ester, 1 (N, N dimethylamino) ethylidene derivative, a (N, N’-dimethylamino) benzylidene derivative, 2-oxacyclopentylidene ortho ester, di— t— butylsilylene group (DTBS), 1, 3 -- (1, 1, 3, 3 -tetrai sopropyl disil oxanyli dene) derivative (TIPDS), tetra-t-butoxydisiloxane-1, 3-diylidene derivative (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

[0078] In some embodiments, a hydroxyl protecting group is acetyl, t-butyl, tbut oxymethyl, methoxymethyl, tetrahydropyran yl, 1 -ethoxy ethyl, 1 - (2-chloroethoxy) ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2, 4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2, 6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4, 4'-dimethoxytrityl, trimethyl silyl, tri ethyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl,tri isopropyl silyl, benzoylformate, chloroacetyl, tri chloroacetyl, trifiuoroacetyl, pivaloyl, 9-704.101.419fluorenyl methyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl (MMTr), 4, 4-dimethoxytrityl, (DMTr) and 4, 4', 4”-trimethoxytrityl (TMTr), 2 -cyanoethyl (CE or Cne), 2-(trimethylsilyl) ethyl (TSE), 2- (2-nitrophenyl) ethyl, 2- (4-cyanophenyl) ethyl 2- (4-nitrophenyl) ethyl (NPE), 2- (4-nitrophenylsulfonyl) ethyl, 3, 5-dichlorophenyl, 2, 4-dimethyl phenyl, 2-nitrophenyl, 4-nitrophenyl, 2, 4, 6-trimethylphenyl, 2- (2-nitrophenyl) ethyl, butylthiocarbonyl, 4, 4', 4”-tris (benzoyloxy) trityl, di phenyl carbamoyl, levulinyl, 2-(dibromomethyl) benzoyl (Dbmb), 2- (isopropylthiomethoxymethyl) benzoyl (Ptmt), 9-phenylxanthen-9-yl (pixyl) or 9- (p-methoxyphenyl) xanthine-9-y 1 (MOX). In some embodiments, each of the hydroxyl protecting groups is, independently selected from acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl and 4, 4'-dimethoxytrityl. In some embodiments, the hydroxyl protecting group is selected from the group consisting of trityl, monomethoxytrityl and 4, 4'-dimethoxytrityl group. In some embodiments, a protecting group is attached to a sulfur atom of a phosphorothioate group. In some embodiments, a protecting group is attached to an oxygen atom of an intemucleotide phosphorothioate linkage. In some embodiments, a protecting group is attached to an oxygen atom of the internucleotide phosphate linkage. In some embodiments a protecting group is 2-cyanoethyl (CE or Cne), 2-trimethylsilylethyl, 2-nitroethyl, 2-sulfonylethyl, methyl, benzyl, o-nitrobenzyl, 2- (p-nitrophenyl) ethyl (NPE or Npe), 2-phenylethyl, 3- (N-tert-butylcarboxamido) -1 -propyl, 4-oxopentyl, 4-methylthio-l-butyl, 2-cyano-l, 1 -dimethylethyl, 4-N-methylaminobutyl, 3- (2-pyridyl) -1-propyl, 2- [N-methyl-N- (2-pyridyl) ] aminoethyl, 2- (N-formyl, N-methyl) aminoethyl, or 4- [N-methyl-N- (2, 2, 2-trifluoroacetyl) amino] butyl.

[0079] Protected aldehydes are well known in the art and include those described in detail in Greene (1999). Suitable protected aldehydes further include, but are not limited to, acyclic acetals, cyclic acetals, hydrazones, imines, and the like. Examples of such groups include dimethyl acetal, diethyl acetal, diisopropyl acetal, dibenzyl acetal, bis(2-nitrobenzyl) acetal, 1,3- di oxanes, 1,3-di oxolanes, semicarbazones, and derivatives thereof.

[0039] Protected carboxylic acids are well known in the art and include those described in detail in Greene (1999). Suitable protected carboxylic acids further include, but are not limited to, optionally substituted Ci-Cgaliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides, and the like. Examples of such ester groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl ester, wherein each group is704.101.419optionally substituted. Additional suitable protected carboxylic acids include oxazolines and ortho esters.

[0040] Protected thiols are well known in the art and include those described in detail in Greene (1999). Suitable protected thiols further include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates, and the like. Examples of such groups include, but are not limited to, alkyl thioethers, benzyl and substituted benzyl thioethers, triphenylmethyl thioethers, and trichloroethoxycarbonyl thioester, to name but a few.

[0080] “Reduce,” “reduces,” “reduced,” “reduction,” “inhibit,” and similar terms refer to a decrease in the specified parameter of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 100%.

[0081] “Stereoisomer” refers to compounds which have identical chemical constitution, but differ with regards to the arrangement of the atoms or groups in space. These “stereoisomers” have a “stereogenic center” which may be a chiral center.

[0082] “Subject” broadly refers to any animal, including but not limited to, human and non¬ human animals (e g., mice, rats, dogs, pigs, cats, cows, horses, sheep, poultry / , fish, crustaceans, etc.). As used herein, the term “patient” typically refers to a subject that is being treated for a disease or condition.

[0083] “Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.

[0084] “Theranostic agent” refers to compounds that are able to detect as well as treat a disease or condition. For example, the compounds disclosed herein can contain two different halogens, such as a fluorine atom, an iodine atom and an astatine atom. A theranostic agent may be one compound labeled with

[0018] F used for imaging and another theranostic agent may be labeled with

[0131] I or

[0211] At for treatment. Both theranostic agents maintain the same atom connectivity regardless of the radioisotope and are referred to as a “theranostic pair”

[0085] “Effective amount” or “therapeutically effective amount” refers to the amount of a composition sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.

[0086] “Treat,” “treatment,” or “treating" refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of) reduce severity of, and / or reduce704.101.419incidence of one or more symptoms or features of a disease, disorder, and / or condition.Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.Compounds

[0087] Among other things, the present disclosure provides compounds (e g., prosthetic groups) that can be used to construct diagnostic and / or therapeutic agents. As used herein, in some embodiments, a prosthetic group that can be used to construct a diagnostic agent for e g., radioimaging is a diagnostic prosthetic group. As used herein, in some embodiments, a prosthetic group that can be used to construct a therapeutic agent for e.g., radiotherapy is a therapeutic prosthetic group. In some embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:,4 |Formula (I),wherein:Ring A is phenyl, pyridyl, or pyrimidinyl, wherein Ring A is optionally and independently substituted with 1-5 R’;R1is Cl, Br, or I; or a radioisotope selected from the group consisting of

[0076] Br,

[0077] Br,

[0082] Br,

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, and [21 l]At;each R2is independently F or radioisotope

[0018] F;m is 1 or 2;each R3is independently hydrogen, PG, Ci-Ce alkyl, or C3-C10 cycloalkyl;n is 0, 1, or 2;R4is -C(=O)R’, -C(=O)OR’, -C(=O)N(R’)2, - N(R’)2, -NR’C(=O)R’, -NR’C(=O)N(R’)2, - OC(=O)R’, -OC(=O)OR’, or -LS-OH;704.101.419Lsis absent or Ci-Ce alkylene optionally substituted with 1-12 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -O-, -N(R’)-, -C(=O)-, - C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, -N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, - OC(=O)N(R’)S(O)2-, -S(O)-, -S(O)2-, or -S(O)2N(R’)-;L is absent or Ci-C2o alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -CR’=CR’-,§*, -O-, -N(R’)-, -C(=O)-, -C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, - S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-25 amino acids;each -Cy- is independently a bivalent ring selected from C3-C2o cycloalkylene, Ce-C2o arylene, 3- 20 membered heteroarylene, or 3-20 membered heterocycloalkylene, wherein each group is optionally and independently substituted with 1-20 Rs;Q is halogen, R’, -OR’, -SR’, -N=C=O, -NC, -N3, -OS(O)2R’, -OP(O)(OR’)R’, O, O\R1, PG, or leavinggroup, wherein each of O O, norbornene, trans-cyclooctene, andN'xNR' is optionally and indpendently subsituted with 1-5 R’;each PG is independently a protecting group;each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, -S(O)2R, or PG; each R is independently hydrogen, halogen, or an optionally substituted group selected from Ci- Cio aliphatic, C1-C10 heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl, wherein each group is optionally and independently704.101.419substituted with 1-20 Rs, or two R groups are optionally and independently taken together to form a covalent bond or =0; ortwo or more R groups on the same atom are optionally and independently taken together with the atom to form a 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the atom, 0-5 heteroatoms; ortwo or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the intervening atoms, 0-5 heteroatoms;each Rsis independently halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OCi-Ce alkyl, -OC3-C10 cycloalkyl, -OCe-Cio aryl, -0-5-10 membered heteroaryl, -0-3-20 membered heterocycloalkyl, -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-C6 alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, - NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2Ci-C6 alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2C6-CIO aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci- C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci- C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-Ce alkyl)S(=O)25-10 membered heteroaryl, -N(Ci- Cealkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)Ci-Ce alkyl, -C(=O)OH, -C(=O)OCi- C6alkyl, -C(=O)NH2, -C(=O)NHCI-C6alkyl, -C(=O)N(Ci-C6alkyl)2; wherein each Ci-C6alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.

[0088] In some embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:704.101.419(R30)n(R2)mFormula (I),wherein:Ring A is phenyl, pyridyl, or pyrimidinyl, wherein Ring A is optionally and independently substituted with 1-5 R’;R1is Cl, Br, or I; or a radioisotope selected from the group consisting of

[0076] Br,

[0077] Br,

[0082] Br,

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, and

[0211] At;each R2is independently F or radioisotope

[0018] F;m is 1 or 2;each R3is independently hydrogen, PG, Ci-Ce alkyl, or C3-C10 cycloalkyl;n is 0, 1, or 2;R4is -C(=O)R’, -C(=O)OR’, -C(=O)N(R’)2, - N(R’)2, -NR’C(=O)R’, -NR’C(=0)N(R’)2, - OC(=O)R’, -OC(=O)OR’, or -LS-OH;Lsis absent or Ci-Cg alkylene optionally substituted with 1-12 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -O-, -N(R’)-, -C(=O)-, - C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, -N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, - OC(=O)N(R’)S(O)2-, -S(O)-, -S(O)2-, or -S(O)2N(R’)-;L is absent or Ci-C2o alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -CR’=CR’-,, -O-, -N(R’)-, -C(=O)-, -C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, - S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-25 amino acids;each -Cy- is independently a bivalent ring selected from C3-C20 cycloalkylene, C6-C20 arylene, 3- 20 membered heteroarylene, or 3-20 membered heterocycloalkylene, wherein each group is optionally and independently substituted with 1-20 Rs;704.101.419Q is halogen, R’, -OR’, -SR’, -N=C=O, -NC, -N3, -OS(O)2R’, -OP(O)(OR’)R’, O, OA Rnorbomene, trans-cyclooctene,N R', -C(R’)=C(1, or PG, wherein O O.+ + each of 0, 0, norbornene, trans-cyclooctene, and R' is optionally and indpendently subsituted with 1-5 R’;each PG is independently a protecting group;each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, -S(O)2R, or PG; each R is independently hydrogen, halogen, or an optionally substituted group selected from Ci- Cio aliphatic, Ci-Cio heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl, wherein each group is optionally and independently substituted with 1-20 Rs, or two R groups are optionally and independently taken together to form a covalent bond or =0; ortwo or more R groups on the same atom are optionally and independently taken together with the atom to form a 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the atom, 0-5 heteroatoms; ortwo or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the intervening atoms, 0-5 heteroatoms;each Rsis independently halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OCi-Ce alkyl, -OC3-C10 cycloalkyl, -OCe-Cio aryl, -0-5-10 membered heteroaryl, -0-3-20 membered heterocycloalkyl, -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)C6-Cio aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-C6 alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCi-C6alkyl, -S(=O)2N(Ci-C6alkyl)2, -704.101.419NH2, -NHC1-C6 alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2C1-C6 alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci- C6alkyl)S(=O)2Ci-C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci- C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6 alkyl)S(=O)25-10 membered heteroaryl, -N(Ci- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)Ci-Ce alkyl, -C(=O)OH, -C(=O)OCi- C6alkyl, -C(=O)NH2, -C(=O)NHCI-C6alkyl, -C(=O)N(Ci-C6alkyl)2; wherein each Ci-C6alkyl, Ci-C6heteroalkyl, Ce-Cio aryl, C3-Cio cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-Cio cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.

[0089] Certain embodiments for various variables in various formulas (e.g., Formulas (I), (Hyper-R*), etc.) are described herein as examples. Those skilled in the art reading the present disclosure will be able to select an embodiment for each variable and combine them; such combinations are within the scope of the present disclosure. Those skilled in the art also appreciate that embodiments described for one variable (e.g., R) may be utilized for other variables that can be such variable (e.g., R' that can be R).

[0090] In some embodiments, a provided compound has a structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R2)mFormula (II),wherein each variable is independently as described herein.

[0091] In some embodiments, a provided compound has a structure of Formula (Il-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (Il-e), Formula (Il-f), Formula (Il-g), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof704.101.419R4 / r>p3\(R2)m (R2)m (R2)m Formula (Il-a) Formula (Il-b) Formula (II-c) Formula (Il-d) R4(R2)mR4Formula (Il-e)Formula (Il-f) Formula (Il-g)wherein each variable is independently as described herein.

[0092] In some embodiments, a provided compound has a structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R2)mFormula (III),wherein each variable is independently as described herein.

[0093] In some embodiments, a provided compound has a structure of Formula (Ill-a), Formula (Ill-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (Ill-a) Formula (Ill-b)wherein each variable is independently as described herein.

[0094] In some embodiments, a provided compound has a structure of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:704.101.419Formula (IV),wherein each variable is independently as described herein.

[0095] In some embodiments, a provided compound has a structure of Formula (IV-a), Formula (IV-b), Formula (IV-c), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (IV-a) Formula (IV-b) Formula (IV-c) wherein each variable is independently as described herein.

[0096] In some embodiments, a provided compound has a structure of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (V),wherein each variable is independently as described herein.

[0097] In some embodiments, a provided compound has a structure of Formula (V-a), Formula (V-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:R4Formula (V-a) Formula (V-b)wherein each variable is independently as described herein.

[0098] In some embodiments, a provided compound has a structure of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:704.101.419Formula (VI),wherein each variable is independently as described herein.

[0099] In some embodiments, a provided compound has a structure of Formula (Vl-a), Formula (Vl-b), Formula (VI-c), Formula (Vl-d), Formula (Vl-e), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(OR3LFormula (Vl-a) Formula (Vl-b) Formula (VI-c) Formula (Vl-d) OR3Formula (Vl-e)wherein each variable is independently as described herein.

[0100] In some embodiments, a provided compound has a structure of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (VII),wherein each variable is independently as described herein.

[0101] In some embodiments, a provided compound has a structure of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:704.101.419(R2)mFormula (VIII),wherein each variable is independently as described herein.

[0102] In some embodiments, a provided compound has a structure of:704.101.419OMeOMer1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0103] In some embodiments, a provided compound has a structure of:solvate, or stereoisomer thereof.

[0104] In some embodiments, a provided compound has a structure of:704.101.419salt, solvate, or stereoisomer thereof.

[0105] In some embodiments, a provided compound has a structure of:704.101.419pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each variable is independently as described herein.

[0106] In some embodiments, the present disclosure provides compounds comprising hypervalent halogen atoms.

[0107] In some embodiments, a hypervalent halogen compound is a compound of Formula (Hyper-R*), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R3O)n(R2)mFormula (Hyper-R*),wherein:Ring A is phenyl, pyridyl, or pyrimidinyl, wherein Ring A is optionally and independently substituted with 1-5 R’;is a single bond or double bond;each R2is independently F or radioisotope

[0018] F;m is 1 or 2;each R3is independently hydrogen, PG, Ci-Ce alkyl, or C3-C10 cycloalkyl;n is 0, 1, or 2;L* is -C(=O)O-, -C(=NR’)O-, -N=C(R’)O-, -N=C(N(R’)2)O-, -NR’C(=O)NR’-, -OC(=O)O-, or - L-O-;R* is I; or a radioisotope selected from the group consisting of

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, and

[0211] At;X is a counterion;L is absent or C1-C20 alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -CR’=CR’-,, -O-, -N(R’)-, -C(=O)-, -C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-,704.101.419N(R’)C(=0)N(R’)S(0)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(0)-, -S(0)2-, - S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-20 amino acids;each -Cy- is independently a bivalent ring selected from C3-C20 cycloalkylene, C6-C20 arylene, 3- 20 membered heteroarylene, or 3-20 membered heterocycloalkylene, wherein each group is optionally and independently substituted with 1-20 Rs;Q is halogen, R’, -OR’, -SR’, -N=C=O, -NC, -N3, -OS(O)2R’, -OP(O)(OR’)R’„ O, norbomene, trans-cyclooctene,leaving group, wherein each of ° °, norbomene, trans-cyclooctene, andR1is optionally and indpendently subsituted with 1-5 R’;each PG is independently a protecting group;each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C=(O)OR, -C(=O)N(R)2, -S(O)2R, or PG; each R is independently hydrogen, halogen, or an optionally substituted group selected from Ci- C10 aliphatic, C1-C10 heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl, wherein each group is optionally and independently substituted with 1-20 Rs, or two R groups are optionally and independently taken together to form a covalent bond or =0; ortwo or more R groups on the same atom are optionally and independently taken together with the atom to form a 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the atom, 0-5 heteroatoms; ortwo or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-20 membered ring optionally704.101.419substituted with 1-20 Rs, wherein the ring has, in addition to the intervening atoms, 0-5 heteroatoms;each Rsis independently halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OCi-Ce alkyl, -OC3-C10 cycloalkyl, -OCe-Cio aryl, -0-5-10 membered heteroaryl, -0-3-20 membered heterocycloalkyl, -OC(=O)Ci-C6alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)C6-Cio aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, - NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2Ci-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci- C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci- C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-Ce alkyl)S(=O)25-10 membered heteroaryl, -N(Ci- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)Ci-C6 alkyl, -C(=0)0H, -C(=O)OCi- C6alkyl, -C(=0)NH2, -C(=O)NHCI-C6alkyl, -C(=O)N(Ci-C6alkyl)2; wherein each Ci-C6alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C1-C6 heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.

[0108] In some embodiments, a hypervalent halogen compound is a compound of Formula (Hyper-R*), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:.2'\rxJmFormula (Hyper-R*),wherein:Ring A is phenyl, pyridyl, or pyrimidinyl, wherein Ring A is optionally and independently substituted with 1-5 R’;is a single bond or double bond;each R2is independently F or radioisotope

[0018] F;704.101.419m is 1 or 2;each R3is independently hydrogen, PG, Ci-Ce alkyl, or C3-C10 cycloalkyl;n is 0, 1, or 2;L* is -C(=O)O-, -C(=NR’)O-, -N=C(R’)O-, -N=C(N(R’)2)O-, -NR’C(=O)NR’-, -OC(=O)O-, or - L-O-;R* is I; or a radioisotope selected from the group consisting of [123JI,

[0124] I,

[0125] I,

[0131] I,

[0210] At, and [21 l]At;X is a counterion;L is absent or C1-C20 alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -CR’=CR’-,, -O-, -N(R’)-, -C(=O)-, -C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, - S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-20 amino acids;each -Cy- is independently a bivalent ring selected from C3-C20 cycloalkylene, C6-C20 arylene, 3- 20 membered heteroarylene, or 3-20 membered heterocycloalkylene, wherein each group is optionally and independently substituted with 1-20 Rs;O OQ-i [4+ Q is halogen, R’, -OR’, -SR’, -N=C=O, -NC, -N3, -OS(O)2R’, -OP(O)(OR’)R’„ O, Ooptionally and indpendently subsituted with 1-5 R’;each PG is independently a protecting group;each R’ is independently R, -OR, -OC(=O)R, -C( O)R, -C=(O)OR, -C(=O)N(R)2, -S(O)2R, or PG;704.101.419each R is independently hydrogen, halogen, or an optionally substituted group selected from Ci- Cio aliphatic, C1-C10 heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl, wherein each group is optionally and independently substituted with 1-20 Rs, or two R groups are optionally and independently taken together to form a covalent bond or =0; ortwo or more R groups on the same atom are optionally and independently taken together with the atom to form a 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the atom, 0-5 heteroatoms; ortwo or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the intervening atoms, 0-5 heteroatoms;each Rsis independently halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OCi-Ce alkyl, -OC3-C10 cycloalkyl, -OCe-Cio aryl, -0-5-10 membered heteroaryl, -0-3-20 membered heterocycloalkyl, -OC(=O)Ci-C6 alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)C6-Cio aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-C6 alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, - NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2C6-Cio aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci- C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci- C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-Ce alkyl)S(=O)25-10 membered heteroaryl, -N(Ci- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)Ci-Ce alkyl, -C(=O)OH, -C(=O)OCi- C6alkyl, -C(=0)NH2, -C(=O)NHCI-C6alkyl, -C(=O)N(Ci-C6alkyl)2; wherein each Ci-C6alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.I* and704.101.419

[0109] In some embodiments, L* is -C(=O)O-. In some embodiments, -L*-R*- is -C(=O)O-R*-, wherein R* is as described herein. In some embodiments, L* is -C(=;:NR’)O-, wherein R’ is as described herein. In some embodiments, L* is -C(=NR’)O- and R’ is hydrogen, Cj-Cio alkyl, C1-C10 heteroalkyl, Cs-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 Rs, wherein each Rsis independently as described herein. In some embodiments, L* is -C(=NH)O-. In some embodiments,? is -C(=NR’)O- andR’ is C1-C10 alkyl, C1-C10 heteroalkyl, Ce-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, -L’-R+- is -C(=NR’)O-R*- wherein each of R’ and R’ is as described herein. In some embodiments, I,' is -N=C(R’)O-. In some embodiments, L* is -N =C(R’)O- and R’ is hydrogen, C1-C10 alkyl, Ci-C 10 heteroalkyl, Cs-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 Rs, wherein each Rsis independently as described herein. In some embodiments, L* is -N=C(R’)O- and R’ is C1-C10 alkyl. In some embodiments, L* is -N=C(Me)O-. In some embodiments, -L*-R*- is -N=C(R’)O-1 -. In some embodiments, L* is -N=C(NI(R’)2)O-. In some embodiments, L* is - N=C(N(R’)2)O- and each R’ is independently hydrogen, C1-C10 alkyl, Ci-C 10 heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloal kyl, optionally substituted with 1-20 Rs, wherein each Rsis independently as described herein. In some embodiments, I. / is -N=C(N(R’)2)O- and each R’ is independently hydrogen or C1-C10 alkyl. In some embodiments, L* is -N=C(NHMe)O-. In some embodiments, -L*-R*- is — N=C(N(R’)2)O-R*-, wherein each of R’ and R* is independently as described herein. In some embodiments, L* is -NR’C(=O)NR’-. In some embodiments, -NR’C(=O)NR’- and each R’ is independently hydrogen, Ci-C 10 alkyl, C1-C10 heteroalkyl, Ce-Cioaryl, C3-C 10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 Rs, wherein each Rsis independently as described herein. In some embodiments, L* is -OC(=O)O-In some embodiments, L* is -L-O-. In some embodiments, I, is -L-O- and L is Ci-Ce alkylene optionally substituted with 1-12 Rs; or one or more methylene units of L are optionally and independently replaced with -O-, -N(R’)-, -C(=O)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, -N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S(O)-, -S(O)2-, or - S(O)2N(R’)-, wherein each of R’ and Rsis independently as described herein. In some704.101.419embodiments, L* is -L-O- and L is Ci-Ce alkylene optionally substituted with 1-6 Rs, wherein each Rsis independently as described herein. In some embodiments, 1 / is -L-O- and L is C1-C3 alkylene optionally substituted with 1-4 Rs, wherein each Rsis independently as described herein. In some embodiments, 1 / is -CII2-O- and -CII2- is optionally substituted with 1-2 Rs, wherein each Rsis independently as described herein. In some embodiments, L* is -CH2-O- and -CH2- is optionally substituted with 1-2 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, L* is -CH2-O- and -CH2- is substituted with 1-2 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, L* is -CH2-O- and -CH2- is substituted with 2 identical electron-withdrawing groups. In some embodiments, L’ is -CH2-O- and -CH2- is substituted with 2 identical groups selected from halogen, -OH, -CN, -OMe, methyl, or\ / F3C CF3halomethyl. In some embodiments, L* is O In some embodiments,lJ is O some embodiments, -L*-R*- is -L-O-R’-, wherein L and R* are independently as described herein. In some embodiments, R* is I; or a radioisotope selected from the group consisting of

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, and [21 l]At. In some embodiments, R’ is I. In some embodiments, R* is a radioisotope selected from the group consisting of

[0123] I,

[0124] I,

[0125] I, and

[0131] I. In some embodiments, R* is a radioisotope selected from the group consisting of

[0210] At and

[0211] At. In some embodiments, X is O'. In some embodiments, X is OAc’.X

[0110] In some embodiments, X is a counterion. In some embodiments, X is an anion. In some embodiments, X is a counterion to hypervalent halogen atom In some embodiments, X is in an ionized form disassociated from R*. In some embodiments, X is Br’. In some embodiments, X is Cl’. In some embodiments, X is F. In some embodiments, X is OAc’. In some embodiments, X forms a bond with R\ In some embodiments, X is F. In some embodiments, X is Cl. In some embodiments, X is Br. In some embodiments, X is OAc.

[0111] In some embodiments, X is a cation. In some embodiments, X is a counterion to borate. In some embodiments, X is Li+. In some embodiments, X is Na+. In some embodiments, X is K7.

[0112] In some embodiments, a provided compound has a structure of:704.101.419, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each variable is independently as described herein.In some embodiments, a provided compound has a structure of:pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each variable is independently as described herein.

[0113] In some embodiments, a provided compound has a structure of704.101.419pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each variable is independently as described herein.Ring A

[0114] In some embodiments, Ring A is phenyl, pyridyl, or pyrimidinyl, wherein Ring A is optionally and independently substituted with 1-5 R’ and each R’ is independently as described herein. In some embodiments, Ring A is phenyl optionally and independently substituted with 1-5 R’ and each R’ is independently as described herein. In some embodiments, Ring A is phenyl optionally and independently substituted with 1-2 R’ and each R’ is independently as described herein. In some embodiments, Ring A is phenyl optionally and independently substituted with 1-2 R’ groups independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl (e.g., -CF3), -CN, -NO2, -OH, -O-C1-C4 alkyl, -N(RSB)2, -C(O)ORSB, and - S(O)2N(RSB)2, wherein each RSBis independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl (e.g., - CF3), or phenyl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is phenyl independently substituted with 1-2 R’ groups independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl (e.g., -CF3), -CN, -NO2, -OH, -O-C1-C4 alkyl, -N(RSB)2, -C(O)ORSB, and -S(O)2N(RSB)2, wherein each RSBis independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl (e.g., -CF3), or phenyl.

[0115] In some embodiments. Ring A is pyridyl optionally and independently substituted with 1-5 R’ and each R’ is independently as described herein. In some embodiments, Ring A is pyridyl optionally and independently substituted with 1-3 R’ and each R’ is independently as described herein In some embodiments, Ring A pyridyl, wherein Ring A is optionally and independently substituted with 1-3 R’ groups independently selected from halogen, C1-C4 alkyl,704.101.419C1-C4 haloalkyl (e.g., -CF3), -CN, -NO2, -OH, -O-C1-C4 alkyl, -N(RSB)2, -C(O)ORSB, and - S(O)2N(RSB)2, wherein each RSBis independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl (e.g., - CF3), or phenyl.

[0116] In some embodiments, Ring A is pyrimidinyl optionally and independently substituted with 1-5 R’ and each R’ is independently as described herein. In some embodiments, Ring A is pyrimidinyl optionally and independently substituted with 1-2 R’ and each R’ is independently as described herein. In some embodiments, Ring A pyrimidinyl, wherein Ring A is optionally and independently substituted with 1-2 R’ groups independently selected from halogen, C1-C4 alkyl, Ci-C4haloalkyl (e.g., -CF3), -CN, -NO2, -OH, -O-C1-C4 alkyl, -N(RSB)2, -C(O)ORSB, and -S(O)2N(RSB)2, wherein each RSBis independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl (e.g., -CF3), or phenyl.

[0117] (OR3),R1

[0118] In some embodiments,(R )m, wherein each variable isindependently as described herein. In some embodiments,(R2)m, whereineach variable is independently as described herein, hi some embodiments,(R2)m isR4(R)m, wherein each variable is independently as described herein. In some704.101.419(R30)n(0R3)nAvR1VKAXR1— ( A A- X JR4\embodiments,(Ris (R, wherein each variable is independently as described (R3m R4herein. In some embodiments,(Ris (R, wherein each variable isindependently as described herein. In some embodiments,wherein each variable is independently as described herein. In some embodiments,wherein each variable is independently as described herein.wherein each variable is independently as described herein.

[0119] wherein each variable isindependently as described herein. In some embodiments,704.101.419wherein each variable is independently as described herein. In some embodiments,, wherein each variable is independently as described herein.

[0120] In some embodiments,wherein each variable isindependently as described herein. In some embodiments,wherein each variable is independently as described herein. In some embodiments,R1, wherein each variable is independently as described herein. Insome embodiments,wherein each variable is independently as described herein.704.101.419

[0121] In some embodiments,wherein each variable isindependently as described herein. In some embodiments,wherein each variable is independently as described herein. In some embodiments,, wherein each variable is independently as described herein.

[0122] In some embodiments,wherein each variable isindependently as described herein. In some embodiments,wherein each variable is independently as described herein. In some embodiments,ism-1, wherein each variable is independently as described herein.In some embodiments,wherein each variable is independently704.101.419(OR3)nR TTR1 / R2fn^r2as described herein. In some embodiments,, wherein eachvariable is independently as described herein. In some embodiments,, wherein each variable is independently as described herein.

[0123] In some embodiments,(R)m is (R2)m, wherein each variable is independently as described herein.

[0124] In some embodiments,is independently as described herein.

[0125] In some embodiments.independently as described herein. In some embodiments.704.101.419 wherein each variable is independently as described herein. In some embodiments,3 (R3O)noWRT T(Ris F wherein each variable is independently as described herein. Inwherein each variable is independently asvariable is independently as described herein. In some embodiments,, wherein each variable is independently as described herein. In some embodiments,OMe, wherein each variable is independently as704.101.419described herein. In some embodiments,wherein each variable isindependently as described herein. In some embodiments,wherein each variable is independently as described herein. In some embodiments,OEtOMe, wherein each variable is independently as described herein. Indescribed herein. In some embodiments,wherein eachvariable is independently as described herein. In some embodiments,704.101.419OMe?wherein each variable is independently as described herein. In some embodiments,OMe;wherein each variable is independently as described herein. Inwherein each variable is independently asdescribed herein. In some embodiments,wherein eachvariable is independently as described herein. In some embodiments,OMe, wherein each variable is independently as described herein. In somewherein each variable is independently as704.101.419described herein. In some embodiments,wherein eachvariable is independently as described herein. In some embodiments,OMe, wherein each variable is independently as described herein. In someembodiments,, wherein each variable is independently asdescribed herein. In some embodiments,wherein each variableis independently as described herein. In some embodiments,wherein each variable is independently as described herein. In some embodiments,704.101.419, wherein each variable is independently as described herein. In some embodiments,, wherein each variable is independently asdescribed herein. In some embodiments,wherein each variable is independently as described herein. In some embodiments,wherein each variable is independently as described herein. In some embodiments,, wherein each variable is independently as OMedescribed herein. In some embodiments,wherein each704.101.419variable is independently as described herein. In some embodiments,OMe, wherein each variable is independently as described herein. In someembodiments,, wherein each variable is independently as OMedescribed herein. In some embodiments,wherein each variableis independently as described herein. In some embodiments,wherein each variable is independently as described herein. In some embodiments,, wherein each variable is independently as described704.101.419wherein each variable is independently as described herein. In some embodiments,wherein each variable is independently as describedherein. In some embodiments,independently as described herein. In some embodiments,wherein each variable is independently as described herein. In some embodiments,F, wherein each variable is independently as described herein.704.101.419

[0126] in some embodiments,independently as described herein. In some embodiments,wherein each variable is independently as described herein. In some embodiments,wherein each variable is independently as described herein

[0127] wherein each variableis independently as described herein. In some embodiments,wherein each variable is independently as described herein.

[0128] wherein each variableis independently as described herein. In some embodiments,704.101.419, wherein each variable is independently as described herein. In someembodiments,wherein each variable is independently asdescribed herein. In some embodiments,variable is independently as described herein.

[0129] In some embodiments,wherein each variableis independently as described herein. In some embodiments,wherein each variable is independently as described herein.

[0130] In some embodiments,wherein each variable is (R3O)nindependently as described herein. In some embodiments,(Ris704.101.419wherein each variable is independently as described herein. In some embodiments,, wherein each variable is independently as described herein. Insome embodiments,(R2)m, wherein each variable is independently asdescribed herein. In some embodiments,wherein each variableis independently as described herein. In some embodiments,wherein each variable is independently as described herein. In some embodiments,, wherein each variable is independently as described herein. In (R3O)nXsome embodiments.is wherein each variable is independently asdescribed herein. In some embodiments,wherein each variable704.101.419wherein each variable is independently as described herein. In some embodiments,(R3O)nL R X OMe, wherein each variable is independently as described herein.(R3O)nXIn some embodiments,(R2)m is OMe, wherein each variable is independently as described herein.R3

[0131] In some embodiments, each R1is Cl, Br, or I; or a radioisotope selected from the group consisting of

[0076] Br,

[0077] Br,

[0082] Br,

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, and [21 l]At. In some embodiments, each R1is Cl, Br, or I; or a radioisotope selected from the group consisting of

[0076] Br,

[0077] Br,

[0082] Br,

[0123] I,

[0124] 1,

[0125] I,

[0131] I,

[0210] At, and

[0211] At, and at least one of R1and R2is a radioisotope. In some embodiments, R1is Cl. In some embodiments, R1is Br. In some embodiments, R1is I. In some embodiments, R1is

[0076] Br,

[0077] Br, or

[0082] Br. In some embodiments, Rlis

[0076] Br. In some embodiments, R1is

[0077] Br. In some embodiments, R1is

[0082] Br. In some embodiments, R1is

[0123] I,

[0124] I,

[0125] I, or

[0131] I. In some embodiments, Rlis

[0123] I. In some embodiments, R1is

[0124] I. In some embodiments, R1is

[0125] I. Tn some embodiments, R1is

[0131] I. In some embodiments, R1is

[0210] At or

[0211] At. In some embodiments, R1is

[0210] At. In some embodiments, R1is

[0211] At.R2

[0132] In some embodiments, R2is F or radioisotope

[0018] F. In some embodiments, R2is F. In some embodiments, R2is radioisotope

[0018] F. In some embodiments, R2is

[0018] F and R1is704.101.419Cl, Br, or I. In some embodiments, R2is F and R1is

[0076] Br,

[0077] Br,

[0082] Br,

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, or

[0211] At. In some embodiments, at least one of R1and R2is a radioisotope. In some embodiments, one of R1and R2is a radioisotope and one of R1and R2is not a radioisotope.m

[0133] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.R3

[0134] In some embodiments, R3is independently hydrogen, PG, Ci-Cg alkyl, or C3-C10 cycloalkyl. In some embodiments, R3is independently hydrogen or Ci-Ce alkyl. In some embodiments, R3is independently C3-C10 cycloalkyl. In some embodiments, R3is hydrogen. In some embodiments, R3is independently Me.n

[0135] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.R4

[0136] In some embodiments, R4is a stabilizing group as described herein. In some embodiments, R stabilizes a radioisotope. In some embodiments, R4is stabilizes a radioisotope of iodine. In some embodiments, R4is stabilizes a radioisotope of astatine. In some embodiments, R4is -C(=O)R’, -C(=O)OR’, -C(=O)N(R’)2, - N(R’)2, -NR’C(=O)R’, - NR’C(:;:O)N(R’)2, -OC(= O)R’, -OC( =O)OR’, or -LS-OH, where each variable is independently as described herein. In some embodiments, R4is -C(=O)R’, wherein R’ is as described herein. In some embodiments, R4is -C(:=:O)R’ and R’ is C1-C10 alkyl, C1-C10 heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R4is -C(=O)OR’ and R’ is hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, Ce-Cio aryl, Cs-Cio cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R4is -C(=O)OR’ and R’ is hydrogen or Ci-Ce alkyl. In some embodiments, R4is704.101.419-C(=O)OH. In some embodiments, R4is -C(=O)OR’ and R’ is Ci-Ce alkyl. In some embodiments, R4is -C(=O)OMe. In some embodiments, R4is -C(=O)OEt. In some embodiments, R4is ~-C(=O)N(R’)2 and each R’ is independently hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, Cs-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, or two R’ are taken together with the nitrogen atom they are attached to form 3-8 membered heterocycloalkyl optionally substituted with 1-5 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, R4is -C(=O)N(R’)2 and each R’ is independently hydrogen or Ci-Ce alkyl. In some embodiments, R4is -C(=O)NH2. In some embodiments, R4is -C(=O)NHMe. In some embodiments, R4is -C(=O)NMe2In some embodiments, R4is - C(=O)N(R’)2 and two R’ are taken together with the nitrogen atom they are attached to form 3-8 membered heterocycloalkyl optionally substituted with 1-5 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, R4is -N(R’) and each R’ is independently hydrogen, Ci-C10 alkyl, C1-C10 heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, or two R’ are taken together with the nitrogen atom they are attached to form 3-8 membered heterocycloalkyl optionally substituted with 1-5 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, R4is NR’C(=O)R’, and each R’ is independently hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, Ce-Cioaryl, C3-C 10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, or two R’ are taken together with the intervening atoms they are attached to form 3-8 membered heterocycloalkyl optionally substituted with 1-5 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, R4is NR’C(=O)R’, and each R’ is independently hydrogen or C1-C6 alkyl. In some embodiments, R is -NHC(=O)Me. In some embodiments, R4is -NR’C(=O)N(R’)2, and each R’ is independently hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, Ce-Cjoaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, or two R’ are taken together with the intervening atom or atoms they are attached to form 3-8 membered heterocycloal kyl optionally substituted with 1-5 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, R4is -NR’C(=:O)N(R’)2, and each R’ is independently hydrogen or Ci-Cb alkyl. In some embodiments, R4is -NHC(=O)NHMe. In some embodiments, R4is ~OC(=O)R’, and R’ is hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, Ce-Cioaryl, C3-C 10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R4is OC(=O)R’, and R’ is hydrogen or Ci-Ce alkyl. In some embodiments, R4is -OC(=O)Me. Tn some704.101.419embodiments, R4is ~OC(=O)OR’, and R’ is hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R4is -LS-OH, wherein L is as described herein. In some embodiments, R4is -Ls-OH and L is Ci-CN alkylene optionally substituted with 1-12 Rs; or one or more methylene units of L are optionally and independently replaced with -O-, -N(R’)-, -C(=O)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, -N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, - OC(=O)N( ’)S(O)2-, -S(O)-, -S(O)2-, or -S(O)2N(R’)-. In some embodiments, R4is -LS-OH and L is Ci-Ce alkylene optionally substituted with 1-6 Rs, wherein Rsis as described herein. In some embodiments, R4is -LS-OH and Lsis C1-C3 alkylene optionally substituted with 1-4 Rs, wherein Rsis as described herein. In some embodiments, R4is -CH2-OH and -CH2- is optionally substituted with 1-2 R, wherein Rsis as described herein. In some embodiments, R4is -CII2-OH and -CH2- is optionally substituted with 1-2 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, R4is -CH2-OH and -CH2- is substituted with 1-2 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, R4is'^^OH in some embodiments, R4is F3C CF3^OHL

[0137] In some embodiments, L is absent or C1-C20 alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -CR’=CR’-, -O-, -N(R’)-, -C(=O)-, -C(=S)-, -C(=O)O-, -C(=O)N(R’)-, - N(R’)C(=O)O-, -N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-25 amino acids, wherein each variable is independently as described herein. In some embodiments, L is absent. In some embodiments, L is Ci-C2o alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -CR’=CR’-,, -O-, -N(R’)-, -C(=O)-, -C(=S)-, -C(=O)O-, - C(=O)N(R’)-, -N(R’)C(=O)O-, -N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-25 amino acids, wherein each variable is704.101.419independently as described herein. In some embodiments, L is C1-C20 alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with — CR’=CR’-,, -O-, -N(R’)-, -C(=O)-, -C(=S)-, -C(=O)O-, - C(=O)N(R’)-, -N(R’)C(=O)O-, -N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, - OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(R’)-, or -Cy-, wherein each variable is independently as described herein. In some embodiments, L is Ci-C20 alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with an amino acid sequence comprising 2-25 amino acids. In some embodiments, L is C1-C20 alkylene optionally substituted with 1-30 Rs, wherein each variable is independently as described herein. In some embodiments, L is C1-C20 alkylene optionally substituted with 1-30 Rs, wherein each variable is independently as described herein. In some embodiments, L is C1-C10 alkylene optionally substituted with 1-20 Rs, wherein each variable is independently as described herein. In some embodiments, L is C1-C10 alkylene optionally substituted with 1-10 Rs, wherein each variable is independently as described herein. In some embodiments, L is Ci-Ce alkylene optionally substituted with 1-5 Rs, wherein each variable is independently as described herein. In some embodiments, L is Ci-Ce alkylene. In some embodiments, one or more methylene units of L are independently replaced with - CR’=CR’-, -O-, -N(R’)-, -C(=O)-, -C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, -N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(R’)-, or -Cy-, wherein each variable is independently as described herein. In some embodiments, one or more methylene units of L are independently replaced with CR’=CR’- or. In some embodiments, one or more methylene units of the group are independently replaced with -O-, -N(R’)-, -C(=O)-, -C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, -N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(R’)-, or -Cy-, wherein each variable is independently as described herein. In some embodiments, one or more methylene units of L are independently replaced with -O-, -N(R’)-, -C(=O)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, -N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, wherein each variable is independently as described herein. In some embodiments, one or more methylene units of L are independently replaced with -O-, -C(=O)-, -N(R’)-, or -C(=O)N(R’)-,704.101.419wherein each variable is independently as described herein. In some embodiments, one or more methylene units of L are independently replaced with -O-, -C(=O)-, -N(R’)-, or -C(=O)N(R’)-, wherein each R’ is independently hydrogen, Ci-Ce alkyl, or a protecting group. In some embodiments, one or more methylene units of L are independently replaced with -O-, -C(=O)-, -N(R’)-, or -C(=O)N(R’)-, wherein each R’ is independently hydrogen or C1-C3 alkyl. In someembodiments, one or more methylene units of L are independently replaced withP, wherein p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, one or more methylene unitsof L are independently replaced with, wherein r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, one or more methylene units of L are independently replaced withR'R', wherein r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and each R’ is independently as described herein. In some embodiments, one or more methylene units of L are N~1,r 1,independently replaced withR'R', wherein r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and each R’ is independently hydrogen, Ci-Ce alkyl, or a protecting group. In some embodiments, one or more methylene units of L are independently replaced with -C(=O)N(R’)-, wherein each R’ is independently as described herein. In some embodiments, one or more methylene units of L are independently replaced with -C(=O)N(R’)-, where each R’ is independently hydrogen, Ci-Ce alkyl, or a protecting group. In some embodiments, one or more methylene units of L are independently replaced with -C(=O)N(R’)-, where each R’ is independently hydrogen or C1-C3 alkyl. In some embodiments, one or more methylene units ofO0qL are independently replaced withRl, wherein q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein each R’ is independently as described herein. In some embodiments, one or moreO° Nqmethylene units of L are independently replaced withRl, wherein q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and each R’ is independently hydrogen, Ci-Ce alkyl, or a protecting group. In704.101.419some embodiments, one or more methylene units of L are independently replaced withOR, wherein q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and each R’ is independently hydrogen or C1-C3 alkyl. In some embodiments, one or more methylene units of L areO O* A AIindependently replaced with R', wherein each R’ is independently as described herein. In some embodiments, one or more methylene units of L are independently replaced O OI,with R1, and each R’ is independently hydrogen, Ci-Ce alkyl, or a protecting group. In some embodiments, one or more methylene units of L are independently replaced withO O* A A1R', and each R’ is independently hydrogen or C1-C3 alkyl. In some embodiments, one or more methylene units of L are independently replaced with -Cy-, wherein each -Cy- is independently as described herein. In some embodiments, one or more methylene units of L are independently replaced with -Cy-, wherein each -Cy- is independently a bivalent ring selected from C3-C10 cycloalkylene, Ce-Cio arylene, 3-10 membered heteroarylene, or 3-10 membered heterocycloalkylene, wherein each group is optionally and independently substituted with 1-5 Rsand each Rsis independently as described herein. In some embodiments, one or more methylene units of L are independently replaced with -Cy-, wherein each -Cy- is independently a bivalent ring selected from C3-C6 cycloalkylene, phenylene, 3-6 membered heteroarylene, or 3-6 membered heterocycloalkylene, wherein each group is optionally and independently substituted with 1-3 Rsand each Rsis independently as described herein. In some embodiments, one or more methylene units of L are independently replaced with -Cy-, wherein each -Cy- is independently a bivalent ring selected from phenylene, 3-6 membered heteroarylene, or 3-6 membered heterocycloalkylene. In some embodiments, one or more methylene units of L areindependently replaced withIn some embodiments, one or more methylene units704.101.419of L are independently replaced withIn some embodiments, one or more methyleneunits of L are independently replaced with O. In some embodiments, one or more methylene units of L are independently replaced with an amino acid sequence comprising 2-25 amino acids. In some embodiments, one or more methylene units of L are independently replaced with an amino acid sequence comprising 8-25 amino acids. In some embodiments, one or more methylene units of L are independently replaced with an amino acid sequence comprising 8-15 amino acids. In some embodiments, an amino acid sequence is capable of undergoing self-catalyzed covalent bond (e.g., isopetide) formation in a manner described in a SpyTag / SpyCatcher system. As will be understood by those skilled in the art, SpyTag / SpyCatcher type system is well known in the art. See, e.g., Hatlem et al., Int. J. Mol. Sci., 2019, 20, 2129; Keeble, et al., Bioconjugate Chem., 2023, 34, 1019-1036; Zakeri et al., Proceedings of the National Academy of Sciences, 109.12 (2012): E690-E697, the entirety of each of which is hereby incorporated by reference. In some embodiments, one or more methylene units of L are independently replaced with an amino acid sequence having at least about 80% sequence identify with the sequence of AHIVMVDAYKPTK (SEQ ID NO: 1), AHIVMVDAYKPTK (SEQ ID NO: 1), AHIVMVDAYKPTK(SEQ ID NO: 1), ATHIKFSKRD (SEQ ID NO: 2), KLGDIEFIKVNK (SEQ ID NO: 3), VPTIVMVDAYKRYK (SEQ ID NO: 4), KLGSIEFIKVNK(SEQ ID NO: 5), DIPATYEFTDGKHYITNEPIPPK (SEQ ID NO: 6), DIPATYEFTDGKHYITNEPLPPK (SEQ ID NO: 7), or VPTIVMVDAYKRYK (SEQ ID NO: 4), KLGDIEFIKVNK (SEQ ID NO: 3), KLGSIEFIKVNK (SEQ ID NO: 5), KLGYIEFYKVEK(SEQ ID NO: 8), AHIVMVDA (SEQ ID NO: 9), RSGAHIVMVDAGSR (SEQ ID NO: 10), RSGAHIVMVDA (SEQ ID NO: 11), AHIVMVDAGSR (SEQ ID NO: 12), AHIVMVDAYKP (SEQ ID NO: 13), or GDAHIVMVDA (SEQ ID NO: 14). In some embodiments, one or more methylene units of L are independently replaced with an amino acid sequence having at least about 90% sequence identify with the sequence of AHIVMVDAYKPTK (SEQ ID NO: 1), AHIVMVDAYKPTK (SEQ ID NO: 1), AHIVMVDAYKPTK (SEQ ID NO: 1), ATHIKFSKRD (SEQ ID NO: 2), KLGDIEFIKVNK (SEQ ID NO: 3), VPTIVMVDAYKRYK (SEQ ID NO: 4), KLGSIEFIKVNK (SEQ ID NO: 5),704.101.419DIPATYEFTDGKHYITNEPIPPK (SEQ ID NO: 6), DIPATYEFTDGKHYITNEPLPPK (SEQ ID NO: 7), or VPTIVMVDAYKRYK (SEQ ID NO: 4), KLGDIEFIKVNK (SEQ ID NO: 3), KLGSIEFIKVNK (SEQ ID NO: 5), KLGYIEFYKVEK (SEQ ID NO: 8), AHIVMVDA (SEQ ID NO: 9), RSGAHIVMVDAGSR (SEQ ID NO: 10), RSGAHIVMVDA (SEQ ID NO: 11), AHIVMVDAGSR (SEQ ID NO: 12), AHIVMVDA YKP (SEQ ID NO: 13), or GD AHIVMVDA (SEQ ID NO: 14). In some embodiments, one or more methylene units of L are independently replaced with an amino acid sequence having at least about 95% sequence identify with the sequence of AHIVMVDAYKPTK (SEQ ID NO: 1), AHIVMVDAYKPTK (SEQ ID NO: 1), AHIVMVDAYKPTK (SEQ ID NO: 1), ATHIKFSKRD (SEQ ID NO: 2), KLGDIEFIKVNK (SEQ ID NO: 3), VPTIVMVDAYKRYK (SEQ ID NO: 4), KLGSIEFIKVNK (SEQ ID NO: 5), DIPATYEFTDGKHYITNEPIPPK (SEQ ID NO: 6), DIPATYEFTDGKHYITNEPLPPK (SEQ ID NO: 7), or VPTIVMVDAYKRYK (SEQ ID NO: 4), KLGDIEFIKVNK (SEQ ID NO: 3), KLGSIEFIKVNK (SEQ ID NO: 5), KLGYIEFYKVEK (SEQ ID NO: 8), AHIVMVDA (SEQ ID NO: 9), RSGAHIVMVDAGSR (SEQ ID NO: 10), RSGAHIVMVDA (SEQ ID NO: 11), AHIVMVDAGSR (SEQ ID NO: 12), AHIVMVDA YKP (SEQ ID NO: 13), or GD AHIVMVDA (SEQ ID NO: 14). In some embodiments, one or more methylene units of L are independently replaced with an amino acid sequence of AHIVMVDAYKPTK (SEQ ID NO: 1), AHIVMVDAYKPTK (SEQ ID NO: 1), AHIVMVDAYKPTK (SEQ ID NO: 1), ATHIKFSKRD (SEQ ID NO: 2), KLGDIEFIKVNK (SEQ ID NO: 3), VPTIVMVDAYKRYK (SEQ ID NO: 4), KLGSIEFIKVNK (SEQ ID NO: 5), DIPATYEFTDGKHYITNEPIPPK (SEQ ID NO: 6), DIPATYEFTDGKHYITNEPLPPK (SEQ ID NO: 7), or VPTIVMVDAYKRYK (SEQ ID NO: 4), KLGDIEFIKVNK (SEQ ID NO: 3), KLGSIEFIKVNK (SEQ ID NO: 5), KLGYIEFYKVEK (SEQ ID NO: 8), AHIVMVDA (SEQ ID NO: 9), RSGAHIVMVDAGSR (SEQ ID NO: 10), RSGAHIVMVDA (SEQ ID NO: 11), AHIVMVDAGSR (SEQ ID NO: 12), AHIVMVDA YKP (SEQ ID NO: 13), or GD AHIVMVDA (SEQ ID NO: 14). In some embodiments, one or more methylene units of L are independently replaced with an amino acid sequence and the amino acid sequence is bonded to the remaining parts of the molecule through a terminal amino group, a terminal carboxyl group, or an internal residual of the amino acid sequence as valence permits. In some embodiments, one or more methylene units of L are independently replaced with an amino acid sequence and the amino acid sequence is bonded to the remaining parts of the molecule through a terminal amino group and a terminal carboxyl group. In some embodiments,704.101.419one or more methylene units of L are independently replaced with an amino acid sequence and the amino acid sequence is bonded to the remaining parts of the molecule through internal residues of the amino acid sequence as valence permits.

[0138] In some embodiments, L is -CH2-. In some embodiments, L is -CH2CH2-. In some embodiments, L is -C(CH3)2-. In some embodiments, L is -CH2CH2CH2-. In some embodiments, L is -CH2CH2CH2CH2-. In some embodiments, L is -CH2C(CH.3)2-. In some embodiments, L is -CH2CH2CH2CH2CH2-. In some embodiments, L is -CH2CH2C(CH3)2-. In some embodiments, L is -CH2CH2CH2CH2CH2CH2-. In some embodiments, L is - O CH2CH2CH2C(CH3)2-. In some embodiments, L isIn some embodiments, L is O OR', wherein R’ is as described herein. In some embodiments, L isRl, wherein R’ is hydrogen or C1-C3 alkyl. In some embodiments, L isk / uzr k and each of u, r, and k is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Insome embodiments, L isand each of r and k is independently 0, 1, 2, 3, 4, 5, 6,7, 8, 9 or 10. In some embodiments, L isand r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.In some embodiments, L isand r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some Oembodiments, L isRland k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is as describedOherein. In some embodiments, L is R' and k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is704.101.419ohydrogen or C1-C3 alkyl. In some embodiments, L isR' and k is 0, 1, 2, 3, 4, 5, 6,O7, 8, 9 or 10, and R’ is as described herein. In some embodiments, L isR' and k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and R’ is hydrogen or C1-C3 alkyl. In some embodiments, L is OR', and each of r and k is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 Oand R’ is as described herein. In some embodiments, L isR', and each of r and k is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is hydrogen or C1-C3 alkyl. Insome embodiments, LisR' and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ isas described herein. In some embodiments, L isRland r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is hydrogen or C1-C3 alkyl. In some embodiments, L isR' and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is as described herein.In some embodiments, LisRland r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and OR’ is hydrogen or Ci -C3 alkyl. In some embodiments, L isR', and each of r and k is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is as described herein. In Osome embodiments, LisRl, and each of r and k is independently 0,704.101.4191, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is hydrogen or C1-C3 alkyl. In some embodiments, L is ORland r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is as describedOherein. In some embodiments, L is R' and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is hydrogen or C1-C3 alkyl. In some embodiments, L isOand r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is as describedherein. In some embodiments, L isand r is 0, 1, 2, 3, 4, 5, 6, 7,O8, 9 or 10 and R’ is hydrogen or C1-C3 alkyl. In some embodiments, L is R' and each of s and k is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is as described herein. InOsome embodiments, L is R1and each of s and k is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is hydrogen or C1-C3 alkyl. In some embodiments, L isOR' and each of r and k is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and O1 ' 'rv / kR’ is as described herein. In some embodiments, L isR' and each of r and k is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is hydrogen or C1-C3 alkyl. In someembodiments, L is, wherein each of k, r, and t is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is as described herein. In some embodiments, L is704.101.419o, wherein each of k, r, and t is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and R’ is hydrogen or C1-C3 alkyl. In some embodiments, L iswherein each of u, r, and k is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.u

[0139] In some embodiments, u is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, us is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, u is 6. In some embodiments, u is 7. In some embodiments, u is 8. In some embodiments, u is 9. In some embodiments, u is 10.r

[0140] In some embodiments, r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, r is 7. In some embodiments, r is 8. In some embodiments, r is 9. In some embodiments, r is 10.k

[0141] In some embodiments, k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4. In some embodiments, k is 5. In some embodiments, k is 6. In some embodiments, k is 7. In some embodiments, k is 8. In some embodiments, k is 9. In some embodiments, k is 10.. S'704.101.419

[0142] In some embodiments, s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4. In some embodiments, s is 5. In some embodiments, s is 6. In some embodiments, s is 7. In some embodiments, s is 8. In some embodiments, s is 9. In some embodiments, s is 10.

[0143] In some embodiments, t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 5. In some embodiments, t is 6. In some embodiments, t is 7. In some embodiments, t is 8. In some embodiments, t is 9. In some embodiments, t is 10.0

[0144] In some embodiments, halogen, R’, -OR’, -SR’, -N=C=O, -NC, -N3, -OS(O)2R’, - o o$4- OP(O)(OR’)R’, O O, norbomene, trans-cyclooctene,Ri C(R’)=C(R’)2,, PG, or leaving group, wherein each of O, norbornene,\ trans-cyclooctene, and R' is optionally and indpendently subsituted with 1-5 Rs. In some embodiments, Q is halogen. In some embodiments, Q is Cl. In some embodiments, Q is Br. In some embodiments, Q is I. In some embodiments, Q is R’ wherein R’ is as described herein. In some embodiments, Q is -OR’ wherein R’ is as described herein. In some embodiments, Q is -OR’ and R’ is hydrogen, Ci-Ce alkyl, or a protecting group. In some embodiments, Q is -SR’ wherein R’ is as described herein. In some embodiments, Q is -SR’ and R’ is hydrogen, Ci-Ce alkyl, or a protecting group. In some embodiments, Q is -N=C=O. In704.101.419some embodiments, Q is -NC. In some embodiments, Q is -N3. In some embodiments, Q is -OS(O)2R’, wherein R’ is as described herein. In some embodiments, Q is -OS(O)2R’ and R’ is hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, or phenyl optionally substituted with 1-5 Rsas described herein. In some embodiments, Q is -OS(O)2R’ and R’ is hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, or phenyl optionally substituted with 1-5 Ci-Ce alkyl or halogen. In some embodiments, Q is -OS(O)2CH3. In some embodiments, Q is -OS(O)2CF3. In some embodiments, Q is -OS(O)2Ph.°xx,04-0's'O.In some embodiments, QisCH3. In some embodiments, Q is -OP(O)(OR’)R’, wherein each R’ is independently as described herein. In some embodiments, Q is -OP(O)(OR’)R’, wherein each R’ is independently hydrogen, Ci-Ce alkyl, or phenyl optionally substituted with 1-5 Rsas described herein. In some embodiments, Q is -OP(O)(OR’)R’, wherein each R’ is independently hydrogen, Ci-Ce alkyl, or phenyl optionally substituted with 1-5 Ci-Ce alkyl or halogen. In some embodiments, Q is -0P(0)(0Et)CH3. In some embodiments, Q is -OP(O)(OEt)Et. In some embodiments, Q is -OP(O)(OEt)Ph. In some embodiments, Q is 0C<-+0optionally substituted with 1-5 R’ and each R’ is independently as described herein. In OH- some embodiments, In some embodiments, Q is0optionally substituted with 1-5 halogen 0 0 iA+or C1-C3 alkyl. In some embodiments, Q is 0. In some embodiments, Q is 0 optionally substituted with 1-5 R’ and each R’ is independently as described herein. In some O[ -!embodiments, In some embodiments, Q is0optionally substituted with 1-5 halogen or Ci-704.101.419oC3 alkyl. In some embodiments, Qis0. In some embodiments, Q is norbomene optionally substituted with 1-5 R’, wherein each R’ is independently as described herein. Insome embodiments, Q isoptionally substituted with 1-5 R’, wherein each R’ isindependently as described herein. In some embodiments, Q isoptionally substitutedwith 1-5 halogen or C1-C3 alkyl. In some embodiments, Q isIn some embodiments, Q is trans-cyclooctene optionally substituted with 1-5 R’, wherein each R’ is independently asdescribed herein. In some embodiments, Q isoptionally substituted with 1-5 R’,wherein each R’ is independently as described herein. In some embodiments, Q isoptionally substituted with 1-5 halogen or C1-C3 alkyl. In some embodiments, Q is'NIn some embodiments,is Q is N R' and R’ is as described herein. In someN,'Nembodiments,is Q is 'N R’ and R’ is hydrogen, Ci-Ce alkyl, phenyl optionally substituted with 1-5 Rs, or 5-10 membered heteroaryl optionally substituted with 1-5 Rs. In someN.'NN\embodiments,is Q is N R’ and R’ is hydrogen, Ci-Ce alkyl, phenyl optionally substituted with 1-5 Rsas described herein, or 5-10 membered heteroaryl optionally substituted704.101.419with 1-5 Rsas described herein. In some embodiments,is Q is hydrogen, Ci-Ce alkyl, phenyl optionally substituted with 1-5 Ci-Ce alkyl or halogen, or 5-10 membered heteroaryl optionally substituted with 1-5 Ci-Cg alkyl or halogen. In someembodiments,is Q is N In some embodiments, Q is -C(R’)=C(R’)2, wherein each R’ is independently as described herein. In some embodiments, Q is -C(R’)=C(R’)2 and each R’ is hydrogen, halogen, or Ci-Ce alkyl. In some embodiments, Q is -C(R’)=CH2 and R’ is hydrogen, halogen, or Ci-Ce alkyl. In some embodiments, Q is -C(F)=CH2. In some— piembodiments, Q is -CH=CH2. In some embodiments, Q is5, wherein R’ is as described _ — _ o'herein. In some embodiments, Q is5and R’ is hydrogen or Ci-Ce alkyl. In some - I Iembodiments, Q is5. In some embodiments, Q is a protecting group. In some embodiments, Q is a leaving group as described herein. Various leaving groups may be utilized in accordance with the present disclosure. For example, in some embodiments, a leaving group is a halogen. In some embodiments, LG is Cl. In some embodiments, LG is Br. In some embodiments, LG is I. In some embodiments, LG is -S(O)2R wherein R is as described herein and is not H. In some embodiments, R is optionally substituted Ci-Ce aliphatic. In some embodiments, R is optionally substituted phenyl. In some embodiments, a leaving group is 3-nitro-l,2,4-triazole, imidazole, alkyltriazole, tetrazole, pentafluorobenzene, or 1-hy dr oxy b enz otri azol e.-Z-0

[0145] In some embodiments, -L-Q is -CFLBr. In some embodiments, -L-Q is -CH2NC.O OIn some embodiments, -L-Q isRlwherein R’ is as described herein. In some704.101.419o oembodiments, -L-Q isR', wherein R’ is hydrogen or C1-C3 alkyl. In someONwkNCO embodiments,-L-Q is O. In some embodiments, L-Q isH and k is1, 2, 3, 4, 5, or 6. In some embodiments, -L-Q is and r is 0, 1,O** N k N3 2, 3, 4, 5, or 6 and R’ is as described herein. In some embodiments, -L-Q isH and k is O2, 3, 4, 5, or 6. In some embodiments,-L-Q isRl, r is 0, 1, 2, 3, 4, 5, or 6Oand R’ is as described herein. In some embodiments, -L-Q isR', r is 0, 1,2, 3, 4, 5, or 6 and R’ is hydrogen or C1-C3 alkyl. In some embodiments, -L-Q isand k is 1, 2, 3, 4, 5, or 6. In some embodiments,-L-Q isRland r is 0, 1, 2, 3, 4, 5, or 6, and R’ is as described herein. In some embodiments, -L-Q isR' and r is 0, 1, 2, 3, 4, 5, or 6, and R’ is hydrogen, Ci-Ce alkyl, or aprotecting group. In some embodiments, -L-Q is R' and r is 0, 1, 2, 3, 4,704.101.4195, or 6, and R’ is hydrogen or C1-C3 alkyl. In some embodiments,-L-Q is 4 O-1- In someembodiments, -L-Q is and k is 2, 3, 4, 5, or 6. In some embodiments, -L-Q is, r is 0, 1, 2, 3, 4, 5, or 6 and R’ is hydrogen or C1-C3 alkyl.In some embodiments,-L-Q is hydrogen, Ci-Ce alkyl, phenyl optionally substituted with 1-5 Rsas described herein, or 5-10 membered heteroaryl optionally substituted with 1-5 Rsas described herein. In someOembodiments, -L-Q is, k is 0, 1, 2, 3, 4, 5, or 6, and R’ is hydrogen, Ci-Ce alkyl, phenyl optionally substituted with 1-5 Ci-Ce alkyl or halogen, or 5-10 membered heteroaryl optionally substituted with 1-5 Ci-Ce alkyl or halogen.R

[0146] Various variable groups can be R’ as described herein. In some embodiments, R’ is hydrogen. In some embodiments, R’ is R as described herein. In some embodiments, R’ is - OR, wherein R as described herein. In some embodiments, R’ is -OC(=O)R, wherein R as described herein. In some embodiments, R’ is -C(=O)R, wherein R as described herein. In some embodiments, R’ is -C=(O)OR, wherein R as described herein. In some embodiments, R’ is -C(=:O)N( )2, wherein R as described herein In some embodiments, R’ is -S(O)? R, wherein R as described herein. In some embodiments, R’ is a protecting group as described herein.704.101.419R

[0147] Various variable groups can be R as described herein. Various embodiments for R are extensively described herein, including in various sections for other variables that can be R (e.g., R’).

[0148] In some embodiments, R is hydrogen. In some embodiments, R is not hydrogen.

[0149] In some embodiments, each R is independently hydrogen, halogen, or an optionally substituted group selected from Ci-Cio aliphatic, Ci-Cio heteroaliphatic, Ce-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl. In some embodiments, each R is independently hydrogen, halogen or an optionally substituted group selected from C1-C10 aliphatic, Ci-Cio heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-Ci-Ce aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatom s-Cj-Cs aliphatic. In some embodiments, each R is independently hydrogen, halogen, or an optionally substituted group selected from C1-C10 aliphatic, Ci-Cio heteroalkyl having 1-3 heteroatoms, C6-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl having 1-6 heteroatoms, and 3-20 membered heterocycloalkyl having 1-6 heteroatoms. In some embodiments, each R is independently hydrogen, halogen, or an optionally substituted group selected from C1-C10 alkyl, Ci-C 10 heteroalkyl having 1-3 heteroatoms, Cs-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl having 1-6 heteroatoms, and 3-20 membered heterocycloalkyl having 1-6 heteroatoms.

[0150] In some embodiments, R is optionally substituted C1-6 aliphatic, hi some embodiments, R is optionally substituted Ci-6 alkyl. In some embodiments, R is optionally substituted methyl. In some embodiments, R is optionally substituted ethyl. In some embodiments, R is optionally substituted n-propyl. In some embodiments, R is optionally substituted isopropyl. In some embodiments, R is n-butyl. In some embodiments, R is t-butyl. In some embodiments, R is pentyl. In some embodiments, R is hexyl.

[0151] In some embodiments, R is optionally substituted C1-C6 heteroaliphatic having 1- 3 (e g., 1, 2, or 3) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, R is optionally substituted Ci-Ce heteroaliphatic having 1-3 (e.g., 1, 2, or 3) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some704.101.419embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur.

[0152] In some embodiments, R is optionally substituted C3-C10 (e.g., C4 -C10, C3-C9, C3-C7, or 3, 4, 5, 6, 7, 8, 9, or 10-membered) cycloalkyl. In some embodiments, a cycloalkyl group is a cycloalkyl group. In some embodiments, a cycloalkyl group is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., C4-C10, C3-C9, C3-C7, or 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered cycloalkyl ring. In some embodiments, a cycloalkyl group is saturated. In some embodiments, it is partially unsaturated. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is optionally substituted cyclopentyl. In some embodiments, R is optionally substituted cyclohexyl. In some embodiments, R is optionally substituted cycloheptyl. In some embodiments, R is cyclopropyl. In some embodiments, R is cyclobutyl. In some embodiments, R is cyclopentyl. In some embodiments, Ris cyclohexyl. In some embodiments, R is cycloheptyl.

[0153] In some embodiments, R is optionally substituted 3-10 (e.g., 3-9, 3-6, 3-5, or 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered heterocycloalkyl having 1-4 (e g., 1, 2, 3, or 4, etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, R is optionally substituted 3-10 (e.g., 3-9, 3-6, 3-5, or 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered heterocycloalkyl having 1-4 (e.g., 1, 2, 3, or 4, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, a heterocycloalkyl group is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently a 3- 10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered heterocycloalkvl ring having 1-4 (e.g., 1, 2, 3, or 4 etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl group is saturated. In some embodiments, it is partial ly unsaturated. In some embodiments, a heterocycloalkyl ring has one heteroatom. In some embodiments, a heterocycloalkyl ring has two or more heteroatoms. In some embodiments, a heterocycloalkyl ring has three or more heteroatoms. In some embodiments, a heterocycloalkyl ring has four or more heteroatoms. In some embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur.704.101.419

[0154] In some embodiments, R is optionally substituted Cg-Cio (e.g., Ce, Cw, etc.) aryl. In some embodiments, R is optionally substituted Ce-Cio aryl. In some embodiments, an aryl ring is monocyclic. In some embodiments, an aryl ring is bicyclic. In some embodiments, an aryl ring is polycyclic. In some embodiments, each monocyclic unit is independently a 6-membered aromatic ring. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is optionally substituted 10-membered aryl. In some embodiments, R is optionally substituted naphthyl. In some embodiments, R is naphthyl.

[0155] In some embodiments, R is optionally substituted 5-10 (e.g., 5-9, or 5, 6, 7, 8, 9, or 10 etc.) membered heteroaryl having 1-6 (e g., 1-6, 1-5, 1-4, or 1, 2, 3, 4, 5, or 6 etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, R is 5-10 (e.g., 5-9, or 5, 6, 9, 10 etc.) membered heteroaryl having 1-4 (e.g., 1, 2, 3, or 4, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a heteroaryl ring is monocyclic. In some embodiments, a heteroaryl ring is bicyclic. In some embodiments, a heteroaryl ring is polycyclic. In some embodiments, each monocyclic unit is independently a 5- or 6-membered aromatic ring having 0-4 heteroatoms, e.g., independently selected from nitrogen, oxygen and sulfur, wherein at least one monocyclic unit contains 1-4 heteroatoms. In some embodiments, R is optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a heteroaryl ring has one heteroatom. In some embodiments, a heteroaryl ring has two or more heteroatoms. In some embodiments, a heteroaryl ring has three or more heteroatoms. In some embodiments, a heteroaryl ring has four or more heteroatoms. In some embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur.

[0156] In some embodiments, R is optionally substituted Ce-Cio aryl-Ci-Ce aliphatic, wherein the aryl and aliphatic are independently as described herein. In some embodiments, R is optionally substituted Ce-Cio aiyl-Ci-Ce alkyl.704.101.419

[0157] In some embodiments, R is optionally substituted 5-10 membered heteroaryl having 1-6 (e.g., 1, 2, 3, 4, 5, or 6) heteroatom s-Ci -Ct, aliphatic wherein the heteroaryl and aliphatic are independently as described herein. In some embodiments, R is optionally substituted 5-10 membered heteroaryl having 1-5 heteroatoms-Ci-Cc, aliphatic. In some embodiments, R is optionally substituted 5-6 membered heteroaryl having 1-4 heteroatom s-Ci-Ce aliphatic. In some embodiments, R is optionally substituted 5-10 membered heteroaryl having 1-6 (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms-Ci-Cc alkyl wherein the heteroaryl and aliphatic are independently as described herein. In some embodiments, is optionally substituted 5-10 membered heteroaryl having 1-5 heteroatom s-Ci -6 alkyl. In some embodiments, Ris optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms-Ci-Ce alkyl. Various suitable heteroaryl and aliphatic groups are as described herein.

[0158] In some embodiments, two R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered ring having, in addition to the atom, 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms. In some embodiments, two R groups on two atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered ring having, in addition to the intervening atoms, 0-4 (e.g, 0, 1, 2, 3, or 4) heteroatoms

[0159] As described herein, in various instances, two R groups, or two groups that are or can be R (e.g., R’), can be taken together with their intervening atom(s) to form an optionally substituted ring as described herein. In some embodiments, a formed ring is substituted (in addition to groups attached to the intervening atom (s)). In some embodiments, a formed ring is unsubstituted. In some embodiments, a formed ring is 3-membered. In some embodiments, a formed ring is 4-membered. In some embodiments, a formed ring is 5-membered. In some embodiments, a formed ring is 6-membered. In some embodiments, a formed ring is 7- membered. In some embodiments, a formed ring is 8-membered. In some embodiments, a formed ring is 9-membered. In some embodiments, a formed ring is 10-membered. In some embodiments, a formed ring is saturated. In some embodiments, a formed ring is partially unsaturated. In some embodiments, a formed ring is aromatic. In some embodiments, a formed ring is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., 3-8, 3-6, 5-6, or 3, 4,704.101.4195, 6, 7, 8, 9, or 10, etc.) membered ring which is independently saturated, partially unsaturated or aromatic and has 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., 3-10, 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered ring which is independently saturated, partially unsaturated or aromatic and has 0-4 (e.g., 0, 1, 2, 3, or 4, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, each monocyclic ring unit is independently 3-7 membered. In some embodiments, each monocyclic ring unit is independently 3-6 membered. In some embodiments, each monocyclic ring unit is independently 5-7 membered. In some embodiments, each monocyclic unit is independently saturated or partially unsaturated. In some embodiments, at least one monocyclic unit is saturated. In some embodiments, at least one monocyclic unit is partially unsaturated. In some embodiments, at least one monocyclic unit is aromatic. In some embodiments, a formed ring has, in addition to the intervening atom(s), 0-4 (e.g., 0, 1, 2, 3, or 4, etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, there are no additional heteroatoms. In some embodiments, there is one additional heteroatom. In some embodiments, there are 2 additional heteroatoms. In some embodiments, there are 3 additional heteroatoms. In some embodiments, there are 4 additional heteroatoms. In some embodiments, there are 5 additional heteroatoms. In some embodiments, there are 6 or more additional heteroatoms. In some embodiments, an additional heteroatom is nitrogen. In some embodiments, an additional heteroatom is oxygen. In some embodiments, an additional heteroatom is sulfur. For example, in some embodiments, R2and R3are taken together with their intervening atoms to form a ring as described herein.

[0160] As described herein, various groups may be optionally substituted. Substituents are routinely utilized in chemistry including in development of various therapeutics. Many substituents can be utilized in accordance with the present disclosure. In some embodiments, an optionally substituted group is un substituted. In some embodiments, an optionally substituted group is substituted. Substituents are preferably those that result in the formation of compounds for a desired property, activity, use, etc., as described herein. In some embodiments, compounds are stable for therapeutic use as described herein. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a substituent is a hydrocarbon704.101.419group. In some embodiments, a substituent comprises a heteroatom. In some embodiments, a substituent comprises multiple heteroatoms. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, sulfur, phosphorus and silicon. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, and sulfur. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, fluorine, chlorine, bromine, iodine, nitrogen, oxygen, and sulfur. In some embodiments, the total number of carbon and non-halogen heteroatom (s) in a substituent is about or no more than about 1; in some embodiments, it is no more than about 2; in some embodiments, it is no more than about 3; in some embodiments, it is no more than about 4; in some embodiments, it is no more than about 5; in some embodiments, it is no more than about 6; in some embodiments, it is no more than about 7, in some embodiments, it is no more than about 8; in some embodiments, it is no more than about 9; in some embodiments, it is no more than about 10; in some embodiments, it is no more than about 11; in some embodiments, it is no more than about 12; in some embodiments, it is no more than about 13; in some embodiments, it is no more than about 14; in some embodiments, it is no more than about 15; in some embodiments, it is no more than about 20. In some embodiments, the total number of carbon and non-halogen heteroatom (s) in each substituent is independently no more than about 20. In some embodiments, the total number of carbon and non-halogen heteroatom (s) in each substituent is independently no more than about 15. In some embodiments, the total number of carbon and non-halogen heteroatom (s) in each substituent is independently no more than about 10. In some embodiments, the total number of carbon and non-halogen heteroatom (s) in each substituent is independently no more than about 6.Rs

[0161] In some embodiments, an optional substituent on a substitutable group is Rsas described herein. In some embodiments, Rsis halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OC1-C6 alkyl, -OC3-C 10 cycloalkyl, -OCs-Cw aryl, -0-5-10 membered heteroaryl, -0-3-20 membered heterocycloalkyl, -OC(=O)Ci-C6 alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)C6-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-C6alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -704.101.419S(=O)2N(CI-C6alkyl)2, -NH2, -NHCi-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)Ci-C6alkyl, -N(Ci-Ce alkyl)C(=0)Ci-C6 alkyl, -NHS(=O)2Ci-Ce alkyl, -NHS(=0)2C.3-CIO cycloalkyl, -NHS(=0)2C6-CIO aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Cj-C6alkyl)S(=0)2C3-Cio cycloalkyl, - N(Ci-C6alkyl)S(=O)2C6-Cn) aryl, -N(Ci-C6 alkyl)S(=O)25-10 membered heteroaryl, -N(Ci- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=0)Ci-C6 alkyl, -C(=O)OH, -C(=O)OCi-Ce alkyl, -C(=O)NH2, -C(=O)NHCI-C6alkyl, or -C(=O)N(Ci-C6alkyl)2; wherein each Ci-C6alkyl, Ci-C6heteroalkyl, Cg-Cio and, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloal kyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Cs-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.

[0162] In some embodiments, each optional substituent on a substitutable group (e.g., Ring A, R, etc.) is independently halogen, C1-4 alkyl, -OH, -CN, -NO2, C1-4 haloalkyl (e.g., -CF3), -ORSB, -N(RSB) 2, -C (O)ORSB, -C(O)N(RSB) 2, or -S(O)2N(RSB)2, wherein each RSBis independently -H, C1-4 alkyl or C1-4 haloalkyl, or is phenyl optionally substituted with halogen, C1.4 alkyl, -OH, -CN, -NO2, C1-4 haloalkyl (e.g., -CF3). In some embodiments, each optional substituent on a substitutable group (e.g., Ring A, R, etc.) is independently halogen, C1-4 alkyl, C1-4 haloalkyl, or -OH. In some embodiments, each optional substituent on a substitutable group (e.g., Ring A, R, etc.) is independently halogen, C1.4 alkyl or C1.4 haloalkyl. In some embodiments, each halogen is -F

[0163] In some embodiments, each heteroatom is independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, each heteroatom is independently selected from oxygen, nitrogen and sulfur.

[0164] In some embodiments, the compounds and salts described herein include isotopically-labeled compounds. In general, isotopically-labeled compounds are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most common in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example, 2H, 3H, 13C, 14C, 15N, 180, 170, 35S, 18F, 36CI, respectively. However, additional isotopes for iodine, bromine, and astatine are also included704.101.419herein. Certain isotopically-labeled compounds described herein, for example those into which radioactive isotopes are also incorporated as they are useful in drug and / or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. For example, in some embodiments, L is -(CD2)n- wherein n is 1, 2, 3, 4, 5, or 6; in some embodiments, L is -CD -.

[0165] In some embodiments, one or more isotopes may be utilized or enriched in compounds of the present disclosure at one or more locations. For example, in some embodiments, deuterium is utilized or enriched at one or more positions. In some embodiments, an enrichment is about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 99% more than a natural abundance as applicable. In some embodiments, a level of an isotope at a position is about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 99% of all compound molecules.PG

[0166] In some embodiments, protecting group or PG is a protecting group as described herein, e.g., those described in the “Definition” section. In some embodiments, PG is -Boc, -benzyl, -Cbz, FMoc, Teoc, Troc, SEM, MOM, TPDPS, TIPS, benzhydryl, or trityl. In some embodiments, PG is -Boc. In some embodiments, PG is -benzyl. In some embodiments, PG is -Cbz. In some embodiments, PG is FMoc. In some embodiments, PG is Troc. In some embodiments, PG is SEM. In some embodiments, PG is MOM. In some embodiments, PG is TPDPS. In some embodiments, PG is TIPS. In some embodiments, PG is benzhydryl. In some embodiments, PG is trityl.

[0167] In some embodiments, a provided compound has a structure of:704.101.419pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each variable is independently as described herein.

[0168] In some embodiments, a provided compound has a structure of:704.101.419stereoisom er thereof, wherein each variable is independently as described herein.

[0169] In some embodiments, a provided compound has a structure of:704.101.419or, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0170] In some embodiments, a provided compound has a structure of:704.101.419T?F 0 0VA OMe O °V\0 1* 0 1* 0 1*MeOxiArA°'^>HOY O V I*F 0O I* O I*OMe OOVA OMe O °y-\ O OMe O0VAJX HJUAO HJ O 'X A x AF CJl I I EKT 'O F3Cpharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein *1 is

[0123] I,

[0124] I,

[0125] I, or

[0131] L704.101.419704.101.419pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ’At is

[0210] At or [21 l]At.

[0172] In some embodiments, a provided compound has a structure of:acceptable salt, solvate, or stereoisomer thereof, wherein *1 is

[0123] I, [ 124JI,

[0125] I, or

[0131] I and X is as described herein.

[0173] In some embodiments, a provided compound has a structure of:704.101.419acceptable salt, solvate, or stereoisomer thereof, wherein *At is

[0210] At or [21 l]At and X is as described herein.Methods of Preparing

[0174] In some embodiments, the present disclosure provides methods for preparing a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. For example, the present disclosure provides three different methods for preparing compounds of Formula (I) comprising a radioactive

[0018] F moiety, which is one of the most important radioisotopes in the radiopharmaceutical industry, as it possesses a diagnostically useful half-life704.101.419(Zi / 2 = 110 min) and decays with high efficiency by positron emission efficiency (97%).Photoredox radiochemistry and late-stage radiolabeling can be utilized to incorporate

[0018] F into aromatic compounds such as compounds of Formula (I). The present disclosure provides three different photoredox radiolabeling methods for the introduction of an

[0018] F moiety using mild reaction conditions providing rapid introduction of an

[0018] F moiety into aromatic compounds such as compounds of Formula (I).

[0175] Method A. Direct C-H bond conversion: Unlike most of the existing methods, the developed arene C-H radiolabeling disclosed herein converts compounds of Formula (I) without harsh conditions (e.g. Ch free, moisture free, high temperature, strong acid or base etc.) or the need for complicated synthesis to achieve the desired product. See, e.g., Science 2019, 364, 1170-1174, hereby incorporated by reference.

[0176] Method B. Direct C-0 bond conversion: Transition metal catalysis and concerted SxAr methods have been utilized for the direct fluorination of activated C-0 bonds, but there is a dearth of methods for site-selective deoxyfluorinations with relatively unactivated nucleofuges. Disclosed herein is a highly efficient method - nucleophilic aromatic substitution (SNAr) -which is able to install a

[0018] F moiety to the target molecules in a site-specific manner using alkoxyarenes as substrates where alcohols are the leaving groups. See, e.g., Nature Catalysis 2020, 3, 734-742, hereby incorporated by reference.

[0177] Method C. Direct C-X (X = F, Cl, Br, I, NO 2) bond conversion. As a major substrate class for arene functionalization, aryl (pseudo)halides are commonly used intermediates en route to synthesizing organometallic or prefunctionalized arene precursors for radiofluorination. The present disclosure provides methods that could directly radiofluorinate electron-rich aryl halides. These methods demonstrate improved simplicity can also be used for the preparation of compounds of Formula (I) containing

[0019] F moieties, i.e., non-radioactive fluorine moieties. See, e.g., Nature Chem 2022, 14, 216-223, hereby incorporated by reference.

[0178] In some embodiments, compounds of Formula (I) comprising radioisotopes of iodine (i.e.,

[0123] I,

[0124] I,

[0125] I and

[0131] !), radioisotopes of astatine (i.e.,

[0210] At and

[0211] At), or radioisotopes of bromine (i.e.,

[0076] Br,

[0077] Br and

[0082] Br), are prepared from boron-, silicon-, tin- or germanium-containing starting materials.704.101.419

[0179] In some embodiments, the present disclosure provides a method for the preparation of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R2)mFormula (I),the method comprising:(a) obtaining a compound of Formula (INT-a) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:>4 IFormula (INT-a),wherein:Ring A is phenyl, pyridyl, or pyrimidinyl, wherein Ring A is optionally and independently substituted with 1-5 R’;R1is a radioisotope selected from the group consisting of

[0076] Br,

[0077] Br,

[0082] Br,

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, and

[0211] At;each R2is independently F or radioisotope

[0018] F;m is 1 or 2;each R3is independently hydrogen, PG, Ci-Cg alkyl, or C3-C10 cycloalkyl;n is 0, 1, or 2;R4is-C(=O)R’, -C(=O)OR’, -C(=O)N(R’)2, - N(R’)2, -NR’C(=O)R’, -NR’C(=O)N(R’)2, - OC(=O)R’, -OC(=O)OR’, or - LS-OH;Lsis absent or Ci-Ce alkylene optionally substituted with 1-12 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -O-, -N(R’)-, -C(=O)-, - C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, -N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, - OC(=O)N(R’)S(O)2-, -S(O)-, -S(O)2-, or -S(O)2N(R’)-;R5is Cl, Br, I, -B(R )2, -B(R’)3X, -Sn(R )3, -Ge(R’)3, or-Si(R’)3;704.101.419X is a counterion;absent or C1-C20 alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -CR’=CR’-,, -O-, -N(R’)-, -C(=O)-, C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, - S(O)2N(R’)-, -P(OR’)-, -P(NR’)-, -P(O)(OR’)-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-25 amino acids;each -Cy- is independently a bivalent ring selected from C3-C20 cycloalkylene, C6-C20 arylene, 3- 20 membered heteroarylene, or 3-20 membered heterocycloalkylene, wherein each group is optionally and independently substituted with 1-20 Rs;O OQ.+ (Vi- Q is halogen, R’, -OR’, -SR’, -N=C=O, -NC, -N3, -OS(O)2R’, -OP(O)(OR’)R’„ O, 0N„ I - R', norbomene, trans-cyclooctene, N R':-C(R’)=C(R’)2,5, or PG,optionally and indpendently subsituted with 1-5 R’;each PG is independently a protecting group;each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C=(O)OR, -C(=O)N(R)2, -S(O)2R, or PG; each R is independently hydrogen, halogen, or an optionally substituted group selected from Ci- C10 aliphatic, C1-C10 heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl, wherein each group is optionally and independently substituted with 1-20 Rs, or two R groups are optionally and independently taken together to form a covalent bond or =0; ortwo or more R groups on the same atom are optionally and independently taken together with the atom to form a 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the atom, 0-5 heteroatoms; or704.101.419two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the intervening atoms, 0-5 heteroatoms;each Rsis independently halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OCi-Ce alkyl, -OC3-C10 cycloalkyl, -OCe-Cio aryl, -0-5-10 membered heteroaryl, -0-3-20 membered heterocycloalkyl, -OC(=O)Ci-C6 alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)C6-Cio aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-C6 alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, - NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci- C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci- C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-Ce alkyl)S(=O)25-10 membered heteroaryl, -N(Ci- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)Ci-C6 alkyl, -C(=O)OH, -C(=O)OCi- C6alkyl, -C(=O)NH2, -C(=O)NHCI-C6alkyl, -C(=O)N(Ci-C6alkyl)2; wherein each Ci-C6alkyl, C1-C6 heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl;(b) contacting the compound of Formula (INT-a) with a radioisotope source for

[0076] Br,

[0077] Br,

[0082] Br,

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, or

[0211] At in the presence of an oxidant to obtain the compound of Formula (I).

[0180] In some embodiments, the present disclosure provides a method of preparing a compound of Formula (INT-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R2)m704.101.419Formula (INT-a),the method comprising:subjecting a compound of Formula (INT-b) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (INT-b),to appropriate conditions, wherein R5is -B(R )2, -B(R’)3X wherein X is a counterion, -Sn(R )s, -Ge(R )s, or -Si(R’)3; and halo is Cl, Br, or I.. In some embodiments, the method is conducted in the presence of a metal catalyst. In some embodiments, a metal is a transition metal

[0181] Those skilled in the art will appreciate that a method of preparation as described herein can be combined with one or more other methods of preparation to provide a multi step process. In some embodiments, the present disclosure provides a method of preparing a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R3O)n(R2)mFormula (I),the method comprising:(1) subjecting a compound of Formula (INT-b) or a pharmaceutically acceptable salt, solvate, or stereoisomer t ereof:(R3O)nHalo — ( A J QR^ T(R2)mFormula (INT-b),under appropriate conditions to provide a compound of Formula (INT-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:704.101.419(R2)mFormula (INT-a),(2) reacting a compound of Formula (INT-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof with a radioisotope source for

[0076] Br,

[0077] Br,

[0082] Br,

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, or

[0211] At in the presence of an oxidant to provide said compound of Formula (I), wherein each variables are independently as described herein.

[0182] Various headings used in the present disclosure are for easy reference only and should not be construed to mean embodiments described in the different headings cannot be combined or cross-referenced. For example, embodiments of variable groups described in the “Compounds” section apply to a same variable group described under the heading of “Methods of Preparing.” Those skilled in the art can refer to the embodiments of variable group described in “Compounds” section, e.g., R1, R2, m, R3, n, R4, L, R’, R, Rs, L*, and R*, etc. for the same variable group described in the “Methods of Preparing” section.R5

[0183] In some embodiments, R3is Cl, Br, I, -B(R )?, -B(R’)3X wherein X is a counterion, -Sn(R )s, -Ge(R)3, or -Si(R’)3, wherein each variable is independently as described herein. In some embodiments, R5is Cl. In some embodiments, R is Br. In some embodiments, R3is I. In some embodiments, each R3is -B(R )2, -B(R’)3X wherein X is a counterion, -Sn(R )3, -Ge(R)3, or -Si(R’)3 and each R’ is independently as described herein. In some embodiments, R5is B(R’)2, wherein each R’ is independently as described herein. In some embodiments, R5is -B(R’)2and each R’ is independently halogen, -OH, -OR, or -OC(=O)R wherein each R is independently as described herein. In some embodiments, R5is -B(OH)2 In some embodiments, R3is -B(OR)2 and each R is independently Ci-Ce aliphatic. In some embodiments, R3is -B(OMe)2. In some embodiments, R3is -B(OR)2 and two R are taken together with the intervening atoms they are attached to form 3-10 membered heterocycloalkyl optionally substituted with 1-4 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some704.101.419o I * \embodiments, R is°. In some embodiments, R is B(R’)sX and each R’ is independently halogen, -OH, or -OR, wherein X and R are each independently as described herein. In some embodiments, R5is B(R’)3X and each R’ is independently halogen, wherein X is as described herein. In some embodiments, R5is -BF3K. In some embodiments, R3is - B(OC( =O)R)2 and two R are taken together with the intervening atoms they are attached to form 3-10 membered heterocycloalkyl optionally substituted with 1-4 halogen, -OH, -CN, -OMe,methyl, or halomethyl. In some embodiments,R' is. In some embodiments, R5in the compound of Formula (INT-a) is transformed into R9in the compound for Formula (I) in a method as described herein.Oxidant

[0184] In some embodiments, oxidant is an N-halosuccinimide. In some embodiments, oxidant is N-chlorosuccinimide. In some embodiments, oxidant is N-astatosuccinimide. In some embodiments, oxidant is H2O2. In some embodiments, oxidant is DDQ. In some embodiments, oxidant is CuCl2.Base Activator

[0185] In some embodiments, a method as described herein is conducted further in the presence of a base activator. In some embodiments, a base activator is selected from organic or inorganic fluoride sources. In some embodiments, a base activator is NaOH, KOH, KOAc, or KOtBu. In some embodiments, a base activator is MgF2, CsF, KF, LiF, CaF2, NaF, KHF2 or F’. In some embodiments, a base activator is quaternary ammonium fluoride salt. In some embodiments, a base activator is TBAF.

[0186] In some embodiments, a compound disclosed herein is the L-isomer of any given amino acid, natural or un-natural (not present in nature). In some embodiments, a compound disclosed herein is the D-isomer of any given amino acid, natural or un-natural (not present in nature)704.101.419

[0187] In some embodiments, the present disclosure provides compounds of high stereochemical purity. In some embodiments, stereochemical purity of a compound is or greater than about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.7%, or 99.9%. In some embodiments, stereochemical purity of a compound is or greater than about 80%. In some embodiments, stereochemical purity of a compound is or greater than about 85%. In some embodiments, stereochemical purity of a compound is or greater than about 90%. hi some embodiments, stereochemical purity of a compound is or greater than about 95%. In some embodiments, stereochemical purity of a compound is or greater than about 96%. In some embodiments, stereochemical purity of a compound is or greater than about 97%. In some embodiments, stereochemical purity of a compound is or greater than about 98%. hi some embodiments, stereochemical purity of a compound is or greater than about 99%. In some embodiments, stereochemical purity of a compound is or greater than about 99.5%. In some embodiments, stereochemical purity of a compound is or greater than about 99.7%. In some embodiments, stereochemical purity of a compound is or greater than about 99.9%.

[0188] In some embodiments, the present disclosure provides compounds of high enantiomeric purity. In some embodiments, enantiomeric purity of a compound is or greater than about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.7%, or 99.9%. In some embodiments, enantiomeric purity of a compound is or greater than about 80%. In some embodiments, enantiomeric purity of a compound is or greater than about 85%. In some embodiments, enantiomeric purity of a compound is or greater than about 90%. In some embodiments, enantiomeric purity of a compound is or greater than about 95%. In some embodiments, enantiomeric purity of a compound is or greater than about 96%. In some embodiments, enantiomeric purity of a compound is or greater than about 97%. In some embodiments, enantiomeric purity of a compound is or greater than about 98%. In some embodiments, enantiomeric purity of a compound is or greater than about 99%. In some embodiments, enantiomeric purity of a compound is or greater than about 99.5%. In some embodiments, enantiomeric purity of a compound is or greater than about 99.7%. In some embodiments, enantiomeric purity of a compound is or greater than about 99.9%.

[0189] In some embodiments, the present disclosure provides compounds of high diastereomeric purity. In some embodiments, the present disclosure provides a compound as described herein having a diastereomeric purity of about or at least about 10%, 15%, 20%, 25%,704.101.41930%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 10%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 15%. In some embodiments, a compound as described herein having a diastereo eric purity of about or at least about 20%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 25%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 30%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 35%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 40%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 45%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 50%. In some embodiments, a compound as described herein having a diastereo eric purity of about or at least about 55%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 60%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 65%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 70%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 75%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 80%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 85%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 90%. In some embodiments, a compound as described herein having a diastereomeric purity of about or at least about 100%.

[0190] Stereochemically pure, e.g., enantiomerically pure (or optically pure), compounds and compositions can be prepared utilizing various technologies in accordance with the present disclosure. The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography and / or recrystallization or by the forming di stereomers, including diastereomeric salts, and separation thereof (Jean Jacques,704.101.419Andre Collet, Samuel ' H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981). Stereoisomers may also be obtained by stereoselective synthesis using synthetic methods known in the art.

[0191] In some embodiments, the present disclosure provides a compound as described herein having a purity of about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100%. In some embodiments, a compound as described herein having a purity of about or at least about 10%. In some embodiments, a compound as described herein having a purity of about or at least about 15%. In some embodiments, a compound as described herein having a purity of about or at least about 20%. In some embodiments, a compound as described herein having a purity of about or at least about 25%. In some embodiments, a compound as described herein having a purity of about or at least about 30%. In some embodiments, a compound as described herein having a purity of about or at least about 35%. In some embodiments, a compound as described herein having a purity of about or at least about 40%. In some embodiments, a compound as described herein having a purity of about or at least about 45%. In some embodiments, a compound as described herein having a purity of about or at least about 50%. In some embodiments, a compound as described herein having a purity of about or at least about 55%. In some embodiments, a compound as described herein having a purity of about or at least about 60%. In some embodiments, a compound as described herein having a purity of about or at least about 65%. In some embodiments, a compound as described herein having a purity of about or at least about 70%. In some embodiments, a compound as described herein having a purity of about or at least about 75%. In some embodiments, a compound as described herein having a purity of about or at least about 80%. In some embodiments, a compound as described herein having a purity of about or at least about 85%. In some embodiments, a compound as described herein having a purity of about or at least about 90%. In some embodiments, a compound as described herein having a purity of about or at least about 100%.

[0192] In some embodiments, the present disclosure provides a compound as described herein having a radiochemical purity of about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 10%. In some embodiments, a compound as described herein having a radiochemical purity of about or at704.101.419least about 15%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 20%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 25%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 30% In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 35%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 40%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 45%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 50% In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 55%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 60%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 65%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 70%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 75%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 80%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 85%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 90%. In some embodiments, a compound as described herein having a radiochemical purity of about or at least about 100%. In some embodiments, a radiochemical purity as described herein is measured at the end of radiochemical synthesis. In some embodiments, a radiochemical purity as described herein is measured 1 hour after the end of radiochemical synthesis. In some embodiments, In some embodiments, a radiochemical purity as described herein is measured 2 hours after the end of radiochemical synthesis. In some embodiments, a radiochemical purity as described herein is measured 3 hours after the end of radiochemical synthesis. In some embodiments, a radiochemical purity as described herein is measured 4 hours after the end of radiochemical synthesis. In some embodiments, a radiochemical purity as described herein is measured 5 hours after the end of radiochemical synthesis. As is well known in the art, radiochemical purity can be ascertained by various known methods, e.g., radioTLC, radioHPLC, etc.704.101.419Bioactive ligands

[0193] In some embodiments, a provided compound (e.g., radiolabeled prosthetic group) is coupled to a bioactive ligand. A bioactive ligand disclosed herein can be found in nature (e.g., in an organism and / or plant) or can be prepared synthetically. Certain disclosed bioactive ligands are able to modulate a biological process in an organism (e.g., a mammal). Exemplary bioactive ligands include, but are not limited to, proteins (natural and designed) and protein complexes (e.g., viral capsid and / or virus-like proteins (VLP), oligonucleotides, polynucleotides, cyclic and linear oligopeptides, cyclic and linear oligonucleotides (with both natural and unnatural bases, and / or natural or unnatural termini), peptoids, messenger molecules, aptamers, and / or antibodies).

[0194] In some embodiments, a bioactive ligand is a drug molecule, e.g., a peptide-based drug molecule. In some embodiments, a bioactive ligand is an oligopeptide (also referred to as “peptide”). In some embodiments, a peptide is natural (i.e., found in nature). In some embodiments, a peptide is unnatural (prepared synthetically). In some embodiments, a peptide is a linear peptide. In some embodiments, a peptide is a cyclic peptide or a peptoid. In some embodiments, a peptide is an approved pharmaceutical drug and / or a clinical drug candidate and / or an investigative research compound.

[0195] In some embodiments, a bioactive ligand contributes to and / or interferes with the pathogenesis of cancer and / or a proliferative disorder. In some embodiments, a bioactive ligand (e.g., peptide) is employed to specifically target cancer cells. In some embodiments, a bioactive ligand is radiolabeled with the radioisotope-containing prosthetic groups (e.g., a compound of Formula (I)) disclosed herein. In some embodiments, a radiolabeled bioactive ligand is used as a diagnostic or radiotherapeutic agent. In some embodiments a radiolabeled bioactive ligand is used as a diagnostic agent. In some embodiments, a radiolabeled bioactive ligand is used as a therapeutic agent. In some embodiments the radiolabeled bioactive ligand can be used to target and reduce / kill cancer cells or to kill / reduce non-cancerous or pre-cancerous hyperpoliferative / hyperpoliferating cells.

[0196] In some embodiments, a bioactive ligand is PSMA-11. In some embodiments, a bioactive ligand is PSMA-617. In some embodiments, a bioactive ligand is ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications704.101.419(“OncoFAP”). In some embodiments, a bioactive ligand isAs will be understood by those skilled in the art, certain OncoFAP was described in the art, e g., in Millul et al., Proceedings of the National Academy of Sciences 118.16 (2021): e2101852118., which is incorporated herein by reference. In some embodiments, a bioactive ligand is Zolbetuximab. As will by understood by those skilled in the art, the sequence of Zolbetuximab is described in public domain. In some embodiments, a bioactive ligand is Glypican-3 (GPC3) small peptide ligand. As will be understood by those skilled in the art, certain GPC3) small peptide ligands were described in the art, e.g., in Qin et al. Biomater. Sci., 2020,8, 5656-5665, which is incorporated herein by reference. In some embodiments, a bioactive ligand is a Nectin-4 targeting bi-cyclic peptide. In some embodiments, a bioactive ligand is N188. As will be understood by those skilled in the art, certain Nectin-4 targeting bi-cyclic peptides were described in the art, e.g., Mudd et al., Med. Chem. 2022, 65, 21, 14337-14347; Duan et al., Clin Cancer Res. 2023 Sep l;29(17):3395-3407, each of which is incorporated herein by reference. In some embodiments, a bioactive ligand is of a single-domain nanobody (such as those targeting cell-surface proteins Claudinl8.2 or Trop2. See, e.g., Qi et al., J. Nucl. Med., 2024; 00:1-8; Zhang et al., EMBO Mol. Med. 2024 May;16(5):l 143-1161, which is incorporated herein by reference.Radiolabeled Bioactive Ligands

[0197] Among other things, the present disclosure provides a radiolabeled bioactive ligand. In some embodiments, the present disclosure provides a method of making radiolabeled bioactive ligands by employing a provided compound (e.g., radiolabeled prosthetic group). In some embodiments, the present disclosure provides a method of making radiolabeled bioactive ligand, comprising:(a) obtaining a bioactive ligand; and(b) contacting the bioactive ligand with a provided compound containing at least one radioisotope to form radiolabeled bioactive ligands.704.101.419

[0198] In some embodiments, a radiolabeled prosthetic group (e.g., those are aromatic electrophilic) is coupled with a bioactive ligand under mild conditions to render imaging agents (e.g., SPECT and / or PET imaging agents) as well as radiolabeled-based therapy agents. In some embodiments, a bioactive ligand is a bioactive ligand as described herein. In some embodiments, a provided compound containing at least one radioisotope is0 1 In some embodiments, a provided compound containing at leastone radioisotope isO I* In some embodiments, a provided compoundcontaining at least one radioisotope isO At*

[0199] In some embodiments, the contacting step comprises a base (e.g., DIPEA, Na2COs). In some embodiments, the contacting step is carried out above room temperature (e.g., at a temperature ranging from about 30 °C to about 75 °C). In some embodiments, the contacting step is carried out in an aprotic non-polar solvent (e.g., acetonitrile (ACN), dimethyl formamide (DMF)). A skilled artisan would be aware that the condition for the contacting step varies, in part, on the functionality of Q.Pharmaceutical Composition and Administration

[0200] In some embodiments, the present disclosure provides a pharmaceutical composition that comprise a provided bioactive ligand or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition is suitable for imaging (e.g., PET, SPECT). In some embodiments, a704.101.419pharmaceutical composition is suitable for radiotherapy (e.g., alpha-particle therapy, beta- particle therapy). In some embodiments, the present disclosure provides a pharmaceutical composition that can deliver a provided bioactive ligand or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, a compound is provided in a pharmaceutically acceptable salt form.

[0201] Various technologies, e.g., routes, modes, dosage regimens, etc. may be utilized to administer and / or deliver provided compounds (e.g., a provided bioactive ligand) and compositions in accordance with the present disclosure. In some embodiments, a route and / or mode of administration can vary depending upon desired results. One with skill in the art, i.e., a physician, is aware that dosage regimens can be adjusted to provide a desired response, e.g., a therapeutic response. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intrathecal, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin. In some embodiments, a compound is administered or delivered topically. In some embodiments, a composition is or comprises a topical composition. In some embodiments, a composition is or comprises a solution. In some embodiments, a composition is or comprises an emulsion. In some embodiments, a composition is or comprises a lotion. In some embodiments, a composition is or comprises an ointment. In some embodiments, a composition is or comprises a cream. In some embodiments, a composition is or comprises a gel. In some embodiments, a mode of administration is left to discretion of a practitioner.

[0202] In some embodiments, compounds can be incorporated into and administered as pharmaceutical compositions for various uses (e.g., imaging, therapy, or both). Such pharmaceutical compositions are useful for, among other things, administration and delivery to a subject in vivo or ex vivo. In some embodiments, pharmaceutical compositions also contain a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier is a pharmaceutical agent that does not itself induce an immune response harmful to the individual receiving a composition, and which may be administered without undue toxicity. Pharmaceutically acceptable carriers (or excipients) include, but are not limited to, liquids such as water, saline, glycerol, sugars and ethanol. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present in such vehicles.704.101.419Suitable excipients may include stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents.

[0203] In some embodiments, pharmaceutical compositions provided herein may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetyl pyridinium chloride.

[0204] Compounds in pharmaceutical compositions may be provided as pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2 -naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0205] In some embodiments, salts are more soluble in aqueous or other protonic solvents than corresponding, free acid or base forms. In some embodiments, a pharmaceutical704.101.419composition may be a lyophilized powder. In some embodiments, a pharmaceutical composition comprises a provided bioactive ligand or a pharmaceutically acceptable salt thereof dissolved in a pharmaceutically acceptable buffer. In some embodiments, a buffer is a saline buffer. In some embodiments, a buffer has a pH around 7.4.

[0206] Pharmaceutical compositions can include solvents (aqueous or non-aqueous), solutions (aqueous or non-aqueous), emulsions (e.g., oil-in-water or water-in-oil), suspensions, syrups, elixirs, dispersion and suspension media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration or in vivo contact or delivery. Aqueous and non-aqueous solvents, solutions and suspensions may include suspending agents and thickening agents. In some embodiments, pharmaceutical compositions or formulations are tablets (coated or uncoated), capsules (hard or soft), microbeads, powder, granules and / or crystals. Supplementary active compounds (e.g., preservatives, antibacterial, antiviral and antifungal agents) can also be incorporated into pharmaceutical compositions.

[0207] In some embodiments, a compound described herein may be formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids (e.g., injectables), gels, syrups, elixirs, slurries, suspensions, aerosols, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, and capsules.

[0208] Pharmaceutical compositions can be formulated to be compatible with a particular route of administration or delivery as set forth herein or known to one of skill in the art. In some embodiments, provided compositions are suitable for parenteral administration.

[0209] In some embodiments, such compositions comprise aqueous and non-aqueous solutions, suspensions or emulsions of active compounds, which preparations are typically sterile and can be isotonic with blood of intended recipients. Non-limiting illustrative examples include water, buffered saline, Hanks' solution, Ringer's solution, dextrose, fructose, ethanol, animal, vegetable or synthetic oils. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Additionally, suspensions of active compounds may be prepared as appropriate oil injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Optionally,704.101.419a suspension may also contain suitable stabilizers or agents which increase solubility to allow for the preparation of highly concentrated solutions.

[0210] Co-solvents and adjuvants may be added to compositions and formulations. Nonlimiting examples of co-solvents contain hydroxyl groups or other polar groups, for example, alcohols, such as isopropyl alcohol; glycols, such as propylene glycol, polyethyleneglycol, polypropylene glycol, glycol ether; glycerol; polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Adjuvants include, for example, surfactants such as, soya lecithin and oleic acid; sorbitan esters such as sorbitan trioleate; and polyvinylpyrrolidone.

[0211] After pharmaceutical compositions have been prepared, they may be placed in an appropriate container and labeled for treatment. Such labeling can include amount, frequency, and method of administration.

[0212] Various pharmaceutical compositions and delivery systems appropriate for compositions, methods and uses of the present disclosure are known in the art (see, e.g., Remington: The Science and Practice of Pharmacy. 21st Edition. Philadelphia, PA. Lippincott Williams & Wilkins, 2005) and can be utilized in accordance with the present disclosure.

[0213] In some embodiments, the present disclosure provides methods for delivering provided compounds (e.g., a provided bioactive ligand) and compositions into cells, animals or subjects. In some embodiments, such methods include contacting a subject (e.g., a cell or tissue of a subject) with, or administering or delivering to a subject (e.g., a subject such as a mammal or human) a provided bioactive ligand, e.g., a compound of formula I or a salt thereof, or a composition thereof.

[0214] A compound (e.g., a provided bioactive ligand) or composition described herein can be administered in a sufficient or effective amount to a subject (or a cell, tissue or organ thereof) in need thereof. Doses can vary and may depend upon the type, onset, progression, severity, frequency, duration, or probability of a condition, disorder or disease to which treatment is directed, a clinical endpoint desired, previous or simultaneous treatments, general health, age, gender, race or immunological competency of a subject and other factors that will be appreciated by a skilled artisan. Dose amount, number, frequency or duration may be proportionally increased or reduced, as indicated by efficacy, any adverse side effects, complications or other risk factors of a treatment or therapy and the status of a subject. A skilled704.101.419artisan will appreciate factors that may influence dosage and timing required to provide an amount sufficient for providing a therapeutic or prophylactic benefit.

[0215] A dose to achieve a therapeutic effect will vary based on several factors including route of administration, amount to achieve a therapeutic effect, specific condition, disorder or disease treated, any host immune response to administered compound or composition, stability of administered compound or composition, etc. Generally, a provided bioactive ligand is administered in an amount effective for treating the disease, disorder, and / or condition (i.e., a therapeutically effective amount). Thus, a therapeutically effective amount can be an amount that is capable of at least partially treating, preventing or reversing a disease, disorder, and / or condition. The dose required to obtain an effective amount may vary depending on the agent, formulation, disease, disorder, and / or condition, and individual to whom the agent is administered.

[0216] Determination of effective amounts may also involve in vitro assays in which varying doses of the compound disclosed herein is administered to cells in culture and the concentration of the compound effective for ameliorating some or all symptoms is determined in order to calculate the concentration required in vivo. Effective amounts may also be based in in vivo animal studies.

[0217] The dosing and administration regimes of radionuclide-based compositions containing a provided bioactive ligand to be administered is based on various factors such as the type of radionuclide present in a provided bioactive ligand, the disease, disorder, and / or condition to be treated, and the subject (age, weight, sex, etc.). Dosing for a therapeutic is typically higher than when used as an imaging agent and can be once a day or multiple times per day for one or more consecutive days. The amount of radioactivity administered during such a treatment course may vary from dose to dose of the radioactive bioactive ligand. The amount of radioactivity of a radioactive bioactive ligand and its frequency and duration of administration is determined by a skilled person in the art, e g., a physician knowledgeable in Nuclear Medicine, as would be apparent to a skilled artisan. For example, a skilled artisan would be aware that for beta-particle therapy (e.g.,

[0131] !) the radiolabeled-based therapeutic is administered over a 100-300 mCi range, whereas for alpha-particle therapy (e.g.,

[0211] At) the radiolabeled-based therapeutic would generally be administered over a 1-10 mCi range. It would be understood by a skilled artisan that the radiolabeled-based therapeutics disclosed herein would be administered at704.101.419doses encompassed by, but not limited to, the above-mentioned ranges depending on the type of therapy (alpha-particle vs. beta-particle).

[0218] An effective amount or a sufficient amount can be provided in a single administration, may require multiple administrations, and, can be, administered alone or in combination with another composition (e.g., comprising or delivering another therapeutic agent). For example, an amount may be proportionally increased as indicated by the need of a subject, type, status and severity of a condition, disorder or disease treated and / or side effects (if any) of treatment. Amounts considered effective also include amounts that result in a reduction of the use of another treatment, therapeutic regimen or protocol.

[0219] In some embodiments, pharmaceutical compositions comprise or deliver active ingredients, e.g., a provided bioactive ligand or pharmaceutically acceptable salts thereof, in effective amounts to achieve intended purposes e.g, diagnostic and / or therapeutic purposes Various technologies may be utilized to determine therapeutically effective amounts in accordance with the present disclosure. Therapeutic doses can depend on, among other factors, ages and general conditions of subjects, severity of conditions, disorders or diseases, etc. In some embodiments, therapeutically effective amounts in humans may fall in a relatively broad range that may be determined by medical practitioners based on responses of individual patients.

[0220] In some embodiments, methods and uses of the present disclosure include delivery and administration systemically, regionally or locally, or by any route, for example, by injection or infusion or orally. In some embodiments, delivery of a pharmaceutical composition in vivo may generally be accomplished via injection using a conventional syringe, although other delivery methods such as convection-enhanced delivery can also be used. In some embodiments, compounds and compositions may be delivered subcutaneously, epidermally, intradermally, intrathecally, intraorbitally, intramucosally, intraperitoneally, intravenously, intra-pleurally, intraarterially, orally, intrahepatically, via the portal vein, or intramuscularly. In some embodiments, modes of administration include oral and pulmonary administration, suppositories, and transdermal applications. Clinicians specializing in treating patients may determine optimal routes for administration of compounds and compositions as described herein.

[0221] Parenteral injections may involve bolus injection or continuous infusion.Pharmaceutical compositions for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative The pharmaceutical704.101.419compositions described herein may be in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or various dextrans. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated soluti ons. Alternati vely, the active ingredient may be in powder form for constitution with a suitable vehicle, e g., sterile pyrogen-free water, before use.

[0222] In certain embodiments, delivery systems for pharmaceutical compounds may be employed, such as, for example, liposomes and emulsions. In certain embodiments, compositions provided herein also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and various dextrans.

[0223] As described herein, a provided compound can exist in various solid-state forms. In some embodiments, a provided compound is amorphous. In some embodiments, a provided compound is crystalline. In some embodiments, a provided compound exists as a mixture of amorphous and crystalline forms.

[0224] In some embodiments, the present disclosure encompasses a prodrug or a metabolite of a provided bioactive ligand as understood by those skill in the art. In some embodiments, a prodrag of a provided bioactive ligand is administered. Active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.Methods of Treatment704.101.419

[0225] The present disclosure provides compounds and methods for utilizing and / or modulating amino acid metabolism. In some embodiments, the present disclosure provides compounds and methods wherein the compounds disclosed herein are substrates of the L-type, also referred to as large neutral, amino acid transporter (LATl ).

[0226] Thus, one aspect of the current disclosure is that the disclosed compounds utilize amino acid transport mechanisms to travel into cancer cells. In some embodiments, the compounds disclosed herein enter cancer cells utilizing one or more amino acid transport of uptake mechanism in amount of at least about 0.1% to about 5%, from about 0.01% to about 3%, from about 001% to about 2%, from about 0.1% to about 1.5%, or from about 0.1% to about 1.0% based on the total amount of compound available. In some embodiments, the disclosed compounds enter cancer cells into an amount ranging from about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or by about 98% based on the total amount of compound available. In some embodiments, the disclosed compounds enter cancer cells into an amount ranging from about 1% to about 100%, from about 2% to about 99%, from about 5% to about 98%, from about 10% to about 95%, from about 15% to about 92%, from about 20% to about 92%, from about 25% to about 90%, from about 30% to about 88%, from about 40% to about 85%, from about 50% to about 82%, from about 60% to about 80%, or from about 70% to about 80% based on the total amount of compound available.

[0227] In some embodiments, the present disclosure provides methods for diagnosing a condition, disorder or disease, comprising administering to a subject in need thereof an effective amount of a provided bioactive ligand or composition thereof. In some embodiments, the present disclosure provides methods for monitoring a condition, disorder or disease, comprising administering to a subject in need thereof an effective amount of a provided bioactive ligand or composition thereof. In some embodiments, the present disclosure provides methods for treating a condition, disorder or disease, comprising administering to a subject in need thereof an effective amount of a provided bioactive ligand or composition thereof. In some embodiments, the disease is selected from a disease associated with expression of cellular targets involved in amino acid metabolism (e g., LATl), aberrant expression, overexpression and / or activity (e g. cancer). In certain embodiments, the disease is mediated by cellular targets involved in amino704.101.419acid metabolism (e.g., LAT1) and / or expression (e.g., aberrant expression, overexpression, etc.). In some embodiments, the disease or condition is treatable by modulation of cellular targets involved in amino acid metabolism (e.g., LAT1). In some embodiments, the method comprises treating a condition, disorder or disease that is treatable by modulation of cellular targets involved in amino acid metabolism (e.g., LAT1) by administering to a subject in need thereof an effective amount of a provided bioactive ligand or composition thereof.

[0228] In certain embodiments, the disclosure provides method of treating a condition, disorder or disease in a subject, wherein the method comprises determining if the subject has an amino acid metabolism -mediated condition (e.g., cancer, neurological diseases, cardiovascular diseases, and / or infection) and administering to a subject in need thereof an effective amount of a provided bioactive ligand or composition thereof.

[0229] The disclosure provides methods for treating a condition, disorder or disease by administering to a subject in need thereof an effective amount of a provided bioactive ligand or composition thereof, wherein the compound binds to or is transported by a cellular target involved in amino acid metabolism (e.g.. LAT1). In some embodiments, the compound binds to or is transported by the cellular target involved in amino acid metabolism (e.g. LAT1).

[0230] In some embodiments, a condition, disorder or disease is neurological diseases, cardiovascular diseases, and / or an infection.

[0231] In some embodiments, a condition, disorder or disease is a hyperproliferative disorder. In some embodiments, a condition, disorder or disease is cancer. In some embodiments, a cancer is mediated by an expression, aberrant expression, overexpression (etc.), of cellular targets (e.g. LAT1) involved in amino acid metabolism and / or activity. In some embodiments, a cancer is acute myeloid leukemia, cancer in adolescents, childhood adrenocortical carcinoma, AIDS-related cancers, e.g., lymphoma and Kaposi's Sarcoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial704.101.419cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Viral-Induced cancer. In some embodiments, the method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin, e.g., psoriasis, restenosis, or prostate, e.g., benign prostatic hypertrophy (BPH). In some cases, the method relates to the treatment of leukemia, hematologi c malignancy, solid tumor cancer, prostate cancer, e.g., castration-resistant prostate cancer, breast cancer, Ewing’s sarcoma, bone sarcoma, primary bone sarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma, liver cancer, e.g., hepatocellular carcinoma, or diabetes. In some embodiments, the cancer is pancreatic cancer, breast cancer or brain cancer. In some embodiments, brain cancer is selected from the group consisting of Meningioma, Astrocytomas, Gliomas, Glioblastoma multiforme, Medulloblastoma, Ependymoma, Oli odendroglioma, Craniopharyngioma, Pituitary adenoma, Brainstem glioma,704.101.419Schwannoma, Vestibular schwannoma, Anaplastic astrocytoma, Primary central nervous system lymphoma, Germ cell tumor, Primitive neuroectodermal tumor, Pilocytic astrocytoma, Mixed glioma, Chordoma, Optic nerve glioma or diffuse Astrocytomas.

[0232] In some embodiments, a cancer is brain cancer. In some embodiments, brain cancer is selected from the group consisting of Meningioma, Astrocytomas, Gliomas, Glioblastoma multiforme, Medulloblastoma, Ependymoma, Oligodendroglioma, Craniopharyngioma, Pituitary adenoma, Brainstem glioma, Schwannoma, Vestibular schwannoma, Anaplastic astrocytoma, Primary central nervous system lymphoma, Germ cell tumor, Primitive neuroectoderm l tumor, Pilocytic astrocytoma, Mixed glioma. Chordoma, Optic nerve glioma and diffuse Astrocytomas.

[0233] In some embodiments, a cancer is pancreatic cancer. In some embodiments, a cancer is breast cancer.

[0234] In some embodiments, a provided bioactive ligand disclosed herein is administered to a subject with a family history of the disease, disorder, and / or condition, or who has a phenotype that may indicate a predisposition to a disease, disorder, and / or condition, or who has a genotype which predisposes the subject to the disease, disorder, and / or condition.

[0235] In some embodiments, a subject who is suitable for a method described herein has been diagnosed as having acute myeloid leukemi a, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers, e.g., lymphoma and Kaposi's Sarcoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma,704.101.419islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pl europul monary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Viral- Induced cancer, leukemia, hematologic malignancy, solid tumor cancer, prostate cancer, castration-resistant prostate cancer, breast cancer, Ewing's sarcoma, bone sarcoma, primary bone sarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma, hepatocellular carcinoma, liver cancer, or di betes In some embodiments subjects that are treated with the compounds of the disclosure include subjects that have been diagnosed as having a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin, e.g., psoriasis, restenosis, or prostate, e g., benign prostatic hypertrophy (BPH)

[0236] In some embodiments, the present disclosure provides methods of modulating activity of a cellular target that is involved in amino acid metabolism (e.g. LAT1) in a cell comprising contacting the cell with an effective amount of a provided bioactive ligand or composition thereof. In some embodiments, a condition, disorder or disease is neurological diseases, cardiovascular diseases, and / or an infection.

[0237] In some embodiments, the disclosure provides methods of modulating activity of the cellular target for amino acid metabolism (e.g., LAT1) in a tissue by contacting the tissue with an effective amount of a provided bioactive ligand or composition thereof. In some704.101.419embodiments, provided compounds or compositions utilize the cellular targets for amino acid metabolism (e.g., LAT1) as a means to get transported into the diseased cell (e.g., a cancer cell).

[0238] In some embodiments, a provided bioactive ligand or composition thereof is administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease, in an amount sufficient to cure or at least partially arrest the symptoms of the disease. Amounts effective for this use will depend on the severity and course of the disease, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating clinician.

[0239] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0240] In some embodiments, a provided bioactive ligand or composition thereof is administered in combination with other therapeutic agents, such as other anti-cancer agents, antiallergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof.

[0241] In another embodiment, a provided bioactive ligand or composition thereof is administered in combination with another therapeutic agent capable of inhibiting BRAF, MEK, KRAS, S0S1, CDK4 / 6, SHP-2, HD AC, EGFR, MET, mTOR, PI3K or AKT, or anti-PDl drugs such as Nivolumab, Prembolamab, Cemiplimab, or anti-PDLl drugs such as Atezolizumab, Durvalumab, Avelumab, or anti-CTL4 drugs such as Ipilimumab or Tremelinumab, or other checkpoint inhibitors including bi-specific antibodies, or PARP inhibitors such as Olaparib, Niraparib, Velaparib, Rucaparib, Talazoparib, Pamiparib, Fluzoparib, or cell therapies such as T- cell receptor therapies, tumor-infiltrating lymphocytes, CAR-T, or immunotherapies such as APC-directed and macrophage-directed antibodies, or vaccines such as mRNA neoantigen vaccines, GM-CSF producing vaccines, peptide vaccines, or a combination thereof.

[0242] A compound as disclosed herein can be administered prior to, concurrently with and subsequent to the appearance of symptoms of a disease, disorder, and / or condition. In some embodiments, a provided bioactive ligand is administered or delivered concurrently with another704.101.419therapeutic agent. In some embodiments, a provided bioactive ligand is administered or delivered in a single composition with another therapeutic agent. In some embodiments, a provided bioactive ligand is administered or delivered concurrently with another therapeutic agent but in different compositions. In some embodiments, a provided bioactive ligand is administered or delivered prior to another therapeutic agent (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, or about 1, 2, 3, 4, or 5 weeks, or about 1, 2, 3, 4, or 5 months prior to another therapeutic agent). In some embodiments, a provided bioactive ligand is administered or delivered after another therapeutic agent (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, or about 1, 2, 3, 4, or 5 weeks, or about 1, 2, 3, 4, or 5 months after another therapeutic agent). In some embodiments, a provided bioactive ligand is administered or delivered when a subject is under the therapeutic effect of another therapeutic agent.Methods of Use

[0243] Among other things, compounds and compositions described herein can not only be used as radiolabeled-based therapy agents but can also be used as imaging agents in imaging modalities such as PET and SPECT technologies. In some embodiments, imaging modalities are employed to screen for and / or di agnose various disease states and / or follow treatment of various disease states in subjects. In some embodiments, a disease is a hyperproliferative disease. In some embodiments, a disease is cancer. In some embodiments, cancer is pancreatic cancer, breast cancer or brain cancer. In some embodiments, a disease is a cancer over-expressing LATE

[0244] Thus, one aspect of the present disclosure is that provided compounds (eg, a provided bioactive ligand) or compositions thereof can be used as a therapeutic agent and as an imaging agent, i.e., theranostic agents or as a “theranostic pair” of compounds (a first theranostic agent and a second theranostic agent). In some embodiments, a theranostic agent disclosed herein comprise at least two halogen atoms.

[0245] In some embodiments, a first theranostic agent and a second theranostic agent are the same, comprising the same radionuclide. Such a theranostic pair would have the same agent that can be served as both a radiolabeled-based therapy agent and an imaging agent (e.g.,

[0131] I and

[0211] At).704.101.419

[0246] In some embodiments, a first theranostic agent and a second theranostic agent are not the same. In some embodiments, a first theranostic agent is a therapeutic agent and is a provided bioactive ligand containing no radioisotopes. In such embodiments, a second theranostic agent is a provided bioactive ligand comprising a radionuclide generally known to be used in PET and SPEC!' imaging modalities (e.g.,

[0018] F,

[0124] I,

[0075] Br,

[0076] Br, and

[0077] Br,

[0123] I,

[0125] I,

[0131] I,

[0210] At or [21 l]At).

[0247] In an alternate embodiment, a first theranostic agent is a radiolabeled-based therapy agent and is a provided bioactive ligand or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof containing a radioi sotope generally known to be used in radiolabeled-based therapy agents (e.g.,

[0131] I and / or [21 l]At). In such embodiments, a second theranostic agent is a provided bioactive ligand or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof comprising a radionuclide generally known to be used in PET and SPECT imaging modalities (e.g.,

[0018] F,

[0124] I,

[0075] Br,

[0076] Br,

[0077] Br,

[0123] I,

[0125] I,

[0131] I,

[0210] At or [21 l]At).

[0248] In some embodiments, the atom connectivity (regardless of radioactivity) is the same in both theranostic agents. In other words, often a non-radioactive halogen can be replaced in one theranostic agent with the same or similar halogen but now being a radioisotope, and vice versa. In some embodiments, iodine or bromine can be swapped with radioisotopes of astatine.

[0249] Thus, one aspect of the present disclosure is to employ a provided bioactive ligand in methods of imaging a subject for diagnosing a disease or monitoring efficacy of treatment of a disease by a) administering to a subject in need thereof a radioactive compound as disclosed herein in an effective amount; and b) acquiring at least one image of at least a portion of the subject.

[0250] In some embodiments, a provided bioactive ligand contains a radioisotope suitable for use in imaging modalities such as PET and SPECT technologies. For example, a suitable radioisotope for use in PET imaging is selected from the group consisting of

[0018] F,

[0124] I,

[0075] Br,

[0076] Br,

[0077] Br and

[0210] At. A suitable radioisotope for use in SPECT imaging is

[0123] I,

[0125] I,

[0131] I, or

[0211] At. Thus, the compounds employed in the methods disclosed herein are prepared from compounds wherein R1is a radioisotope selected from the group consisting of

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0076] Br,

[0077] Br,

[0082] Br,

[0210] At and [21 l]At; orR2is

[0018] F. In some embodiments, the compounds employed in the methods disclosed herein are704.101.419prepared from compounds wherein R1is a radioisotope selected from the group consisting of

[0123] I,

[0124] I, [131 JI,

[0210] At and [21 IJAt; or R2is

[0018] F.

[0251] In some embodiments, a radioactive compound disclosed herein is part of a theranostic pair as described above. In some embodiments, a radioactive compound disclosed herein is used by itself and is not part of a theranostic pair as described herein.

[0252] In some embodiments, a radioactive compound disclosed herein is formulated into a pharmaceutical composition / formulation comprising at least one pharmaceutically acceptable excipient and / or carrier. As will be apparent to those skilled in the art, that one or more phar aceutically acceptable excipients or carriers will vary depending on the mode of administration of the radioactive compound to a subject in need thereof. In some embodiments, a pharmaceutical composition is in the form of a saline-based solution, a suspension, an emulsion, liposome-based preparation, microsphere-based preparation or any other pharmaceutical formulations in liquid form suitable for injection.

[0253] In some embodiments, an imaging method disclosed herein are employed for diagnosing a disease or assessing efficacy of treatment of a condition, disorder or disease in a subject in need thereof. In some embodiments, a condition, disorder or disease is cancer. In some embodiments, an imaging method is employed for diagnosing cancer.

[0254] In other embodiments, an imaging method described herein is employed for assessing the efficacy of a treatment to treat a condition, disorder or disease in a subject in need thereof. In some embodiments, a condition, disorder or disease is cancer.

[0255] In some embodiments, using an imaging method disclosed herein can aid in identifying the presence or absence of tumors and / or changes in size of identified tumors.

[0256] In some embodiments, a therapeutic method described herein comprises administration to the subject in need thereof a therapeutically effective amount of at least one therapeutic agent, i.e., an anti-cancer agent. A skilled artisan would generally be familiar with current anti-cancer treatments, which include, but are not limited to, administration of one or more anti-cancer drags, radiation, surgery', radiolabeled-based therapy, and / or any combination thereof. In some embodiments, the anti-cancer treatment comprises administration of a compound as described herein. In some embodiments, a provided bioactive ligand is not radioactive (e.g., neither of R1and R2are radioisotopes). In some embodiments, a provided bioactive ligand is radioactive (and thus contains a radionuclide).704.101.419

[0257] In some embodiments, the anti-cancer treatment comprises administration of a commercially available anti-cancer agent. Exemplary anti-cancer agents include, but are not limited to, Altretamine, Bendamustine, Busulfan, Carmustine, Chlorambucil, Cyclophosphamide, Dacarbazine, Ifosfamide, Lomustine, Lurbinectedin, Mechlorethamine, Melphalan, Procarbazine, Streptozocin, Temozolomide, Thiotepa, Trabectedin, Carboplatin, Cisplatin, Oxaliplatin, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitomycin, Mitoxantrone, Plicamycin, Valrubicin, Methotrexate, Pemetrexed, Pralatrexate, Trimetrexate, Azathioprine, Cladribine, Fludarabine, Mercaptopurine, Thioguanine, Azacitidine, Capecitabine, Cytarabine, Decitabine, Floxuridine, Fluorouracil, Gemcitabine, Trifluridine / Tipracil, Aldesleukin (IL-2), Denileukin Diftitox, Interferon Gamma, Belinostat, Panobinostat, Romidepsin, Vorinostat, Anti androgens: Abiraterone, Apalutamide, Bicalutamide, Cyproterone, Enzalutamide, Flutamide, Nilutamide, Antiestrogens (including Aromatase Inhibitors): Anastrozole, Exemestane, Fulvestrant, Letrozole, Raloxifene, Tamoxifen, Toremifene, Gonadotropin Releasing Hormone Analogues: Degarelix, Goserelin, Histrelin, Leuprolide, Relugolix, Triptorelin, Lanreotide, Octreotide, Pasireotide, Alemtuzumab, Atezolizumab, Avelumab, Bevacizumab, Blinatumomab, Brentuximab, Cemiplimab, Cetuximab, Daratumumab, Dinutuximab, Dostarlimab, Durvalumab, Elotuzumab, Gemtuzumab, Inotuzumab Ozogamicin, Ipilimumab, Mogamulizumab, Moxetumomab Pasudotox, Necitumumab, Nivolumab, Ofatumumab, Olaratumab, Panitumumab, Pembrolizumab, Pertuzumab, Ramucirumab, Rituximab, Teclistamab, Tositumomab, Trastuzumab, Tremelimumab, Abemaciclib, Acalabrutinib, Afatinib, Alectinib, Alpelisib, Axitinib, Binimetinib, Bortezomib, Bosutinib, Brigatinib, Cabozantinib, Carfilzomib, Ceritinib, Cobimetinib, Copanlisib, Crizotinib, Dabrafenib, Dacomitinib, Dasatinib, Duvelisib, Enasidenib, Encorafenib, Entrectinib, Erdafitinib, Erlotinib, Fedratinib, Futibatinib, Gefitinib, Gilteritinib, Glasdegib, Ibrutinib, Idelalisib, Imatinib, Infigratinib, Ivosi denib, Ixazomib, Lapatinib, Larotrectinib, Lenvatinib, Lorlatinib, Midostaurin, Neratinib, Nilotinib, Niraparib, Olaparib, Osimertinib, Palbociclib, Pazopanib, Pemigatinib, Pexidartinib, Ponatinib, Regorafenib, Ribociclib, Rucaparib, Ruxolitinib, Selumetinib, Sonidegib, Sorafenib, Sunitinib, Talazoparib, Trametinib, Vandetanib, Vemurafenib, Vismodegib, Zanubrutinib, Cabazitaxel, Docetaxel, Paclitaxel, Etoposide, Irinotecan, Teniposide, Topotecan, Vinblastine, Vincristine, Vinorelbine, Asparaginase (Pegaspargase), Belzutifan, Bexarotene, Cedazuridine, Eribulin, Everolimus, Hydroxyurea,704.101.419Ixabepilone, Lenalidomide, Mitotane, Omacetaxine, Pomalidomide, Selinexor, Tagraxofusp, Tazemetostat, Tebentafusp, Telotristat, Temsirolimus, Thalidomide, and Venetoclax.

[0258] In some embodiments, the treatment comprises a commercially available radiolabeled-based therapeutic agent. Exemplary commercially available radiolabel-based therapeutic agent include, but are not limited to, radium-223 dichloride (Xofigo®), sodium iodide 1-131 (Hicon®), lobenguane iodine-131 (Azedra®), lutetium-177 (Lutathera® and Pluvicto®) and yttrium-90 (Zevalin®).

[0259] In some embodiments, the therapeutic agent is administered prior to administration of the imaging agent disclosed herein.EXAMPLESPreparation of Precursors and Prosthetic GroupsExample 1: Synthesis SI

[0260] Carboxylic acid SI is prepared according to a procedure disclosed in Nature Catalysis 2020, 3 (9), 734-742, which is incorporated herein by reference.Example 2: Synthesis of S2704.101.419

[0261] Alcohol S2 is prepared according to a procedure disclosed in Nature Catalysis 2020, 3 (9), 734-742, which is incorporated herein by reference.Example 3: Synthesis of Pl

[0262] To a solution of SI (0.050 mmol) in DMF (0.2 mL) is added HATU (0.10 mmol) and DIPEA (0.25 mmol). After 1 hour, 3 -azidopropylamine (1 equiv.) is added. After 3 days, flash chromatography affords Pl.Example 4: Synthesis of P2

[0263] To a solution of SI (0.050 mmol) in DMF (0.2 mL) is added HATU (0.10 mmol) and DIPEA (43.5 pL, 0.25 mmol). After 1 hour, amine S4 (0.050 mmol) is added. After 2 days, gradient flash chromatography affords P2.Example 5: Synthesis of P3

[0264] To a solution of carboxylic acid SI (0.89 mmol) in DMF (3.0 mL) is added A, A, V’, A’-tetramethyl-(?-(jV-succinimidyl)uronium tetrafluoroborate (TSTU, 1.78 mmol) and704.101.419DIPEA (472 pL, 2.70 mmol). After 20 hours, flash chromatography furnishes the succinimidyl ester P3.Example 6: Synthesis of P4

[0265] To a solution of alcohol S2 (1.44 mmol) in DCM (14.4 mL) is added phosphorus tribromide solution (1 M solution in DCM, 2.16 mmol). After 6 hours, water (1 mL) is added.The mixture is extracted with EtOAc. Concentration and flash chromatography furnishes P4.Example 7: Synthesis of P5

[0266] To a solution of alcohol S2 (1.13 mmol) in THF (11.3 mL) is added chloroacetyl isocyanate (1.13 mmol). After 4 hours, mixture is concentrated. P5 is purified by flash chromatography.Example 8: Synthesis of P6

[0267] To a solution of alcohol S3 (2.91 mmol) in DCM (5.8 mL) is added diethyl chlorophosphate (5.8 mmol) and pyridine (7.3 mmol). After 3.5 hours, water (10 mL) is added.704.101.419The mixture is extracted with DCM. Concentration and flash chromatography affords Intermediate. To a solution of Intermediate (0.50 mmol) in 1,4-dioxane (1 mL) is added silver oxide (0.05 mmol) and TMSCN (1.0 mmol). The mixture was heated at 85 °C for 30 min. P6 is purified by flash chromatography.Example 9: Synthesis of P7NCOS2 P7

[0268] To a solution of alcohol S2 (0.13 mmol) in THF (152 pL) is added hexamethylene diisocyanate (0.76 mmol). After 7 days, the mixture is concentrated and P7 is purified by chromatography.RadiochemistryExample 10:18F-labeling of Various Prosthetic Groups

[0269] 18F-Labeling - General photoredox method: A solution of precursor, e.g., Pl, (0.05 mmol) in a solvent mixture ( / -butyl alcohol: DCM: MeCN = 4:3:1, 800 pL or 400 pL) isprepared in a 5 mL V vial in the open air. A photocatalyst, e.g., SIS1(1.5 mg, 0.0025 mmol) and tetrabutylammonium bicarbonate solution (60 mg / mL solution in MeCN, 25 pL, 15 pL or 0 pL) are then added. [18F]TBAF / MeCN solution (typically 10 -20 mCi) is added last. A balloon (filled with pure oxygen or air) is attached to a needle, which is inserted into the reaction mixture and provided steady oxygen (or air) flow in a bubbling manner. The V vial containing the mixture is then irradiated top-down with a laser (MDL-D-450, 450 nm, 3.5 W, 30 min or 20 min irradiation). An aliquot of the resulting mixture is analyzed and purified by HPLC, furnishing the corresponding18F-labeled synthons.704.101.419Photocatalyst S118F O O2flow, 450 nm laser t-BuOH, MeCN, DCE [18F]TBAF10a

[0270] [ 18F] 10a is prepared via general photoredox procedure (800 pL solvent mixture, 15 pL TBAB / MeCN, oxygen flow and 30 min laser irradiation).

[0271] [18F]10b is prepared via general photoredox procedure (800 pL solvent mixture, 15 pL TBAB / MeCN, oxygen flow and 30 min laser irradiation).Photocatalyst S1O2flow, 450 nm laser t-BuOH, MeCN, DCE [18F]TBAF10c

[0272] [18F]10c is prepared synthesized via general photoredox procedure (800 pL solvent mixture, air flow and 20 min laser irradiation).Photocatalyst S118FO2flow, 450 nm laser t-BuOH, MeCN, DCE [18F]TBAFO I

[0273] [18F]10d is prepared from bromide precursor P4 via general photoredox procedure (400 pL solvent mixture, 25 pL TBAB / MeCN, air flow and 20 min laser irradiation.704.101.419Photocatalyst S1 O2flow, 450 nm laser t-BuOH, MeCN, DCE [18F]TBAF10e

[0274] [ 18F] 1 Oe is prepared from chloride precursor P5 via general photoredox procedure (400 pL solvent mixture, 25 pL TBAB / MeCN, air flow and 20 min laser irradiation).Photocatalyst S1O2flow, 450 nm laser t-BuOH, MeCN, DCE TBAB, [18F]TBAF

[0275] [ 18F] 1 Of is prepared via a modified procedure where isocyanide P6 (0.016 mmol) is dissolved in solvent mixture ( / -butyl alcohol: DCM: MeCN = 4:3:1, 133 pL) in a quartz tube opened to air. Photocatalyst S I (8.5 pmol), tetrabutylammonium bicarbonate solution (60 mg / mL solution in MeCN, 8.3 pL), and [18F]TBAF / MeCN solution (1.7 mCi to 8.1 mCi) are added. The quartz tube is then sealed with a plastic screw cap, and irradiated with a 450 nm LED for 20 min. An aliquot of the resulting mixture is analyzed and purified by HPLC, affording lOf.

[0276] [18F]10g is prepared prepared from isocyanate precursor P7 via general photoredox procedure (400 pL solvent mixture, air flow and 20 min laser irradiation).Example 11:131I / 211At Labeling of Various Prosthetic Groups704.101.419

[0277] 131I / 211At labeling:. Various prosthetic groups is labeled with

[0131] I /

[0211] At from the appropriate precursor as described herein, e.g., a compound of Formula (INT-a).

[0131] I / [21 l]At will be preferentially used for radionuclide-based therapy.Conjugation of radiolabeled prosthetic groups to bioactive ligandsExample 12: Conjugation to PSMA-617DIPEA, DMF, H2O

[0278] To a solution of [18F]10c in MeCN / H2O is added PSMA-617. After 0.5-1 hours, the mixture is purified by HPLC.704.101.419DiPEA MeCN, H2O

[0279] To a solution of [211At]10h in MeCN / H2O is added PSMA-617. After 0.5-l hours, the mixture is purified by HPLC. *At is [211At].Example 13: Conjugation to Zolbetuximab (IMAB362)

[0280] The present Example demonstrates the conjugation of radiolabeled prosthetic groups as described herein to Zolbetuximab.

[0281] To a solution of [18F]10c or [*At]10h in DMF is added Zolbetuximab. After 0.5-1 hours, the mixture is purified by HPLC. *At is [211At],704.101.419

[0282] To a solution of [18F]10i or [*At]10j in DMF is added Zolbetuximab. After 0.5-1 hours, the mixture is purified by HPLC. *At is [211At],Example 14: Conjugation to GIypican-3 (GPC3) Small Peptide Ligand

[0283] The present Example demonstrates the conjugation of radiolabeled prosthetic groups as described herein to Glypican-3 (GPC3) small peptide ligand through serine NH2.(SEQ IDNO: 15) (SEQ ID NO: 15)704.101.419•At ODIPEA, DMF (SEQ ID NO: 15) (SEQ ID NO: 15)

[0284] To a solution of [18F] 10c or [*At]10h in DMF is added Glypican-3 (GPC3) small peptide ligand. After 0.5-1 hours, the mixture is purified by HPLC. *At is [211At],(SEQ ID NO: 15)(SEQ ID NO: 15)704.101.419RKQLINPPRDN OMeNH2'At (SEQ ID NO: 15)

[0285] To a solution of [18F] lOi or [*At] lOj in DMF is added Glypican-3 (GPC3) small peptide ligand. After 0.5-1 hours, the mixture is purified by HPLC. *At is [211At],

[0286] The present Example demonstrates the conjugation of radiolabeled prosthetic groups as described herein to Glypican-3 (GPC3) small peptide ligand through cys-SH.(SEQ ID NO: 16) (SEQ ID NO: 16)10m *At 0RKQLINPPRDNS DIPEA, DMF(SEQ ID NO: 16) (SEQ ID NO: 16)

[0287] To a solution of [18F] 101 or [*At]10m in DMF is added Glypican-3 (GPC3) small peptide ligand. After 0.5-1 hours, the mixture is purified by HPLC. *At is [211At],704.101.419RKQLINPPRDNS NH2(SEQ IDNO: 16)18F RKQLINPPRDNS OMeNH2(SEQ IDNO: 16)RKQLINPPRDNSNH2(SEQ IDNO: 16)F RKQLINPPRDNS N2*At O (SEQ ID NO: 16)

[0288] To a solution of [18F]10n or [*At]10o in DMF is added Glypican-3 (GPC3) small peptide ligand. After 0.5-1 hours, the mixture is purified by HPLC. *At is [211At],Example 15: Conjugation to N188 Nectin-4 Targeting Bi-eyclic Peptide704.101.419O | J! I N^ J P I H \I18F o J-Y 10c oxDIPEA, DMFO I (SEQ ID NO: 17)704.101.419O ‘AtMe0VY°'j5 10hF° DIPEA, DMF(SEQ IDNO: 17)

[0289] To a solution of [18F]10c or [*At]10h in DMF is added Nectin-4 targeting bicyclic peptide. After 0.5-1 hours, the mixture is purified by HPLC. *At is [211At], D-Asp = D-Aspartic acid; Nal = L-3-(2-naphthyl)alanine; Hyp = L-hydroxyproline (e.g., 4 (or 3)-hydroxyproline).704.101.419Example 16: Conjugation to Single-Domain Nanobody

[0290] To a solution of [18F]10c or [*At]10m in DMF is added single chain nanobody.After 0.5-1 hours, the mixture is purified by HPLC. *At is [211At].Example 17: Synthesis of / ert-Butyl 3-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoate Scheme 1: Representation of / / 7-Butyl 3-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoateScheme 2: Representative synthetic route for Zert-Butyl 3-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoateSTEP 1: 5-fluoro-2-methoxy-3-methylbenzaldehydeTo a stirred of 5 -fluoro-2-hydroxy-3 -methylbenzaldehyde (25.0 g, 162 mmol) in DMF (400 mL) was added K2CO3 (33.6 g, 243 mmol) and CH3I (34.6 g, 243 mmol). After 2 h, the mixture was704.101.419poured into ice-water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 20%) to afford 5-fluoro-2-methoxy-3-methylbenzaldehyde (23.0 g, 84%) as a white solid. LCMS (ES, m / z): 169.10 [M+H]+.STEP 2: 3-fluoro-2-iodo-6-methoxy-5-methylbenzaldehydeTo a stirred mixture of 5-fluoro-2-methoxy-3-methylbenzaldehyde (10.0 g, 59.5 mmol) in DCE (240 mL) was added / V-Iodosuccinimide (16.1 g, 71.4 mmol), Pd(OAc)2 (3.35 g, 14.9 mmol), 2-Amino-5-chlorobenzotrifluoride (5.81 g, 29.8 mmol) and TFA (48 mL), dropwise. After heating at 60 °C for 24 h, the mixture was cooled to rt, poured into ice-water (500 mL) and extracted with DCM (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 0-60% with 0.1% FA) to afford 3-fluoro-2-iodo-6-methoxy-5-methylbenzaldehyde (4.00 g, 22%) as a yellow solid. LCMS (ES, m / z): 294.90 [M+Hf.STEP 3: 3-fluoro-2-iodo-6-methoxy-5-methylbenzoic acidTo a solution of 3-fluoro-2-iodo-6-methoxy-5-methylbenzaldehyde (4.00 g, 13.6 mmol) in ACN (60 mL) was added a solution of NaFLPCL (1.80 g, 15.0 mmol) in H2O (12 mL), NaClCL (80%, 1.70 g, 15.0 mmol) and H2O2 (25% aq, 2.04 g, 15.0 mmol), dropwise. After 4 h, the mixture was concentrated under reduced pressure and purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 0-50% with 0.1% FA) to afford 3-fluoro-2-iodo-6-methoxy-5-methylbenzoic acid (3.5 g, 82%) as a white solid. LCMS (ES, m / z): 310.95 [M+H]+.STEP 4: tert-butyl 3-fluoro-2-iodo-6-methoxy-5-methylbenzoateTo a mixture of 3-fluoro-2-iodo-6-methoxy-5-methylbenzoic acid (2.00 g, 6.45 mmol) in t-BuOH (20 mL) was added DMAP (80 mg, 0.65 mmol) followed by di-tert-butyl dicarbonate (7.03 g, 32.3 mmol). After heating at 80 °C for 2 h, the mixture was cooled to rt, poured into icewater (200 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 10%), affording tert-butyl 3-fluoro-2-iodo-6-methoxy-5-methylbenzoate (2.0 g, 84%) as a yellow solid. GCMS (El, m / z): 365.90 [M],704.101.419STEP 5: tert-butyl 3-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoateTo a mixture of / e / V-butyl 3 -fluoro-2-iodo-6-m ethoxy-5 -methylbenzoate (1.80 g, 4.92 mmol) in CCh (18 mL) was added A-bromosuccinimide (1.31 g, 7.38 mmol) and benzoyl peroxide (75% aq, 59 mg, 0.49 mmol). After heating at 70 °C for 16 h, the mixture was cooled to room temperature, poured into ice-water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 9%) to afford Zc / 7-butyl 3-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoate (700 mg, 32%) as a colorless oil. GCMS (El, m / z): 443.90 [M] Example 18: Synthesis of methyl 3-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoate Scheme 3: Representation of methyl 3-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoateScheme 4: Representative synthetic route for methyl 3-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoateSTEP 1: methyl 3-fluoro-2-iodo-6-methoxy-5-methylbenzoateTo a mixture of 3-fluoro-2-iodo-6-methoxy-5-methylbenzoic acid (1.50 g, 4.84 mmol) in DME (15 mL) was added K2CO3 (2.01 g, 14.5 mmol) and CH3I (1.37 g, 9.68 mmol). After 16 h, the mixture was poured into ice-water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 20%) to afford methyl 3-fluoro-2-iodo-6-methoxy-5-methylbenzoate (1.30 g, 82%) as a white solid. LCMS (ES, m / z): 324.90 [M+H]+.STEP 2: methyl 3-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoate704.101.419To a solution of methyl 3-fluoro-2-iodo-6-methoxy-5-methylbenzoate (1.30 g, 4.01 mmol) in CCI4 (13 mL) was added A-bromosuccinimide (1.07 g, 6.02 mmol) and benzoyl peroxide (96.8 mg, 0.40 mmol). After heating the mixture at 70 °C for 16 h, it was cooled to rt poured into icewater (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NazSCL and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 10%) to afford methyl 3-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoate (800 mg, 49%) as a colorless oil. GCMS (El, m / z): 401.90 [M],Example 19: Synthesis of Methyl 5-(4-chlorophenoxy)-3-(hydroxymethyl)-2-iodobenzoate Scheme 5: Representation of methyl 5-(4-chlorophenoxy)-3-(hydroxymethyl)-2 -iodobenzoate1Scheme 6: Representative synthesis of methyl 5-(4-chlorophenoxy)-3-(hydroxymethyl)-2-iodobenzoateSTEP 1: 5-fluoro-3-methyl-2-nitrobenzoic acidTo a mixture of 3-fluoro-5-methylbenzoic acid (20.0 g, 129 mmol) in H2SO4 (200 mL) at 0 °C was added KNO3 (14.4 g, 143 mmol), portion-wise. After 2 h at rt, the mixture was slowly quenched by addition into crushed-ice by drop-wise addition. The resulting solids were collected704.101.419by filtration, washed with water (2 x 100 mL) and dried under vacuum to afford 5-fluoro-3-methyl-2-nitrobenzoic acid (16 g, 62%) as a yellow solid. LCMS (ES, m / z):198.10 [M-H]’ STEP 2: methyl 5-fluoro-3-methyl-2-nitrobenzoateTo a mixture of 5-fluoro-3-methyl-2-nitrobenzoic acid (16.0 g, 80.3 mmol) and K2CO3 (33.3 g, 241 mmol) in DMF (250 mL) was added and CH3I (13.7 g, 96.4 mmol). After 2 h, the mixture was poured into water (300 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 25%) to afford methyl 5-fluoro-3-methyl-2-nitrobenzoate (12 g, 70%) as a yellow oil. GCMS (El, m / z): 213.10 [M]STEP 3: methyl 5-(4-chlorophenoxy)-3-methyl-2-nitrobenzoateA mixture of methyl 5-fluoro-3-methyl-2-nitrobenzoate (13.0 g, 61.0 mmol), chlorophenol (7.84 g, 61.0 mmol) and K2CO3 (25.3 g, 183 mmol) in DMF (200 mL) was stirred at 80 °C for 2 h. Upon cooling to rt, it was poured into water (200 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 50%) to afford methyl 5-(4-chlorophenoxy)-3-methyl-2-nitrobenzoate (13 g, 66%) as a yellow solid. GCMS (El, m / z): 321.10 [M]STEP 4: methyl 2-amino-5-(4-chlorophenoxy)-3-methylbenzoateTo a solution of methyl 5-(4-chlorophenoxy)-3-methyl-2-nitrobenzoate (1.60 g, 4.93 mmol) and B2(OH)4 (490 mg, 5.47 mmol) in DMF (15 mL) at 0 °C was added a solution of 4-(pyridin-4-yl)pyridine (3.88 g, 0.25 mol) in DMF (1 mL). After 30 min at rt, the mixture was poured into water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 10-80% with 0.1% FA), affording methyl 2-amino-5-(4-chlorophenoxy)-3-methylbenzoate (800 mg, 5%) as a yellow solid. LCMS (ES, m / z): 292.30 [M+H]+STEP 5: methyl 5-(4-chlorophenoxy)-2-iodo-3-methylbenzoateTo a solution of methyl 2-amino-5-(4-chlorophenoxy)-3-methylbenzoate (4.00 g, 13.7 mmol) in HC1 (6 M, 40 mL) at 0 °C was added a solution of NaNO2 (1.42 g, 20.5 mmol) in water (5 mL), dropwise. After 30 min at 0 °C, a solution of KI (3.41 g, 20.5 mmol) in water (5 mL) was added.704.101.419After an additional 1 h rt, the mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 17%), affording methyl 5-(4-chlorophenoxy)-2-iodo-3-methylbenzoate (3.0 g, 54%) as a yellow oil. LCMS (ES, m / z): 403.30 [M i ll] STEP 6: 5-(4-chlorophenoxy)-2-iodo-3-(methoxycarbonyl)benzoic acidTo a mixture of methyl 5-(4-chlorophenoxy)-2-iodo-3-methylbenzoate (7.90 g, 19.6 mmol) in t-BuOH / water (1: 1, 60 mL) was added KMnO₄ (9.31 g, 58.8 mmol). After heating at 70 °C for 16 h, the mixture was cooled to rt, diluted with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude residue was purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 5-80% with 0.1% FA), affording 5-(4-chlorophenoxy)-2-iodo-3-(methoxycarbonyl)benzoic acid (2.6 g, 30%) as a white solid. LCMS (ES, m / z): 433.15 [M+H]~.STEP 7: methyl 5-(4-chlorophenoxy)-3-(hydroxymethyl)-2-iodobenzoateTo a mixture of 5-(4-chlorophenoxy)-2-iodo-3-(methoxycarbonyl)benzoic acid (2.60 g, 6.01 mmol) in THF (15 mL) at 0 °C was added a solution of BH3-THF complex (1.0 M in THF, 30 mL), dropwise. After 5 h at rt, the mixture was slowly poured into MeOH (30 mL), whereupon it was heated at 70 °C for 1 h, cooled to rt, then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 50%) to afford methyl 5-(4-chlorophenoxy)-3-(hydroxymethyl)-2-iodobenzoate (1.3 g, 51%) as a white solid. ’HNMR (400 MHz, DMSO-tL) 57.51-7.45 (m, 2H), 7.22 (d, J= 3.0 Hz, 1H), 7.15-7.09 (m, 3H), 5.63 (t, J= 5.5 Hz, 1H), 4.42 (d, J= 5.5 Hz, 2H), 3.83 (s, 3H). LCMS (ES, m / z): 418.95 [M+H]+; 99.8% purity (254 nm).Example 20: Synthesis of Methyl 3-(bromomethyl)-5-(4-chlorophenoxy)-2 -iodobenzoate Scheme 7 - Representation of methyl 3-(bromomethyl)-5-(4-chlorophenoxy)-2-iodobenzoate704.101.419Scheme 8 - Representative synthetic method for methyl 3-(bromomethyl)-5-(4-chlorophenoxy)-2-iodobenzoateTo a solution of methyl 5-(4-chlorophenoxy)-3-(hydroxymethyl)-2-iodobenzoate (1.30 g, 3.10 mmol) in DCM (15 mL) at 0 °C was added PBn (1.67 g, 6.22 mmol), dropwise. After 1 h at rt, the mixture was concentrated under reduced pressure and purified by silica gel chromatography (EA-Petroleum ether, 50%) to afford methyl 3-(bromomethyl)-5-(4-chlorophenoxy)-2-iodobenzoate (1.2 g, 80%) as a white solid.NMR (400 MHz, DMSO) 87.52-7.46 (m, 3H), 7.16-7.10 (m, 3H), 4.78 (s, 2H), 3.84 (s, 3H). LCMS (ES, m / z): 480.75, 482.75 [M+H]1; 99.8% purity (254 nm).Example 21: Synthesis of 2,5-Dioxopyrrolidin-l-yl 2-(( / c77-butoxycarbonyl)amino)-3-(5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodophenyl)propanoateScheme 9: Representation of 2,5-dioxopyrrolidin-l-yl 2-((ter / -butoxycarbonyl)amino)-3-(5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodophenyl)propanoateScheme 10: Representative synthetic route for,5-dioxopyrrolidin-l-yl 2-((lerl-butoxycarbonyl)amino)-3-(5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodophenyl)propanoate704.101.419STEP 1: methyl 3-(3-(teH-butoxy)-2-((dipheiiylmethylene)amino)-3-oxopropyl)-5-(4- chlorophenoxy)-2-iodobenzoateTo a mixture of methyl 3-(bromomethyl)-5-(4-chlorophenoxy)-2-iodobenzoate (600 mg, 1.25 mmol) in ACN (4 mL) was added / cvz-butyl 2-((diphenylmethylene)amino)acetate (552 mg, 1.86 mmol), tetrabutylammonium bromide (40 mg, 0.12 mmol) and K2CO3 (517 mg, 3.75 mmol). After 16 h, the mixture was fdtered, the filter cake was washed ACN (3 x 20 mL) and the filtrate was concentrated under reduced pressure. The crude residue was purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 5-100% with 10 mM NH4HCO3), affording methyl 3-(3-(te / 7-butoxy)-2-((diphenylmethylene)amino)-3-oxopropyl)-5-(4-chlorophenoxy)-2- iodobenzoate (350 mg, 40%) as a white solid. 'H NMR (400 MHz, DMSO-t / e) 87.50-7.35 (m, 8H), 7.21-7.15 (m, 2H), 7.08 (d, J= 2.9 Hz, 1H), 6.92 (d, J= 2.9 Hz, 1H), 6.83-6.77 (m, 2H), 6.49 (br d, J= 4.4 Hz, 2H), 4.21 (dd, J= 9.9, 3.8 Hz, 1H), 3.84 (s, 3H), 3.38-3.32 (m, 1H), 3.25 (dd, J= 13.3, 9.9 Hz, 1H), 1.39 (s, 9H). LCMS (ES, m / z): 696.10 [M+H]+; 95.9% purity (254 nm).STEP 2: 3-(3-(tert-butoxy)-2-((diphenylmethylene)amino)-3-oxopropyl)-5-(4- chlorophenoxy)-2-iodobenzoic acid704.101.419To a mixture of methyl methyl 3-(3-(tert-butoxy)-2-((diphenylmethylene)amino)-3-oxopropyl)-5-(4-chlorophenoxy)-2 -iodobenzoate (620 mg, 0.89 mmol) in THF / MeOH (1:1, 6 mb) was added LiOH»H2O (748 mg, 17.8 mmol). After 16 h, the mixture was cooled to 0 °C, acidified to pH~7 with HC1 (2 M) and extracted with EA (3 x 50 mb). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 5-100% with 10 mM NH4HCO3) to afford 3-(3-(tert-butoxy)-2-((diphenylmethylene)amino)-3-oxopropyl)-5-(4-chlorophenoxy)-2-iodobenzoic acid (360 mg, 59%) as a white solid. LCMS (ES, m / z): 682.05 [M+H]+.STEP 3: tert-butyl 3-[5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodophenyl]-2-[(diphenylmethylidene)aminojpropanoateTo a solution of 3-[3-(tert-butoxy)-2-[(diphenylmethylidene)amino]-3-oxopropyl]-5-(4-chlorophenoxy)-2-iodobenzoic acid (360 mg, 0.52 mmol) in MeCN (2 mb) was added dimethylamine hydrochloride (86 mg, 1.05 mmol), TCFH (444 mg, 1.58 mmol) and N-methylimidazole (433 mg, 5.27 mmol). After 16 h, the mixture was purified by reverse flash chromatography (C18 silica gel, ACN-water, 5-100% with 10 mM NH4HCO3) to afford tertbutyl 3-[5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodophenyl]-2-[(diphenylmethylidene)amino]propanoate (200 mg, 53%) as a white solid. LCMS (ES, m / z): 709.15 [M+H]~.STEP 4: 2-amino-3-[5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodophenyl]propanoic acidTo a solution of tert-butyl 3-[5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodophenyl]-2-[(diphenylmethylidene)amino]propanoate (200 mg, 0.28 mmol) in DCM (1.5 mb) was added TFA (1.5 mL). After 2 h, the mixture was concentrated under reduced pressure then re-dissolved in EtOH / water (4:1, 2.5 mL), whereupon hydroxylamine hydrochloride (253 mg, 3.67 mmol) was added. After heating at 50 °C for 4 h, the mixture was cooled to rt and purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 5-40% with 10 mM NH4HCO3), affording 2-amino-3-[5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodophenyl]propanoic acid (100 mg, 72%) as a white solid. LCMS (ES, m / z): 489.15 [M+H]+.STEP 5: 2-[(tert-butoxycarbonyl)amino]-3-[5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodophenyl] propanoic acid704.101.419To a mixture of 2-amino-3-[5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodophenyl]propanoic acid (100 mg, 0.20 mmol) in DCM (2 mL) was added TEA (62 mg, 0.61 mmol) and di- / c / 7-butyl dicarbonate (54 mg, 0.24 mmol). After 1 h, the mixture was concentrated under reduced pressure and the crude residue was purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 5-80% with 10 mM NH4HCO3), affording 2-[(tert-butoxycarbonyl)amino]-3-[5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodophenyl]propanoic acid (100 mg, 83%) as a white solid. LCMS (ES, m / z): 589.10 [M+H]+.STEP 6: 2,5-dioxopyrrolidin-l-yl 2-[(tert-butoxycarbonyl)amino]-3-[5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodophenyl]propanoateTo a mixture of 2-[(tert-butoxycarbonyl)amino]-3-[5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodophenyl]propanoic acid (90 mg, 0.15 mmol) in DMF (1 mL) was added EDCI (37 mg, 0.19 mmol) and A-hydroxysuccinimide (27 mg, 0.23 mmol). After 1 h, the mixture was diluted with ice-water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (Column: XBridge Prep Shield RP18 OBD C18 5 pm, 30 x 150 mm; Mobile Phase: ACN-water, 39-69%; Flow Rate: 60 mL / min; Wavelength: 254 / 220 nm), affording the title compound (25.7 mg, 24%) as a white solid.NMR (400 MHz, DMSO-c / e) 8 *7.72 (d, J= 8.6 Hz, 0.3H), *7.66 (d, J= 9.3 Hz, 0.5H), 7.50-7.39 (m, 2H), 7.19-7.03 (m, 3H), 6.84-6.76 (m, 1H), 4.89-*4.79 (m, 0.5H), 4.70-4.55 (m, 0.5H), 3.39-3.33 (m, 1H), 3.20-3.02 (m, 1H), 3.01-2.92 (m, 3H), 2.83 (s, 4H), 2.78-2.69 (m, 3H), 1.40-1.18 (m, 9H). *Partial integration due to presence of rotamers. LCMS (ES, m / z): 630.00 [M-tBu+H]+.Example 22: Synthesis of 2,5-Dioxopyrrolidin-l-yl 3 -carbamoyl-5 -(4-chlorophenoxy)-2-iodobenzoateScheme 11: Representation of 2,5-dioxopyrrolidin-l-yl 3-carbamoyl-5-(4-chlorophenoxy)-2-iodobenzoate704.101.419Scheme 12: Representative synthetic route for 2,5-dioxopyrrolidin-l-yl 3-carbamoyl-5-(4- chlorophenoxy)-2-iodobenzoateSTEP 1: 5-fluoro-3-methyl-2-nitrobenzoic acidTo a mixture of 3-fluoro-5-methylbenzoic acid (20.0 g, 129 mmol) in H2SO4 (200 mL) at 0 °C was added KNO3 (14.4 g, 143 mmol), portion-wise. After 2 h at rt, the mixture was slowly quenched by addition into crushed-ice by drop-wise addition. The resulting solids were collected by filtration, washed with water (2 x 100 mL) and dried under vacuum to afford 5-fluoro-3- methyl-2-nitrobenzoic acid (16 g, 62%) as a yellow solid. LCMS (ES, m / z):198.10 [M-H]’. STEP 2: methyl 5-fluoro-3-methyl-2-nitrobenzoateTo a mixture of 5-fluoro-3-methyl-2-nitrobenzoic acid (16.0 g, 80.3 mmol) and K2CO3 (33.3 g, 241 mmol) in DMF (250 mL) was added and CH3I (13.7 g, 96.4 mmol). After 2 h, the mixture was poured into water (300 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 25%) to afford methyl 5-fluoro-3-methyl-2-nitrobenzoate (12 g, 70%) as a yellow oil. GCMS (El, m / z): 213.10 [M],STEP 3: methyl 5-(4-chlorophenoxy)-3-methyl-2-nitrobenzoate704.101.419A mixture of methyl 5-fluoro-3-methyl-2-nitrobenzoate (13.0 g, 61.0 mmol), chlorophenol (7.84 g, 61.0 mmol) and K2CO3 (25.3 g, 183 mmol) in DMF (200 mL) was stirred at 80 °C for 2 h. Upon cooling to rt, it was poured into water (200 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 50%) to afford methyl 5-(4-chlorophenoxy)-3-methyl-2-nitrobenzoate (13 g, 66%) as a yellow solid. GCMS (El, m / z): 321.10 [M],STEP 4: methyl 2-amino-5-(4-chlorophenoxy)-3-methylbenzoateTo a solution of methyl 5-(4-chlorophenoxy)-3-methyl-2-nitrobenzoate (1.60 g, 4.93 mmol) and B2(OH)4 (490 mg, 5.47 mmol) in DMF (15 mL) at 0 °C was added a solution of 4-(pyridin-4-yl)pyridine (3.88 g, 0.25 mol) in DMF (1 mL). After 30 min at rt, the mixture was poured into water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 10-80% with 0.1% FA), affording methyl 2-amino-5-(4-chlorophenoxy)-3-methylbenzoate (800 mg, 5%) as a yellow solid. LCMS (ES, m / z): 292.30 [M+H]+.STEP 5: methyl 5-(4-chlorophenoxy)-2-iodo-3-methylbenzoateTo a solution of methyl 2-amino-5-(4-chlorophenoxy)-3-methylbenzoate (4.00 g, 13.7 mmol) in HC1 (6 M, 40 mL) at 0 °C was added a solution of NaNCh (1.42 g, 20.5 mmol) in water (5 mL), dropwise. After 30 min at 0 °C, a solution of KI (3.41 g, 20.5 mmol) in water (5 mL) was added. After an additional 1 h rt, the mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 17%), affording methyl 5-(4-chlorophenoxy)-2-iodo-3-methylbenzoate (3.0 g, 54%) as a yellow oil. LCMS (ES, m / z): 403.30 [M+H].STEP 6: 5-(4-chlorophenoxy)-2-iodo-3-methylbenzoic acidTo a solution of methyl 5-(4-chlorophenoxy)-2-iodo-3-methylbenzoate (1.20 g, 2.98 mmol) in MeOH (4 mL) at 0 °C was added a solution of LiOH (358 mg, 14.9 mmol) in water (4 mL). After 3 h, the mixture was partially concentrated under reduced pressure, cooled to at 0 °C, acidified with HC1 (2 M) to pH~4, then extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated704.101.419under reduced pressure to afford 5-(4-chlorophenoxy)-2-iodo-3-methylbenzoic acid (1.0 g, 86%) as an off-white solid. LCMS (ES, m / z): 387.10 [M-H]'.STEP 7: 5-(4-chlorophenoxy)-2-iodo-3-methylbenzamideTo a mixture of 5-(4-chlorophenoxy)-2-iodo-3-methylbenzoic acid (500 mg, 1.29 mmol) in DMF (3 mL) was added NH4CI (82 mg, 1.54 mmol), HATU (489 mg, 1.29 mmol) and DIEA (499 mg, 3.86 mmol). After 1 h, the mixture was directly purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 0-80% with 0.1% FA) to afford 5-(4-chlorophenoxy)-2-iodo-3-methylbenzamide (400 mg, 80%) as a white solid. LCMS (ES, m / z): 388.20 [M+H]+.STEP 8: 3-carbamoyl-5-(4-chlorophenoxy)-2-iodobenzoic acidA mixture of 5-(4-chlorophenoxy)-2-iodo-3-methylbenzamide (300 mg, 0.77 mmol) and KMnO₄ (611 mg, 3.87 mmol) in z-BuOH / water (1:1, 4 mL) was heated at 80 °C for 16 h. Upon cooling to rt, the mixture was directly purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 10-80% with 0.1% FA) to afford 3-carbamoyl-5-(4-chlorophenoxy)-2-iodobenzoic acid (80 mg, 24%) as an off-white solid. LCMS (ES, m / z): 418.10 [M+H]+.STEP 9: 2,5-dioxopyrrolidin-l-yl 3-carbamoyl-5-(4-chlorophenoxy)-2-iodobenzoate To a solution of 3-carbamoyl-5-(4-chlorophenoxy)-2-iodobenzoic acid (80 mg, 0.19 mmol) in DMF (1 mL) was added A-hydroxysuccinimide (33 mg, 0.29 mmol) and EDCI (55 mg, 0.29 mmol). After 1 h, the mixture was directly purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 10-80% with 0.1% FA) to afford the title compound (42.0 mg, 42.6%) as a white solid. 'H NMR (400 MHz, DMSO-t / 6) 87.98 (s, 1H), 7.74 (s, 1H), 7.53 (d, J= 8.8 Hz, 2H), 7.30 (dd, J= 19.0, 2.6 Hz, 2H), 7.20 (d, J= 8.8 Hz, 2H), 2.87 (s, 4H). LCMS (ES, m / z): 514.85 [M+Hf; 98.8% purity (254 nm).Example 23: Synthesis of 2,5-Dioxopyrrolidin-l-yl 5-(4-chlorophenoxy)-2-iodo-3-(methylcarbamoyl)benzoateScheme 13: Representation of 2,5-dioxopyrrolidin-l-yl 5-(4-chlorophenoxy)-2-iodo-3-(methylcarbamoyl)benzoate704.101.419Scheme 14: Representative synthetic method for 2, 5-dioxopyrrolidin-l-yl 5-(4-chlorophenoxy)-2-iodo-3-(methylcarbamoyl)benzoateSTEP 1: 5-(4-chlorophenoxy)-2-iodo- / V,3-dimethylbenzamideTo a solution of 5-(4-chlorophenoxy)-2-iodo-3-methylbenzoic acid (400 mg, 1.03 mmol) in DMF (3 mb) was added methylamine hydrochloride (84 mg, 1.24 mmol), HATU (391 mg, 1.03 mmol) and DIEA (399 mg, 3.09 mmol). After 1 h, the mixture was directly purified by reverse flash chromatography (C18 silica gel, ACN-water, 10-80% with 0.1% FA) to afford 5-(4-chlorophenoxy)-2-iodo-A,3-dimethylbenzamide (300 mg, 72%) as a white solid. LCMS (ES, m / z): 402.10 [M+H]+.STEP 2: 5-(4-chlorophenoxy)-2-iodo-3-(methylcarbamoyl)benzoic acidA mixture of 5-(4-chlorophenoxy)-2-iodo-N,3-dimethylbenzamide (300 mg, 0.75 mmol) and KMnO₄ (590 mg, 3.74 mmol) in / -BuOH / water (1:1, 3 mL) was heated at 50 °C for 7 h, whereupon it was cooled to rt and purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 10-80% with 0.1% FA) to afford 5-(4-chlorophenoxy)-2-iodo-3-(methylcarbamoyl)benzoic acid (100 mg, 31%) as an off-white solid. LCMS (ES, m / z): 432.05 [M+H]+.STEP 3: 2, 5-dioxopyrrolidin-l-yl 5-(4-chlorophenoxy)-2-iodo-3-(methylcarbamoyl)benzoateTo a mixture of 5-(4-chlorophenoxy)-2-iodo-3-(methylcarbamoyl)benzoic acid (100 mg, 0.23 mmol), A-hydroxysuccinimide (40 mg, 0.35 mmol) in DMF (1 mL) was added EDCI (66 mg, 0.35 mmol). After 1 h, the mixture was purified by Prep-HPLC (Column: Xselect CSH Prep C18 OBD 5 pm, 30 x 150 mm; Mobile phase: ACN-water, 26-55% with 0.1% FA; Flow Rate: 60 mL / min; Wavelength: 254 / 220 nm), affording the title compound (27.0 mg, 22%) as an off-white solid. ’H NMR (400 MHz, DMSO4) 58.48-8.39 (m, 1H), 7.53 (d, J= 8.7 Hz, 2H), 7.35 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 2.88 (s, 4H), 2.75 (d, J = 4.4 Hz, 3H). LCMS (ES, m / z): 528.95 [M+H]+; 95.3% purity (254 nm).704.101.419Example 24: Synthesis of 2,5-Dioxopyrrolidin-l-yl 3-carbamoyl-5-fluoro-4-iodo-2-methoxybenzoateScheme 15: Representation of 2,5-dioxopyrrolidin-l-yl 3 -carbarn oyl-5-fluoro-4-iodo-2-m ethoxybenzoateScheme 16: Representative synthesis of 2,5-dioxopyrrolidin-l-yl 3-carbamoyl-5-fluoro-4-iodo-2-STEP 1: 5-fluoro-2-methoxy-3-methylbenzaldehydeTo a stirred of 5 -fluoro-2-hydroxy-3 -methylbenzaldehyde (25.0 g, 162 mmol) in DMF (400 mL) was added K2CO3 (33.6 g, 243 mmol) and CH3I (34.6 g, 243 mmol). After 2 h, the mixture was poured into ice-water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 20%) to afford 5-fluoro-2-methoxy-3-methylbenzaldehyde (23.0 g, 84%) as a white solid. LCMS (ES, m / z): 169.10 [M+H]+.STEP 2: 3-fluoro-2-iodo-6-methoxy-5-methylbenzaldehydeTo a stirred mixture of 5-fluoro-2-methoxy-3-methylbenzaldehyde (5.00 g, 29.8 mmol) in DCE (120 m ) was added A-Iodosuccinimide (8.04 g, 35.7 mmol), Pd(OAc)2 (1.67 g, 7.44 mmol), 2-Amino-5-chlorobenzotrifluoride (2.90 g, 14.9 mmol) and TFA (245 mL), dropwise. After 24 h,704.101.419the mixture was poured into ice-water (200 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na SO4 and concentrated under reduced pressure. The crude residue was purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 0-70% with 0.1% FA) to afford 3-fluoro-2-iodo-6-methoxy-5-methylbenzaldehyde (2.0 g, 23%) as a yellow solid. LCMS (ES, m / z): 294.90 [M+H]+.STEP 3: 3-fluoro-2-iodo-6-methoxy-5-methylbenzoic acidTo a solution of 3-fluoro-2-iodo-6-methoxy-5-methylbenzaldehyde (2.00 g, 6.80 mmol) in ACN (30 mL) was added a solution of NaH₂PO₄ (1.03 g, 7.48 mmol) in H2O (6 mL), NaCICh (80%, 673 mg, 7.48 mmol) and H2O2 (25% aq, 1.02 g, 7.48 mmol), dropwise. After 4 h, the mixture was concentrated under reduced pressure and purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 0-50% with 0.1% FA) to afford 3-fluoro-2-iodo-6-methoxy-5-methylbenzoic acid (3.5 g, 82%) as a white solid. LCMS (ES, m / z): 308.90 [M-H]'.STEP 4: 3-fluoro-2-iodo-6-methoxy-5-methylbenzamideTo a mixture of 3-fluoro-2-iodo-6-methoxy-5-methylbenzoic acid (1.00 g, 3.23 mmol, 1.00 equiv) in DMF (10 mL) was added DIEA (2.08 g, 16.1 mmol), HATU (1.84 g, 4.84 mmol) and ammonium chloride (345 mg, 6.45 mmol). After 16 h, the mixture was directly purified by reverse flash chromatography (C18 silica gel, ACN-water, 0-40% with 0.1% FA) to afford 3-fluoro-2-iodo-6-methoxy-5-methylbenzamide (350 mg, 35%) as a white solid. LCMS (ES, m / z): 310.00 [M+H]⁺STEP 5: 3-carbamoyl-5-fluoro-4-iodo-2-methoxybenzoic acidTo a mixture of 3-fluoro-2-iodo-6-methoxy-5-methylbenzamide (350 mg, 1.13 mmol) in H2O (8 mL) was added pyridine (415 mg, 5.32 mmol) and KMnO₄ (537 mg, 3.40 mmol), whereupon it was heated at 50 °C. After 16 h, the mixture was cooled to rt and purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 0-70% with 0.1% FA) to afford 3-carbamoyl-5-fluoro-4-iodo-2-methoxybenzoic acid (150 mg, 39%). LCMS (ES, m / z): 339.90 [M+H]+.STEP 6: 2,5-dioxopyrrolidin-l-yl 3-carbamoyl-5-fluoro-4-iodo-2-methoxybenzoateTo a mixture of 3-carbamoyl-5-fluoro-4-iodo-2-methoxybenzoic acid (150 mg, 0.44 mmol) in DMF (3 mL) was added EDCI (106 mg, 0.55 mmol) and 1 -hydroxypyrrolidine-2, 5-dione (77 mg, 0.66 mmol) at 30 °C. After 4 h, the mixture was directly purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 0-40% with 0.1% FA) to afford the title compound704.101.419(114 mg, 59%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.84 (s 1H), 7.74(d, J= 7.6 Hz, 1H), 3.82 (s, 3H), 2.90 (s, 4H).19F NMR (376 MHz, DMSO-d6) δ -95.94. LCMS(ES, m / z): 436.90 [M+H]⁺; 97.3% purity (254 nm).Example 25: Synthesis of 2,5-Dioxopyrrolidin-l-yl 5-fluoro-4-iodo-2-methoxy-3-(methylcarbamoyl)benzoateScheme 17: Representation of 2,5-dioxopyrrolidin-l-yl 5-fluoro-4-iodo-2-methoxy-3-(methylcarbamoyl)benzoateFScheme 18: Representative synthetic route for,5-dioxopyrrolidin-l-yl 5-fluoro-4-iodo-2-methoxy-3-(methylcarbamoyl)benzoateSTEP 1: 3-fluoro-2-iodo-6-methoxy- / V,5-dimethylbenzamideTo a mixture of 3-fluoro-2-iodo-6-methoxy-5-methylbenzoic acid (900 mg, 2.90 mmol) in DMF(9 mL) was added DIEA (1.87 g, 14.5 mmol), HATU (1.65 g, 4.35 mmol) and methylamine hydrochloride (392 mg, 5.81 mmol). After 16 h, the mixture was directly purified by reverseflash chromatography (Cl 8 silica gel, ACN-water, 0-60% with 0.1% FA) to afford 3-fluoro-2-iodo-6-methoxy-N,5-dimethylbenzamide (600 mg, 63%) as a white solid. LCMS (ES, m / z):323.90 [M+H]⁺.STEP 2: 5-fluoro-4-iodo-2-methoxy-3-(methylcarbamoyl)benzoic acidTo a mixture of 3-fluoro-2-iodo-6-methoxy- / V,5-dimethylbenzamide (600 mg, 1.86 mmol) inH2O (12 mL) was added pyridine (681 mg, 8.73 mmol) and KMnO₄ (880 mg, 5.57 mmol), whereupon it was heated at 50 °C. After 16 h, it was cooled to rt and purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 0-50% with 0.1% FA) to afford 5-fluoro-4-iodo-2-methoxy-3-(methylcarbamoyl)benzoic acid (150 mg, 23%). LCMS (ES, m / z): 353.90 [M+H]+.STEP 3: 2,5-dioxopyrrolidin-l-yl 5-fluoro-4-iodo-2-methoxy-3-(methylcarbamoyl)benzoate704.101.419To a solution of 5-fluoro-4-iodo-2-methoxy-3-(methylcarbamoyl)benzoic acid (150 mg, 0.43 mmol) in DMF (3 mL) was added EDCI (102 mg, 0.53 mmol) and 1 -hydroxypyrrolidine-2, 5-dione (73 mg, 0.64 mmol). After 4 h, the mixture purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 0-40% with 0.1% FA), affording the title compound (79 mg, 38%) as a white solid. 'HNMR (400 MHz, DMSO-d6) δ 8.55-8.47 (m, 1H), 7.76 (d, J= 7.6 Hz, 1H), 3.79 (s, 3H), 2.90 (s, 4H), 2.80 (d, J= 4.6 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -96.06. LCMS (ES, m / z): 450.95 [M+H]+; 95.1% purity (254 nm).Example 26: Synthesis of Methyl 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodobenzoate Scheme 19: Representation of methyl 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodobenzoateScheme 20: Representative synthetic route for methyl 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodobenzoateMethyl 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodobenzoateTo a mixture of methyl 3-(bromomethyl)-5-(4-chlorophenoxy)-2-iodobenzoate (600 mg, 1.25 mmol) in DMF (6 mL) was added NaNs (406 mg, 6.25 mmol). After heating at 60 °C for 4 h, the mixture was cooled to rt, poured into ice-water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-petroleum ether, 10%) to afford methyl 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodobenzoate (500 mg, 90%) as a colorless oil. 'H NMR (400 MHz, DMSO-d6) δ 7.52-7.45 (m, 2H), 7.32 (d, J= 2.9 Hz, 1H), 7.18 (d, J = 2.9 Hz, 1H), 7.16-7.10 (m, 2H), 4.61 (s, 2H), 3.84 (s, 3H). LCMS (ES, m / z): 415.90 [M-N2+H]+; 99.2% purity (254 nm).704.101.419Example 27: Synthesis of tert-Butyl (5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodobenzyl)carbamateScheme 21: Representation of tert-butyl (5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-i odob enzyl )carb am ateScheme 22: Representative synthetic route for tert-butyl (5-(4-chlorophenoxy)-3- (dimethylcarbamoyl)-2-iodobenzyl)carbamateSTEP 1: 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodobenzoic acidTo a mixture of methyl 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodobenzoate (450 mg, 1.02 mmol) in THF (2.5 mL) was added a solution of LiOH (244 mg, 10.2 mmol) in H2O (2.5 mL). After 16 h, the mixture was diluted with ice-water (30 mL), cooled to 0 °C, acidified to pH~6 with HC1 (2 M) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure to afford 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodobenzoic acid (400 mg, 92%) as a yellow solid. LCMS (ES, m / z): 400.95 [M-N2]’.STEP 2: 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodo-Ar^V-dimethylbenzamide704.101.419To a solution of 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodobenzoic acid (150 mg, 0.35 mmol) in DMF (3 mL) was added DIE A (226 mg, 1.75 mmol), HATU (201 mg, 0.53 mmol) and dimethylamine hydrochloride (57 mg, 0.70 mmol). After 16 h, the mixture was directly purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 0-50% with 10 mM NH4HCO3) to afford 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodo-A, A-dimethylbenzamide (100 mg, 62%) as a colorless oil. 'HNMR (400 MHz, DMSO-d6) δ 7.51-7.45 (m, 2H), 7.18 (d, J= 2.9 Hz, 1H), 7.15-7.09 (m, 2H), 6.89 (d, J= 2.9 Hz, 1H), 4.62-4.52 (m, 2H), 2.97 (s, 3H), 2.74 (s, 3H). LCMS (ES, m / z): 428.85 [M-N2+H]+; 99.8% purity (254 nm).STEP 3: tert-butyl (5-(4-chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodobenzyl)carbamate To a mixture of 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodo-7V, / V-dimethylbenzamide (100 mg, 0.22 mmol) in THF / H2O (10:1, 2.2 mL) was added PPI13 (115 mg, 0.44 mmol). After 16 h, EtsN (67 mg, 0.66 mmol) and di-ter / -butyl dicarbonate (72 mg, 0.33 mmol) were added. After an additional 4 h, the mixture was purified by reverse flash chromatography (Cl 8 silica gel, ACN-water, 0-80% with 10 mM NH4HCO3), affording the title compound (90.6 mg, 77%) as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 7.52-7.43 (m, 3H), 7.14-7.06 (m, 2H), 6.83 (d, J= 2.9 Hz, 1H), 6.74 (br d, J = 2.6 Hz, 1H), 4.11-3.97 (m, 2H), 2.98 (s, 3H), 2.76 (s, 3H), 1.40-1.22 (m, 9H). LCMS (ES, m / z): 474.95 [M-tBu+H]+; 99.7% purity (254 nm).Example 28: Synthesis of 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodo-7V-methylbenzamide Scheme 23: Representation of 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodo-7V-methylbenzamideThe title compound (100 mg) was prepared from 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodobenzoic acid in an analogous manner to methods described for example 27.1H NMR (400 MHz, DMSO-d6) δ 8.38-8.32 (m, 1H), 7.52-7.46 (m, 2H), 7.21 (d, J= 2.9 Hz, 1H), 7.13-7.06 (m, 2H), 6.90 (d, J= 2.9 Hz, 1H), 4.57 (s, 2H), 2.73 (d, J= 4.6 Hz, 3H). LCMS (ES, m / z): 442.90 [M+H]+; 99.7% purity (245 nm).Example 29: Synthesis of fer / -butyl (5-(4-chlorophenoxy)-2-iodo-3- (methylcarbamoyl)benzyl)carbamate704.101.419Scheme 24: Representation of tert-butyl (5-(4-chlorophenoxy)-2-iodo-3- (methylcarbamoyl)b enzyl)carb amateOThe title compound (55 mg) was prepared from 3-(azidomethyl)-5-(4-chlorophenoxy)-2-iodo-7V-methylbenzamide in an analogous manner to methods described for example 27.JH NMR (400 MHz, DMSO-d6) δ 8.31 (br q, J= 4.4 Hz, 1H), 7.53-7.42 (m, 3H), 7.12-7.03 (m, 2H), 6.85 (d, J = 2.8 Hz, 1H), 6.80 (d, J= 2.3 Hz, 1H), 4.11-3.99 (m, 2H), 2.73 (d,.7= 4.6 Hz, 3H), 1.39-1.23 (m, 9H). LCMS (ES, m / z): 460.95 [M-tBu+H]+; 99.4% purity (254 nm).Example 30: Synthesis of 2,5-Dioxopyrrolidin-l-yl 2-((tert-butoxycarbonyl)amino)-3-(3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl)propanoateScheme 25: Representation of 2,5-dioxopyrrolidin-l-yl 2-((tert-butoxycarbonyl)amino)-3-(3-(dimethyl carbamoyl )-5 -fl uoro-2-i odophenyl )propanoateScheme 26: Representative synthetic route for 2,5-dioxopyrrolidin-l-yl 2-((tert-butoxycarbonyl)amino)-3-(3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl)propanoate704.101.419STEP 1: 2-amino-3-bromo-5-fluoro-N,N-dimethylbenzamideTo a solution of 2-amino-3-bromo-5-fluorobenzoic acid (40.0 g, 170 mmol) in DMF (500 mL) was added dimethylamine hydrochloride (13.9 g, 170 mmol), HATU (97.8 g, 258 mmol) and DIEA (66.4 g, 515 mmol). After 2 h, the mixture was diluted with water (1 L) and extracted with EtOAc (3 x 700 mL). The combined organic layers were washed with brine (3 x 1 L), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 50%) to afford 2-amino-3-bromo-5-fluoro-A, A-dimethylbenzamide (40 g, 89%) as a yellow solid. LCMS (ES, m / z): 261.05 [M+H]+.STEP 2: 2-amino-5-fluoro-JV, V-dimethyl-3-vinylbenzamideA mixture of 2-amino-3-bromo-5-fluoro-A, A-dimethylbenzamide (40.0 g, 153 mmol), 2-ethenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (35.4 g, 229 mmol), K2CO3 (63.5 g, 459 mmol) and Pd(dppf)C12*CH2C12 (12.5 g, 15.3 mmol) in 1,4-dioxane / water (4:1, 750 mL) was heated at 90 °C. After 12 h, the mixture was cooled to rt, diluted with water (1 L) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (1 L), dried over anhydrous Na2SCh and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 50%) to afford 2-amino-3-ethenyl-5-fluoro-A, A-dimethylbenzamide (26 g, 81%) as a yellow solid. LCMS (ES, m / z): 209.00 [M+H]+.704.101.419STEP 3: 5-fluoro-2-iodo- / V, / V-dimethyl-3-vinylbenzamideTo a solution of 2-amino-3-ethenyl-5-fluoro- / V, A-dimethylbenzamide (10.0 g, 48.0 mmol) in ACN (150 mL) at 0 °C was added potassium iodide (9.57 g, 57.6 mmol), cuprous iodide (10.9 g, 57.6 mmol) and iodine (14.6 g, 57.6 mmol). After 10 min at 0 °C, 3-methylbutyl nitrite (11.2 g, 96.0 mmol) was added to the mixture dropwise over 20 min. The mixture was held at 0 °C for 30 min, whereupon the cold bath was removed. After 2 h at rt, the mixture was poured into a cold NH4CI (satd, aq, 200 mL) solution followed by extraction with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (THF -Petroleum ether, 33%) to afford 3-ethenyl-5-fluoro-2-iodo-A, A-dimethylbenzamide (3.5 g, 22%) as a yellow solid. LCMS (ES, m / z): 319.90 [M+H]+.STEP 4: 5-fluoro-3-formyl-2-iodo-N,N-dimethylbenzamideTo a mixture of 3-ethenyl-5-fluoro-2-iodo-A, A-dimethylbenzamide (3.50 g, 10.9 mmol) in THF / water (4:1, 50 mL) at 0 °C was added potassium osmate(VI) dihydrate (341 mg, 1.09 mmol) and sodium periodate (11.7 g, 54.8 mmol). After 12 h at rt, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (THF -Petroleum ether, 50%) to afford 5-fluoro-3-formyl-2-iodo-A, A-dimethylbenzamide (3.0 g, 85%) as a yellow oil. LCMS (ES, m / z): 321.85 [M+H]+.STEP 5: 5-fluoro-3-(hydroxymethyl)-2-iodo-N,N-dimethylbenzamideTo a solution of 5-fluoro-3-formyl-2-iodo-A, / V-dimethylbenzamide (3.00 g, 9.34 mmol) in MeOH (30 mL) at 0 °C was added sodium borohydride (710 mg, 18.6 mmol) portion-wise. After 2 h at rt, the mixture was concentrated under reduced pressure and the crude residue was purified by silica gel chromatography (EA-Petroleum ether, 66%), affording 5-fluoro-3-(hydroxymethyl)-2-iodo-A, A-dimethylbenzamide (1.2 g, 40%) as a white solid. LCMS (ES, m / z): 323.90 [M+H]+.STEP 6: 3-(bromomethyl)-5-fluoro-2-iodo-N,N-dimethylbenzamideTo a stirred solution of 5-fluoro-3-(hydroxymethyl)-2-iodo- / V, A-dimethylbenzamide (900 mg, 2.78 mmol) in DCM (10 mL) at 0 °C was added phosphorus tribromide (1.13 g, 4.17 mmol) dropwise. After 1 h at rt, the mixture was concentrated under reduced pressure and the crude residue was purified by silica gel chromatography (EA-Petroleum ether, 50%) to afford 3-704.101.419(bromomethyl)-5-fluoro-2-iodo-A, A-dimethylbenzamide (850 mg, 79%) as a yellow solid.LCMS (ES, m / z): 385.85, 387.85 [M+H]+.STEP 7: ferZ-butyl 3-(3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl)-2-((diphenylmethylene)amino)propanoateA mixture of 3-(bromomethyl)-5-fluoro-2-iodo-A, A-dimethylbenzamide (850 mg, 2.20 mmol), tert-butyl 2-[(diphenylmethylidene)amino]acetate (650 mg, 2.20 mmol), tetrabutylammonium bromide (283 mg, 0.88 mmol) and potassium carbonate (1.22 g, 8.80 mmol) in ACN (10 mL) was heated at 60 °C for 16 h. Upon cooling to rt, the solvent was removed under reduced pressure and the crude residue was purified by silica gel chromatography (EA-Petroleum ether, 50%) to afford tert-butyl 3-[3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl]-2-[(diphenylmethylidene)amino]propanoate (700 mg, 52%) as a colorless oil. LCMS (ES, m / z): 601.25 [M+H]+.STEP 8: 2-amino-3-(3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl)propanoic acidTo a solution of tert-butyl 3-(3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl)-2-((diphenylmethylene)amino)propanoate (300 mg, 0.50 mmol) in DCM (3 mL) was added TFA (3 mL). After 2 h, the mixture was concentrated under reduced pressure and then re-dissolved in EtOH / EEO (4:1, 5 mL), whereupon hydroxylamine hydrochloride (207 mg, 3.00 mmol) was added. After heating at 50 °C for 4 h, the mixture was cooled to rt and purified by reverse flash chromatography (C18 silica gel, ACN-water, 5-100% with 10 mM NH4HCO3) to afford 2-amino-3-(3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl)propanoic acid (140 mg, 74%) as a white solid. LCMS (ES, m / z): 381.05 [M+H]+.STEP 9: 2-((tert-butoxycarbonyl)amino)-3-(3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl)propanoic acidTo a solution of 2-amino-3-[3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl]propanoic acid (140 mg, 0.37 mmol) in DCM (3 mL) were added TEA (111 mg, 1.10 mmol) and di-terz-butyl dicarbonate (97 mg, 0.44 mmol). After 1 h, the mixture was concentrated under reduced pressure and the crude residue was purified by silica gel chromatography (MeOH-DCM, 9%) to afford 2-((tert-butoxycarbonyl)amino)-3-(3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl)propanoic acid (110 mg, 62 %) as a white solid. LCMS (ES, m / z): 481.05 [M+H]+.STEP 10: 2,5-dioxopyrrolidin-l-yl 2-((tert-butoxycarbonyl)amino)-3-(3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl)propanoate704.101.419To a mixture of 2-((tert-butoxycarbonyl)amino)-3-(3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl)propanoic acid (100 mg, 0.21 mmol) and A-hydroxysuccinimide (36 mg, 0.31 mmol) in DMF (2 mL) was added EDCI (59 mg, 0.31 mmol). After 1 h, the mixture was diluted with cold water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (Column: XBridge Prep Shield RP18 OBD C18 5 pm, 30 x 150 mm; Mobile Phase: ACN-water, 27-57%; Flow Rate: 60 mL / min; Wavelength: 254 / 220 nm), affording the title compound (10.2 mg, 89%) as a white solid.JH NMR (400 MHz, DMSO-d6) δ *7.78 (d, J= 8.7 Hz, 0.3H), *7.72 (d, J= 9.4 Hz, 0.5H), *7.49-7.32 (m, 0.3H), *7.29 (dd, J= 9.7, 2.9 Hz, 0.4H), *7.24 (dd, J= 9.8, 2.9 Hz, 0.5H), 7.17-7.07 (m, 1H), *4.91-4.80 (m, 0.5H), *4.72-4.60 (m, 0.5H), 3.41-3.32 (m, 1H), 3.23-3.07 (m, 1H), 3.06-2.94 (m, 3H), 2.84 (s, 4H), 2.77-2.68 (m, 3H), 1.49-1.15 (m, 9H). *Partial integration due to the presence of rotamers.19F NMR (376 MHz, DMSO-d6) δ -114.27, -114.71. LCMS (ES, m / z): 522.05 [M-tBu+H]+.Example 31: Synthesis of 2,5-Dioxopyrrolidin-l-yl 2-((fer / -butoxycarbonyl)amino)-3-(5-(4-chlorophenoxy)-2-iodo-3-(methylcarbamoyl)phenyl)propanoateScheme 27: Representation of 2,5-dioxopyrrolidin-l-yl 2-((te / 7-butoxycarbonyl)amino)-3-(5-(4-chlorophenoxy)-2-iodo-3-(methylcarbamoyl)phenyl)propanoateThe title compound (14.1 mg) was prepared from 3-(3-(tert-butoxy)-2-((diphenylmethylene)amino)-3-oxopropyl)-5-(4-chlorophenoxy)-2-iodobenzoic acid in an analogous manner to methods described for example 21. 'H NMR (400 MHz, DMSO-d6) δ 8.36-8.27 (m, 1H), *7.74 (d, J= 8.6 Hz, 0.7H), 7.49-7.42 (m, 2H), *7.36 (d, J = 8.6 Hz, 0.3H), 7.25-7.19 (m, 1H), 7.10-7.02 (m, 2H), 6...

Claims

704. 101.419CLAIMS1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R3O)n(R2)mFormula (I),wherein:Ring A is phenyl, pyridyl, or pyrimidinyl, wherein Ring A is optionally and independently substituted with 1-5 R’;R1is Cl, Br, or I; or a radioisotope selected from the group consisting of [76]Br, [77]Br, [82]Br,[123]I, [124]I, [125]I, [131]I, [210]At, and [21 l]At;each R2is independently F or radioisotope [ 18]F;m is 1 or 2;each R3is independently hydrogen, PG, Ci-Ce alkyl, or C3-C10 cycloalkyl;n is 0, 1, or 2;R4is -C(=O)R’, -C(=O)OR’, -C(=O)N(R’)2, - N(R’)2, -NR’C(=O)R’, -NR’C(=O)N(R’)2, -OC(=O)R’, -OC(=O)OR’, or -LS-OH; Lsis absent or Ci-Ce alkylene optionally substituted with 1-12 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -O-, -N(R’)-, -C(=O)-, - C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, -N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, - OC(=O)N(R’)S(O)2-, -S(O)-, -S(O)2-, or -S(O)2N(R’)-;L is absent or Ci-C2o alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -CR’=CR’-,-O-, -N(R’)-, -C(=O)-, C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, - S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-25 amino acids;704.101.419each -Cy- is independently a bivalent ring selected from C3-C20 cycloalkylene, C6-C20 arylene, 3- 20 membered heteroarylene, or 3-20 membered heterocycloalkylene, wherein each group is optionally and independently substituted with 1-20 Rs;Q is halogen, R’, -OR’, -SR’, -N=C=O, -NC, -N3, -OS(O)2R’, -OP(O)(OR’)R’, O, O% n ne, trans-cyclooctene,N R orbome1, or PG, wherein 0 0. N.each of ° °, norbomene, trans-cyclooctene,andN'rr R1is optionally and indpendently subsituted with 1-5 R’;each PG is independently a protecting group;each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, -S(O)2R, or PG; each R is independently hydrogen, halogen, or an optionally substituted group selected from Ci- C10 aliphatic, C1-C10 heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl, wherein each group is optionally and independently substituted with 1-20 Rs, or two R groups are optionally and independently taken together to form a covalent bond or =0; ortwo or more R groups on the same atom are optionally and independently taken together with the atom to form a 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the atom, 0-5 heteroatoms; ortwo or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the intervening atoms, 0-5 heteroatoms;each Rsis independently halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OCi-Ce alkyl, -OC3-C10 cycloalkyl, -OCe-Cio aryl, -0-5-10 membered heteroaryl, -0-3-20 membered704.101.419heterocycloalkyl, -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)C6-Cio aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, - NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci- C6alkyl)S(=O)2Ci-C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci- C6alkyl)S(=0)2Ce-Cio aryl, -N(Ci-Ce alkyl)S(=O)25-10 membered heteroaryl, -N(Ci- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)Ci-Ce alkyl, -C(=O)OH, -C(=O)OCi- C6alkyl, -C(=O)NH2, -C(=O)NHCI-C6alkyl, -C(=O)N(Ci-C6alkyl)2; wherein each Ci-C6alkyl, Ci-Ce heteroalkyl, Cg-Cio aryl, C3-Cio cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.

2. The compound of claim 1, wherein at least one of R1and R2comprises the radioisotope.

3. The compound of claim 1, wherein the compound has a structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof(R2)mFormula (II).

4. The compound of claim 3, wherein the compound has a structure of Formula (Il-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R2)mFormula (Il-a).

5. The compound of claim 3, wherein the compound has a structure of Formula (Il-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:704.101.419R4(R2)mFormula (Il-b).

6. The compound of claim 3, wherein the compound has a structure of Formula (II-c), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(OP3:(R2)mFormula (II-c).

7. The compound of claim 3, wherein the compound has a structure of Formula (Il-d), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereofFormula (Il-d).

8. The compound of claim 3, wherein the compound has a structure of Formula (Il-e), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:R4'mFormula (Il-e).

9. The compound of claim 3, wherein the compound has a structure of Formula (Il-f), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R2)m704.101.419Formula (Il-f).

10. The compound of claim 3, wherein the compound has a structure of Formula (Il-g), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereofFormula (Il-g).

11. The compound of claim 1, wherein Ring A is pyridyl.

12. The compound of claim 11, wherein the compound has a structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R2)mFormula (III).

13. The compound of claim 11, wherein the compound has a structure of Formula (Ill-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:XQFormula (Ill-a).

14. The compound of claim 11, wherein the compound has a structure of Formula (Ill-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (Ill-b).

15. The compound of claim 11, wherein the compound has a structure of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:704.101.419Formula (IV).

16. The compound of claim 11, wherein the compound has a structure of Formula (IV-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (IV-a).

17. The compound of claim 11, wherein the compound has a structure of Formula (IV-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (IV-b).

18. The compound of claim 11, wherein the compound has a structure of Formula (IV-c), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:R1Formula (IV-c).

19. The compound of claim 11, wherein the compound has a structure of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:704.101.419Formula (V).

20. The compound of claim 11, wherein the compound has a structure of Formula (V-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereofR4 / *N(R2)mFormula (V-a).

21. The compound of claim 11, wherein the compound has a structure of Formula (V-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:R4< R2MV(°R3)nFormula (V-b).

22. The compound of claim 1, wherein Ring A is pyrimidinyl.

23. The compound of claim 22, wherein the compound has a structure of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R2)mFormula (VI).

24. The compound of claim 22, wherein the compound has a structure of Formula (Vl-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (Vl-a).

25. The compound of claim 22, wherein the compound has a structure of Formula (Vl-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:704.101.419Formula (Vl-b).

26. The compound of claim 22, wherein the compound has a structure of Formula (VI-c), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (VI-c).

27. The compound of claim 22, wherein the compound has a structure of Formula (Vl-d), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(OR3)nR4-J-R12^ N^R2(R )m-1Formula (Vl-d).

28. The compound of claim 22, wherein the compound has a structure of Formula (Vl-e), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:OR3N^VL" QR2 N R1Formula (Vl-e).

29. The compound of claim 22, wherein the compound has a structure of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:L / QN(OR3)nR4-[tR1(R2)mFormula (VII).704.101.41930. The compound of claim 22, wherein the compound has a structure of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(OR3)nFormula (VIII).

31. The compound of claim 1, wherein the compound has a structure of704.101.41932. The compound of claim 1, wherein the compound has a structure ofsolvate, or stereoisomer thereof.

33. The compound of claim 2, wherein the compound has a structure of:704.101.419pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

34. A compound of Formula (Hyper-R*), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereofFormula (Hyper-R*),wherein:Ring A is phenyl, pyridyl, or pyrimidinyl, wherein Ring A is optionally and independently substituted with 1-5 R’;is a single bond or double bond;each R2is independently F or radioisotope [ 18]F;m is 1 or 2;each R3is independently hydrogen, PG, Ci-Ce alkyl, or C3-C10 cycloalkyl;n is 0, 1, or 2;L* is -C(~O)O-, -C(~NR’)O-. -N=C(R’)O-, -N=C(N(R’)2)O-, -NR’C(=O)NR’-, -OC(~O)O-, or - L-O-;704.101.419R* is I; or a radioisotope selected from the group consisting of [123]I, [124]I, [125]I, [131]I,[210] At, and [211] At;X is a counterion;L is absent or C1-C20 alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -CR’=CR’-,-O-, -N(R’)-, -C(=O)-, -C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, - S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-20 amino acids;each -Cy- is independently a bivalent ring selected from C3-C20 cycloalkylene, C6-C20 arylene, 3- 20 membered heteroarylene, or 3-20 membered heterocycloalkylene, wherein each group is optionally and independently substituted with 1-20 Rs;Q is halogen, R’, -OR’, -SR’, -N=C=O, -NC, -N3, -OS(O)2R’, -OP(O)(OR’)R’„ O, OAR1norbomene, trans-cyclooctene,J'l<, or PG, wherein O Oeach of ° °, norbomene, trans-cyclooctene,and R' is optionally and indpendently subsituted with 1-5 R’;each PG is independently a protecting group;each R’ is independently R, -OR, -OC(=O)R, -C( O)R, -C=(O)OR, -C(=O)N(R)2, -S(O)2R, or PG; each R is independently hydrogen, halogen, or an optionally substituted group selected from Ci- C10 aliphatic, C1-C10 heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl, wherein each group is optionally and independently substituted with 1-20 Rs, or two R groups are optionally and independently taken together to form a covalent bond or =0; or704.101.419two or more R groups on the same atom are optionally and independently taken together with the atom to form a 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the atom, 0-5 heteroatoms; ortwo or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the intervening atoms, 0-5 heteroatoms;each Rsis independently halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OCi-Cs alkyl, -OC3-C10 cycloalkyl, -OCe-Cio aryl, -0-5-10 membered heteroaryl, -0-3-20 membered heterocycloalkyl, -OC(=O)Ci-C6alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)C6-Cio aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, - NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2C6-Cio aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci- C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci- C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-Ce alkyl)S(=O)25-10 membered heteroaryl, -N(Ci- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)Ci-C6 alkyl, -C(=O)OH, -C(=O)OCi- C6alkyl, -C(=0)NH2, -C(=O)NHCI-C6alkyl, -C(=O)N(Ci-C6alkyl)2; wherein each Ci-C6alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.

35. The compound of claim 34, wherein L* is -C(=O)O-,36. The compound of claim 35, wherein -L*-R*- is -C(=O)O-R*-.

37. The compound of claim 34, wherein L* is -C(=NR’)O-.

38. The compound of claim 34, wherein L* is -C(=NR’)O- and R’ is hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, Ce-Cioaryl, C3-C 10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 Rs.

39. The compound of claim 34, wherein L* is -C(=NH)O-.704.101.41940. The compound of claim 34, wherein L* is -C(=NR’)O- and R’ is C1-C10 alkyl, C1-C10 heteroalkyl, Ce-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 halogen, -OH, -CN, -OMe, methyl, or halom ethyl.

41. The compound of any one of claims 37-40, wherein -L*-R*- is -C(=NR’)O-R*-.

42. The compound of claim 34, wherein L* is -N=C(R’)O-.

43. The compound of claim 34, wherein L* is -N=C(R’)O- and R’ is hydrogen, C1-C10 alkyl, Ci-C 10 heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 Rs.

44. The compound of claim 34, wherein L* is -N=C(R’)O- and R’ is C1-C10 alkyl.

45. The compound of claim 34, wherein L* is -N=C(Me)O-.

46. The compound of any one of claims 42-45, wherein -L*-R*- is -N=C(R’)O-R*-.

47. The compound of claim 34, wherein L* is -N=C(N(R’)2)O-.

48. The compound of claim 34, wherein L* is -N=C(N(R’)2)O- and each R’ is independently hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, Ce-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 Rs.

49. The compound of claim 34, wherein L* is -N=C(N(R’)2)O- and each R’ is independently hydrogen or C1-C10 alkyl.

50. The compound of claim 34, wherein L* is -N=C(NHMe)O-.

51. The compound of any one of claims 47-50, wherein -L*-R*- is -N=C(N(R’)2)O-R*-.

52. The compound of claim 34, wherein L* is -NR’C(=O)NR’-.

53. The compound of claim 34, wherein L* is -NR’C(=O)NR’- and each R’ is independently hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, Ce-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 Rs.

54. The compound of claim 34, wherein L* is -OC(=O)O-.

55. The compound of claim 34, wherein L* is -L-O-.

56. The compound of claim 34, wherein L* is -L-O- and L is Ci-Ce alkylene optionally substituted with 1-12 Rs; or one or more methylene units of L are optionally and independently replaced with -O-, -N(R’)-, -C(=O)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, -N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S(O)-, -S(O)2-, or -S(O)2N(R’)-.704.101.41957. The compound of claim 34, wherein L* is -L-O- and L is Ci-Ce alkylene optionally substituted with 1-6 Rs.

58. The compound of claim 34, wherein L* is -L-O- and L is C1-C3 alkylene optionally substituted with 1-4 Rs.

59. The compound of claim 34, wherein L* is -CH2-O- and -CH2- is optionally substituted with 1-2 Rs.

60. The compound of claim 34, wherein L* is -CH2-O- and -CH2- is optionally substituted with 1-2 halogen, -OH, -CN, -OMe, methyl, or halomethyl.

61. The compound of claim 34, wherein L* is -CH2-O- and -CH2- is substituted with 1-2 halogen, -OH, -CN, -OMe, methyl, or halomethyl.

62. The compound of claim 34, wherein L* isOF3C CF363. The compound of claim 34, wherein L* is64. The compound of any one of claims 55-63, wherein -L*-R*- is -L-O-R*-.

65. The compound of any one of claims 55-64, wherein R* is I.

66. The compound of any one of claims 55-64, wherein R* is a radioisotope selected from the group consisting of [123]I, [124]I, [125]I, and [131]I.

67. The compound of any one of claims 55-64, wherein R* is a radioisotope selected from the group consisting of [210] At and [211 ] At.

68. The compound of any one of claims34-67, wherein X connected to R* is CT.

69. The compound of any one of claims34-67, wherein X connected to R* is OAc".

70. The compound of any one of claims 34-69, wherein the compound has a structure of(R2)m or (R, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

71. The compound of any one of claims 34-69, wherein the compound has a structure of704.101.419pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

72. The compound of any one of claims 1-33, wherein R1is Cl.

73. The compound of any one of claims 1-33, wherein R1is Br.

74. The compound of any one of claims 1-33, wherein R1is I.

75. The compound of any one of claims 1-33, wherein R1is [76]Br, [77]Br, or [82]Br.

76. The compound of any one of claims 1-33, wherein R1is [123]I, [124]I, [125]I, or [131]I.

77. The compound of any one of claims 1-33, wherein R1is [210]At or [211 ] At.

78. The compound of any one of claims 1-77, wherein an R2is F.

79. The compound of any one of claims 1-77, wherein an R2is radioisotope [ 18]F.

80. The compound of any one of claims 1-79, wherein m is 1.

81. The compound of any one of claims 1-79, wherein m is 2.

82. The compound of any one of claims 1-77, wherein an R2is [18]F and R1is Cl, Br, or I.

83. The compound of any one of claims 1-77, wherein an R2is F and R1is [76]Br, [77]Br, [82]Br, [123]I, [124]I, [125]I, [131]I, [210]At, or [21 l]At.

84. The compound of any one of claims 1-81, wherein at least one of R1and R2is a radioisotope.

85. The compound of any one of claims 1-81, wherein one of R1and R2is a radioisotope and one of R1and R2is not a radioisotope.

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