Radiolabeled amino acid derivatives for imaging and therapy and methods thereof

Abstract

Among other things, the disclosure relates to radiolabeled amino acid derivatives, and their use in treating and / or imaging cancer.

Description

703.101.412 RADIOLABELED AMINO ACID DERIVATIVES FOR IMAGING AND THERAPY AND METHODS THEREOF TECHNICAL FIELD

[0001] The present application claims priority pursuant to Article 8 of the Patent Cooperation Treaty to United States Provisional Patent Application Serial Number 63 / 667,412 filed July 3, 2024 which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] Among other things, the disclosure relates to radiolabeled amino acid derivatives (e.g., poly halogenated amino acid derivatives) and their uses in the treatment and diagnosis of various diseases, e.g., cancer. BACKGROUND

[0003] Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest human malignancies characterized by a fast and aggressive progression. Due to a lack of methods to detect pancreatic carcinoma at an early stage and its aggressive progression, the disease is often far advanced in patients by the time a definite diagnosis is established, resulting in only 10-20% of patients having the surgically resectable disease at the time of diagnosis. For patients with locally advanced PDAC, a combination of chemotherapeutic agents has become a standard of care aiming to improve overall survival compared to single agents but at the cost of increased toxicity. Unfortunately, only about 15-20% of patients remain disease-free at 3 years after surgical resection plus the use of potent but toxic chemotherapies.

[0004] Just like in many other cancer types, energy metabolism reprogramming has also been implicated in the tumorigenesis and development of pancreatic cancer. Accumulating evidence suggests that amino acid metabolism orchestrated by genetic alterations contributes to pancreatic cancer malignant characteristics including cell proliferation, invasion, metastasis, angiogenesis and redox balance. In the nutrient-deficient tumor microenvironment (TME), the interactions between cancer cells and stromal components and salvaging processes play critical roles in fulfilling the metabolic requirements and supporting growth of PDAC. Advanced pancreatic tumors, in particular, have been shown to be notoriously difficult to treat because of their highly -1-703.101.412 concentrated fibrous network of stroma that prevents resection and acts as a roadblock to xenobiotic delivery.

[0005] 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 et 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

[0211] At radiolabeled proteins were unstable, leading to fast release of astatine from the protein. Aaij et al., Int. J. Appl. Radiat. Isot. 1975, 26, 25−30.

[0006] Hence, there is an urgent need to develop effective and stable therapeutic and diagnostic compounds (e.g., those comprising halogen atoms and / or radioisotopes of halogen atoms), compositions, and methods for cancer treatment, e.g., PDAC. SUMMARY

[0007] Among other things, the present disclosure provides amino acid derivates (e.g., poly halogenated amino acid derivatives) that exhibit efficient tumor uptake and low background accumulation as imaging agents and / or radionuclide-based therapy agents for various cancers, including but not limited to PDAC.

[0008] In some embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: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 -2-703.101.412 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: *),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:the method comprising: (a) obtaining a compound of Formula (INT-a) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:, (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. -3-703.101.412

[0012] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier(s).

[0013] 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 compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0014] 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, 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.

[0015] 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, a prodrug, or a composition as disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG.1 shows UV-Vis HPLC (212 nm / 254 nm) and RadioHPLC analysis of 2-amino-3-(5-(fluoro-18F)-2-iodo-3 (methylcarbamoyl)phenyl)propanoic acid by using HPLC condition 1.

[0017] FIG.2 shows UV-Vis HPLC (212 nm / 254 nm) and RadioHPLC analysis of 2-amino-3-(5-(fluoro-18F)-2-iodo-3 (methylcarbamoyl)phenyl)propanoic acid by using HPLC condition 2.

[0018] FIG. 3 illustrates F-18 imaging, biodistribution for 2-amino-3-(5-(fluoro-18F)-2-iodo-3-(methylcarbamoyl)phenyl)propanoic acid according to procedures set forth her

[0019] FIG.4 shows UV-Vis HPLC (212 nm / 254 nm) and RadioHPLC analysis of 2-amino-3-(3-(dimethylcarbamoyl)-5-fluoro-2-(iodo-131I)phenyl)propanoic acid by using HPLC condition3.

[0020] FIG.5 shows quality control, according to UV-Vis HPLC (212 nm / 254 nm) and RadioHPLC analyses, of 2-amino-3-(3-(dimethylcarbamoyl)-5-fluoro-2-(iodo-131I)phenyl)propanoic acid using HPLC condition 3.-4-703.101.412

[0021] FIG.6 shows shows UV-Vis HPLC (212 nm / 254 nm) and RadioHPLC analysis of the cold standard 2-amino-3-(3-(dimethylcarbamoyl)-5-fluoro-2-(iodo-phenyl)propanoic acid by using HPLC condition 3. DETAILED DESCRIPTION

[0022] Associated with extremely poor prognosis, pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at late stages in which cancer has already metastasized. Although various treatments have been developed, PDAC remains one of the most fatal malignancies, with a 5- year survival rate of <9%. Key features that make PDAC so extraordinarily difficult to treat include pronounced alterations in stromal responses and immune surveillance programs that prevent successful local therapy. PDAC tumors are characterized by isolated nests of tumor cells surrounded by extensive networks of fibrous growth. As a result, 60-90% of the PDAC tumor volume is made of dense stroma containing extracellular matrix, cancer-associated fibroblasts, and a variety of immunosuppressive cells. This creates a pro-tumorigenic and immunosuppressive microenvironment that downregulates the body’s ability to detect and kill cancer cells. Furthermore, the stromal bulk creates elevated interstitial fluid pressure within the tumor, which prevents efficient drug diffusion into the tumor parenchyma. Therapies targeting tumor cells alone are therefore unlikely to be successful due to physical barriers such as dense desmoplasia and the unique hypoperfused tumor microenvironment (TME) of PDAC. Therefore, there is a clear need to develop diagnostic and therapeutic agents for PDAC treatment.

[0023] Among other things, the present disclosure provides diagnostic and therapeutic compounds for the treatment of PDAC and other cancers by employing the radiolabeled amino acid derivatives as described herein. Unlike most existing diagnosis and therapeutic compounds which rely on glucose metabolism for screening patients, monitoring treatment, or providing a prognosis, the compounds disclosed herein rely on the amino acid metabolism of cancer cells.

[0024] Among other things, the present disclosure provides compounds that are able to either modulate the amino acid metabolism and / or utilize amino acid transport mechanisms of cells (e.g., cancer cells). Changes in amino acid metabolism contribute to PDAC and various other cancers’ malignant characteristics and various enzymes and amino acid transporters take part in the amino acid metabolism (e.g., TCA cycle and / or urea cycle). One such amino acid transporter is the large neutral amino acid transporter referred to as L-type amino acid transporter 1 (LAT1, known to function as an uptake port of amino acids in cells.) LAT1 is over-expressed in a -5-703.101.412 variety of cancer cells and has a role in supplying amino acids as nutrients to cancer tissues. In the nutrient-deficient tumor microenvironment, the interactions between cancer cells, stromal components and salvaging processes play critical roles in fulfilling the metabolic requirements supporting the growth of PDAC and various other cancers. Therefore, the present disclosure provides an insight that radiolabeled amino acid derivatives disclosed herein provide a unique opportunity to image and treat PDAC and certain other cancers by targeting both tumor cells and the TME.

[0025] Among other things, the present disclosure provides an insight that amino acid metabolism is usually enhanced in tumor progression and therefore represents an important pathway for developing diagnostic and / or therapeutic compounds. The present disclosure encompasses an insight that the capability to monitor amino acid metabolism can not only be used for tumor detection, but also provides important information on tumor characteristics (which could guide therapy and lead to personalized medicine). The present disclosure recognizes that in various cancer diseases, e.g., PDAC, amino acid metabolism plays a vital role in the initiation and progression of the cancer, which provides a unique opportunity to image and treat cancers, such as pancreatic cancer once imaging / therapy radionuclides are introduced to the amino acid backbone. Given the important role of amino acids in crosstalk between cancer cells and stromal components, the present disclosure discovers, among other things, that amino acid derivatives can be developed as TME-targeted diagnostic and therapeutic compounds against PDAC or other cancers.

[0026] Without wishing to be bound by any particular theory, the present disclosure encompasses an insight that poly halogenated amino acid derivatives exhibit prominent tumor uptake with low background accumulation, which can be used as imaging / therapy agents for PDAC and other cancer management. In some embodiments, compounds described herein can be used in various imaging modalities e.g., PET / SPECT and exhibit high and persistent tumor retention in comparison to normal pancreatic uptake.

[0027] Among other things, the present disclosure provides poly halogenated amino acid derivatives. In some embodiments, a compound as described herein (e.g., poly halogenated amino acid derivatives) can lead to a “theranostic pair” of radiolabeled compounds, depending on the radiolabeling patterns of such compound. For example, if a compound comprising both fluorine atom and iodine atom is radiolabeled at the fluorine site (e.g., replacing

[0019] F with -6-703.101.412

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

[0127] I with

[0131] I), such compound can be used as 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.

[0028] In some embodiments, a poly halogenated amino acid derivative as described herein comprises one fluorine atom and one iodine atom. The role of a fluorine atom is multifold: (1) a fluorination position allows for tuning the tumor uptake and tumor to background ratio; (2) a

[0019] F atom can be converted to a

[0018] F atom, which leads to a companion diagnostic PET imaging agent of a radionuclide-based therapy agent. The role of the iodine atom is multifold: (1) the iodine in amino acid derivatives could be converted to

[0131] I to deliver beta-particles to the tumor site (beta particle therapy); and (2) the iodine atom could be converted to

[0211] At to be used as an alpha-particle emitting therapeutic agent.

[0029] 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. In 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 I or At. In some embodiments, a -7-703.101.412 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 a halogen 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, a halogen atom is

[0076] Br,

[0077] Br,

[0082] Br,

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, and

[0211] At.

[0030] 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

[0211] 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 -8-703.101.412 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 close proximity 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).

[0031] 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.

[0032] Among other things, the present disclosure provides methods of preparing radiolabeled compounds (e.g., poly halogenated amino acid derivatives) 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 allow for the development of theranostic agents (e.g., poly halogenated amino acid derivatives) 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 (e.g. PDAC). In some embodiments,

[0131] I-based agents and the corresponding

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

[0127] I /

[0019] F) isotope-bearing counterparts, making them a true theranostic pair. Definitions -9-703.101.412

[0033] 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 approximations, 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” that particular 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.

[0034] 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.

[0035] 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 embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention. -10-703.101.412

[0036] 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 that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0037] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0038] “Oxo” refers to =O. 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)2moiety may be represented as S(O)2or SO2.

[0039] “Amino” refers to -NH2.

[0040] “Hydroxy” refers to -OH.

[0041] “Carboxyl” refers to -C(=O)OH.

[0042] “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.

[0043] “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 -11-703.101.412 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 aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof.

[0044] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2- propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl- 1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl- 2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range, such as “C1-C6 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 C1-C10 alkyl. In some embodiments, the alkyl is a C1-C6 alkyl, a C1- C5alkyl, a C1-C4alkyl, or a C1-C3alkyl. 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.

[0045] “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 -12-703.101.412 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 (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range, such as “C2-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 is designated. 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, -NH2, 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.

[0046] “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.

[0047] “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 -13-703.101.412 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. In 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.

[0048] “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.

[0049] “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.

[0050] “Anticancer agent” or “antineoplastic agent,” refers to a therapeutic agent that is useful for treating or controlling the growth of cancerous cells.

[0051] “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 triphenylenyl. 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, -14-703.101.412 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, -NH2, 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 halogen.

[0052] “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 carriers 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.

[0053] “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 -15-703.101.412 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.

[0054] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, 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 saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8fully saturated cycloalkyl or C3-C8cycloalkenyl), from three to six carbon atoms (e.g., C3-C6fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5cycloalkenyl), or three to four carbon atoms (e.g., C3-C4fully saturated cycloalkyl or C3-C4cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis- decalinyl, 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[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]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, -NH2, or -NO2. In some embodiments, a cycloalkyl is independently optionally substituted -16-703.101.412 with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is independently optionally substituted with halogen.

[0055] “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.

[0056] 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 (σ[P] = -0.66 for NH2), σ[P] indicating para substitution. Exemplary electron-withdrawing groups include nitro, acyl, formyl, sulfonyl, trifluoromethyl, cyano, chloride, and the like.

[0057] “Enantiomers” refers to two stereoisomers of a compound which are non-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.

[0058] 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. -17-703.101.412

[0059] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0060] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0061] “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, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0062] “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.

[0063] “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 C1-C6 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)OCH3, -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, -18-703.101.412 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.

[0064] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is 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 non- aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl -19-703.101.412 or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), from two to six carbon atoms (e.g., C2- C6 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-C4fully saturated heterocycloalkyl or C2-C4heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4- piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo- thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl- 2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8- membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is independently optionally substituted, for example, with one or more oxo, halogen, amino, -20-703.101.412 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.

[0065] “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 -21-703.101.412 sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl- 1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, 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.

[0066] “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.

[0067] “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.

[0068] “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 -22-703.101.412 alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0069] “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.

[0070] “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.

[0071] “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.

[0072] “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. -23-703.101.412

[0073] “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.

[0074] “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–trimethylsilylethyl carbamate (Teoc) , 2– phenylethyl carbamate (hZ) , 1– (1–adamantyl) –1–methylethyl carbamate (Adpoc) , 1, 1– dimethyl–2–haloethyl carbamate, 1, 1–dimethyl–2, 2–dibromoethyl carbamate (DB–t–BOC) , 1, 1–dimethyl–2, 2, 2–trichloroethyl carbamate (TCBOC) , 1–methyl–1– (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–isopropylallyl carbamate (Ipaoc) , cinnamyl carbamate (Coc) , 4– nitrocinnamyl carbamate (Noc) , 8–quinolyl carbamate, N–hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz) , p–methoxybenzyl 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–methylsulfonylethyl carbamate, 2– (p–toluenesulfonyl) ethyl carbamate, [2– (1, 3–dithianyl) ] methyl carbamate (Dmoc) , 4–methylthiophenyl carbamate (Mtpc) , 2, 4–dimethylthiophenyl 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– -24-703.101.412 toluenesulfonylaminocarbonyl derivative, N’–phenylaminothiocarbonyl derivative, t–amyl carbamate, S–benzyl thiocarbamate, p–cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p–decyloxybenzyl carbamate, 2, 2–dimethoxycarbonylvinyl carbamate, o– (N, N–dimethylcarboxamido) benzyl carbamate, 1, 1–dimethyl–3– (N, N–dimethylcarboxamido) propyl carbamate, 1, 1– dimethylpropynyl carbamate, di (2–pyridyl) methyl carbamate, 2–furanylmethyl carbamate, 2– iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p– (p’– methoxyphenylazo) benzyl carbamate, 1–methylcyclobutyl carbamate, 1–methylcyclohexyl carbamate, 1–methyl–1–cyclopropylmethyl carbamate, 1–methyl–1– (3, 5–dimethoxyphenyl) ethyl carbamate, 1–methyl–1– (p–phenylazophenyl) ethyl carbamate, 1–methyl–1–phenylethyl carbamate, 1–methyl–1– (4–pyridyl) ethyl carbamate, phenyl carbamate, p– (phenylazo) benzyl carbamate, 2, 4, 6–tri–t–butylphenyl carbamate, 4– (trimethylammonium) benzyl carbamate, 2, 4, 6–trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3–phenylpropanamide, picolinamide, 3– pyridylcarboxamide, N–benzoylphenylalanyl derivative, benzamide, p–phenylbenzamide, o– nitophenylacetamide, o–nitrophenoxyacetamide, acetoacetamide, (N’– dithiobenzyloxycarbonylamino) acetamide, 3– (p–hydroxyphenyl) propanamide, 3– (o– nitrophenyl) propanamide, 2–methyl–2– (o–nitrophenoxy) propanamide, 2–methyl–2– (o– phenylazophenoxy) 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–diphenylmaleimide, N–2, 5–dimethylpyrrole, N–1, 1, 4, 4–tetramethyldisilylazacyclopentane adduct (STABASE) , 5–substituted 1, 3–dimethyl–1, 3, 5–triazacyclohexan–2–one, 5–substituted 1, 3–dibenzyl–1, 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– (1–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– fluorenylmethyleneamine, N–ferrocenylmethylamino (Fcm) , N–2–picolylamino N’–oxide, N–1, 1–dimethylthiomethyleneamine, N–benzylideneamine, N–p–methoxybenzylideneamine, N– -25-703.101.412 diphenylmethyleneamine, N– [ (2–pyridyl) mesityl] methyleneamine, N– (N’, N’– dimethylaminomethylene) 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–1–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 phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o–nitrobenzenesulfenamide (Nps) , 2, 4–dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2–nitro–4–methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3–nitropyridinesulfenamide (Npys) , p–toluenesulfonamide (Ts) , benzenesulfonamide, 2, 3, 6, –trimethyl–4–methoxybenzenesulfonamide (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) , β–trimethylsilylethanesulfonamide (SES) , 9– anthracenesulfonamide, 4– (4’, 8’–dimethoxynaphthylmethyl) benzenesulfonamide (DNMBS) , benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. Suitably protected carboxylic acids further include, but are not limited to, silyl–, alkyl–, alkenyl–, aryl–, and arylalkyl–protected carboxylic acids. Examples of suitable silyl groups include trimethylsilyl, triethylsilyl, t–butyldimethylsilyl, t–butyldiphenylsilyl, triisopropylsilyl, and the like. Examples of suitable alkyl groups include methyl, benzyl, p–methoxybenzyl, 3, 4– dimethoxybenzyl, 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–dichlorobenzyl, p–cyanobenzyl) , and 2–and 4–picolyl.

[0075] Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM) , methylthiomethyl (MTM) , t–butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM) , -26-703.101.412 benzyloxymethyl (BOM) , p–methoxybenzyloxymethyl (PMBM) , (4–methoxyphenoxy) methyl (p–AOM) , guaiacolmethyl (GUM) , t–butoxymethyl, 4–pentenyloxymethyl (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–1–methoxyethyl, 1–methyl–1–benzyloxyethyl, 1–methyl– 1–benzyloxy–2–fluoroethyl, 2, 2, 2–trichloroethyl, 2–trimethylsilylethyl, 2– (phenylselenyl) ethyl, t–butyl, allyl, p–chlorophenyl, p–methoxyphenyl, 2, 4–dinitrophenyl, 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, triphenylmethyl, α– naphthyldiphenylmethyl, p–methoxyphenyldiphenylmethyl, di (p–methoxyphenyl) phenylmethyl, tri (p–methoxyphenyl) methyl, 4– (4’–bromophenacyloxyphenyl) diphenylmethyl, 4, 4’, 4”–tris (4, 5–dichlorophthalimidophenyl) methyl, 4, 4’, 4”–tris (levulinoyloxyphenyl) methyl, 4, 4’, 4”–tris (benzoyloxyphenyl) methyl, 3– (imidazol–1–yl) bis (4’, 4”–dimethoxyphenyl) methyl, 1, 1–bis (4–methoxyphenyl) –1’–pyrenylmethyl, 9–anthryl, 9– (9–phenyl) xanthenyl, 9– (9–phenyl–10–oxo) anthryl, 1, 3–benzodithiolan–2–yl, benzisothiazolyl S, S–dioxido, trimethylsilyl (TMS) , triethylsilyl (TES) , triisopropylsilyl (TIPS) , dimethylisopropylsilyl (IPDMS) , diethylisopropylsilyl (DEIPS) , dimethylthexylsilyl, t–butyldimethylsilyl (TBDMS) , t–butyldiphenylsilyl (TBDPS) , tribenzylsilyl, tri–p–xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS) , t–butylmethoxyphenylsilyl (TBMPS) , formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p–chlorophenoxyacetate, 3– phenylpropionate, 4–oxopentanoate (levulinate) , 4, 4– (ethylenedithio) pentanoate (levulinoyldithioacetal) , pivaloate, adamantoate, crotonate, 4–methoxycrotonate, benzoate, p– phenylbenzoate, 2, 4, 6–trimethylbenzoate (mesitoate) , alkyl methyl carbonate, 9– fluorenylmethyl carbonate (Fmoc) , alkyl ethyl carbonate, alkyl 2, 2, 2–trichloroethyl carbonate -27-703.101.412 (Troc) , 2– (trimethylsilyl) ethyl carbonate (TMSEC) , 2– (phenylsulfonyl) 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) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E) –2–methyl–2–butenoate, o– (methoxycarbonyl) benzoate, α–naphthoate, nitrate, alkyl N, N, N’, N’–tetramethylphosphorodiamidate, alkyl N–phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2, 4–dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate) , benzylsulfonate, 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–dimethoxyethylidene ortho ester, α–methoxybenzylidene ortho ester, 1– (N, N–dimethylamino) ethylidene derivative, α– (N, N’–dimethylamino) benzylidene derivative, 2–oxacyclopentylidene ortho ester, di–t– butylsilylene group (DTBS) , 1, 3– (1, 1, 3, 3–tetraisopropyldisiloxanylidene) derivative (TIPDS) , tetra–t–butoxydisiloxane–1, 3–diylidene derivative (TBDS) , cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

[0076] In some embodiments, a hydroxyl protecting group is acetyl, t-butyl, tbutoxymethyl, methoxymethyl, tetrahydropyranyl, 1 -ethoxyethyl, 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, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifiuoroacetyl, pivaloyl, 9- -28-703.101.412 fluorenylmethyl 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- dimethylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2, 4, 6-trimethylphenyl, 2- (2-nitrophenyl) ethyl, butylthiocarbonyl, 4, 4', 4”-tris (benzoyloxy) trityl, diphenylcarbamoyl, levulinyl, 2- (dibromomethyl) benzoyl (Dbmb) , 2- (isopropylthiomethoxymethyl) benzoyl (Ptmt) , 9- phenylxanthen-9-yl (pixyl) or 9- (p-methoxyphenyl) xanthine-9-y1 (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 internucleotide 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-1, 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.

[0077] 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- dioxanes, 1,3-dioxolanes, 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 C1-C6aliphatic 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 is -29-703.101.412 optionally 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.

[0078] “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%.

[0079] “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.

[0080] “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.

[0081] “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.

[0082] “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”.

[0083] “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.

[0084] “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 reduce -30-703.101.412 incidence 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

[0085] Among other things, the present disclosure provides compounds that can be used as diagnostic and / or therapeutic agents. In some embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein: Ring A is C6-C10 aryl or 5-20 membered heteroaryl, wherein Ring A is optionally and independently substituted with 1-5 R’; R1is hydrogen or C1-C6 alkyl; R2and R3are each independently hydrogen or a group selected from C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6alkenyl, and C2-C6alkynyl, wherein each group is optionally and independently substituted with 1-20 Rs; or R2and R3are taken together with the nitrogen atom they are attached to form 3-20 membered heterocycloalkyl optionally substituted with 1-20 Rs, or R2and R3are taking together with the nitrogen atom they are attached to for ;R4is -C(=O)R’, -C(=O)OR’, -C(=O)N(R’)2, -B(R’)2, –B(R’)3X, or 5-6 membered heteroaryl; R5is hydrogen, -L-C(=O)OH, -L-C(=O)OPG, -L-NHC(=NH)NH2, -L-NHC(=NPG)NH2, -L- NHC(=NPG)NHPG, or -L-NHC(=NPG)-N=C(R’)2; p is 0, 1, 2, or 3; -31-703.101.412 R6is absent, hydrogen, -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 -L-OH; each R7is independently F or radioisotope

[0018] F; m is 1 or 2; each R8is independently hydrogen, PG, C1-C6 alkyl, or C3-C10 cycloalkyl; n is 0, 1, or 2; R9is 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; X is a counterion; each PG is independently a protecting group; L is absent or C1-C6 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’)-; each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, or -S(O)2R; each R is independently hydrogen, halogen, or an optionally substituted group selected from C1- C10 aliphatic, C1-C10 heteroalkyl, C6-C10 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 =O; or two 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; or two 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, C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OC1-C6alkyl, -OC3-C10 cycloalkyl, -OC6-C10 aryl, -O-5-10 membered heteroaryl, -O-3-20 membered heterocycloalkyl, -OC(=O)C1-C6 alkyl, -OC(=O)C3-C10 cycloalkyl, -OC(=O)C6-C10 aryl, - -32-703.101.412 OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, - NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=O)C1-C6alkyl, -N(C1-C6alkyl)C(=O)C1-C6alkyl, -NHS(=O)2C1-C6 alkyl, -NHS(=O)2C3-C10 cycloalkyl, -NHS(=O)2C6-C10 aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(C1- C6alkyl)S(=O)2C1-C6alkyl, -N(C1-C6alkyl)S(=O)2C3-C10cycloalkyl, -N(C1- C6alkyl)S(=O)2C6-C10 aryl, -N(C1-C6 alkyl)S(=O)25-10 membered heteroaryl, -N(C1- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, - C(=O)OC1-C6alkyl, -C(=O)NH2, -C(=O)NHC1-C6alkyl, -C(=O)N(C1-C6alkyl)2; wherein each C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C3- C10cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.

[0086] 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).

[0087] In some embodiments, the present disclosure provides a compound of Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein: Ring A is C6-C10aryl or 5-20 membered heteroaryl, wherein Ring A is optionally and independently substituted with 1-5 R’; R1is hydrogen or C1-C6alkyl; -33-703.101.412 R2and R3are each independently hydrogen or a group selected from C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6alkenyl, and C2-C6alkynyl, wherein each group is optionally and independently substituted with 1-20 Rs; or R2and R3are taken together with the nitrogen atom they are attached to form 3-20 membered heterocycloalkyl optionally substituted with 1-20 Rs, or R2and R3are taking together with the nitrogen atom they are attached to form ; R4is -C(=O)R’, -C(=O)OR’, -C(=O)N(R’)2, -B(R’)2, –B(R’)3X, or 5-6 memberedryl; R5is hydrogen, -L-C(=O)OH, -L-C(=O)OPG, -L-NHC(=NH)NH2, -L-NHC(=NPG)NH2, -L- NHC(=NPG)NHPG, or -L-NHC(=NPG)-N=C(R’)2; R6is absent, hydrogen, -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 -L-OH; each R7is independently F or radioisotope

[0018] F; m ieach R8is independently hydrogen, PG, C1-C6 alkyl, or C3-C10 cycloalkyl; n is 0, 1, or 2; R9is 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; X is a counterion; each PG is independently a protecting group; L is absent or C1-C6alkylene 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’)-; each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, or -S(O)2R; each R is independently hydrogen, halogen, or an optionally substituted group selected from C1- C10aliphatic, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl, wherein each group is optionally and independently with 1-20 Rs, or two R groups are optionally and independently taken together to form a covalent bond or =O; or -34-703.101.412 two 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; or two 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, C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OC1-C6alkyl, -OC3-C10cycloalkyl, -OC6-C10aryl, -O-5-10 membered heteroaryl, -O-3-20 membered heterocycloalkyl, -OC(=O)C1-C6 alkyl, -OC(=O)C3-C10 cycloalkyl, -OC(=O)C6-C10 aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)C1-C6alkyl, -S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, - NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)C(=O)C1-C6 alkyl, -NHS(=O)2C1-C6 alkyl, -NHS(=O)2C3-C10 cycloalkyl, -NHS(=O)2C6-C10 aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(C1- C6alkyl)S(=O)2C1-C6 alkyl, -N(C1-C6alkyl)S(=O)2C3-C10 cycloalkyl, -N(C1- C6alkyl)S(=O)2C6-C10 aryl, -N(C1-C6 alkyl)S(=O)25-10 membered heteroaryl, -N(C1- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)C1-C6alkyl, -C(=O)OH, - C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)NHC1-C6 alkyl, -C(=O)N(C1-C6alkyl)2; wherein each C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 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, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, 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-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:, -35-703.101.412 wherein: Ring A is C6-C10aryl or 5-20 membered heteroaryl, wherein Ring A is optionally and independently substituted with 1-5 R’; R1is hydrogen or C1-C6 alkyl; R2and R3are each independently hydrogen or a group selected from C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6alkenyl, and C2-C6alkynyl, wherein each group is optionally and independently substituted with 1-20 Rs; or R2and R3are taken together with the nitrogen atom they are attached to form 3-20 membered heterocycloalkyl optionally substituted with 1-20 Rs, or R2and R3are taking together with the nitrogen atom they are attached to form ; R4is -C(=O)R’, -C(=O)OR’, -C(=O)N(R’)2, -B(R’)2, –B(R’)3X, or 5-6 membered heteroaryl; R6is absent h dro en -C(=O)R’ -C(=O)OR’ -C(=O)N(R’) , -N(R’)2, -NR’C(=O)R’, -NR’C(=O)N(R’)2, -OC(=O)R’, -OC(=O)OR’, or -L-OH; each R7is independently F or radioisotope

[0018] F; m is 1 or 2; each R8is independently hydrogen, PG, C1-C6alkyl, or C3-C10cycloalkyl; n is 0, 1, or 2; R9is 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; X is a counterion; each PG is independently a protecting group; L is absent or C1-C6 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’)-; each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, or -S(O)2R; each R is independently hydrogen, halogen, or an optionally substituted group selected from C1- C10 aliphatic, C1-C10 heteroalkyl, C6-C10 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 =O; or -36-703.101.412 two 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; or two 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, C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OC1-C6alkyl, -OC3-C10cycloalkyl, -OC6-C10aryl, -O-5-10 membered heteroaryl, -O-3-20 membered heterocycloalkyl, -OC(=O)C1-C6 alkyl, -OC(=O)C3-C10 cycloalkyl, -OC(=O)C6-C10 aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)C1-C6alkyl, -S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, - NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)C(=O)C1-C6 alkyl, -NHS(=O)2C1-C6 alkyl, -NHS(=O)2C3-C10 cycloalkyl, -NHS(=O)2C6-C10 aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(C1- C6alkyl)S(=O)2C1-C6 alkyl, -N(C1-C6alkyl)S(=O)2C3-C10 cycloalkyl, -N(C1- C6alkyl)S(=O)2C6-C10 aryl, -N(C1-C6 alkyl)S(=O)25-10 membered heteroaryl, -N(C1- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)C1-C6alkyl, -C(=O)OH, - C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)NHC1-C6 alkyl, -C(=O)N(C1-C6alkyl)2; wherein each C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 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, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C3- C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.

[0089] In some embodiments, a provided compound has a structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:, -37-703.101.412 wherein each variable is independently as described herein.

[0090] In some embodiments, a provided compound has a structure of Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (II-e), Formula (II-f), Formula (II-g), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein.

[0091] In some embodiments, a provided compound has a structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein.

[0092] In some embodiments, a provided compound has a structure of Formula (III-a), Formula (III-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein. -38-703.101.412

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

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

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

[0096] 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:)wherein each variable is independently as described herein. -39-703.101.412

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

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

[0099] In some embodiments, a provided compound has a structure of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein.

[0100] In some embodiments, a provided compound has a structure of Formula (VII-a), Formula (VII-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein. -40-703.101.412

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

[0102] In some embodiments, a provided compound has a structure of Formula (IX), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein.

[0103] In some embodiments, a provided compound has a structure of Formula (X), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein.

[0104] In some embodiments, a provided compound has a structure of Formula (X-a), Formula (X-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein. -41-703.101.412

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

[0106] In some embodiments, a provided compound has a structure of Formula (XI-a), Formula (XI-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein.

[0107] In some embodiments, a provided compound has a structure of Formula (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein.

[0108] In some embodiments, a provided compound has a structure of Formula (XII-a), Formula (XII-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein. -42-703.101.412

[0109] In some embodiments, a provided compound has a structure of Formula (XIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: ,wherein each variable is independently as described herein.

[0110] In some embodiments, a provided compound has a structure of Formula (XIII-a), Formula (XIII-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein.

[0111] In some embodiments, a provided compound has a structure of Formula (XIV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein.

[0112] In some embodiments, a provided compound has a structure of Formula (XIV-a), Formula (XIV-b), Formula (XIV-c), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:) -43-703.101.412 wherein each variable is independently as described herein.

[0113] In some embodiments, a provided compound has a structure of Formula (XV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein.

[0114] In some embodiments, a provided compound has a structure of Formula (XV-a), Formula (XV-b), Formula (XV-c), Formula (XV-d), Formula (XV-e), Formula (XV-f), Formula (XV-g), Formula (XV-h), Formula (XV-i), Formula (XV-j), Formula (XV-k), Formula (XV-l), Formula (XV-m), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:-44-703.101.412wherein each variable is independently as described herein.

[0115] In some embodiments, a provided compound has a structure of Formula (XVI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein each variable is independently as described herein.

[0116] In some embodiments, a provided compound has a structure of Formula (XVI-a), Formula (XVI-b), Formula (XVI-c), Formula (XVI-d), Formula (XVI-e), Formula (XVI-f), Formula (XVI-g), Formula (XVI-h), Formula (XVI-i), Formula (XVI-j), Formula (XVI-k), Formula (XVI-l), Formula (XVI-m), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:703.101.412wherein each variable is independently as described herein.

[0117] In some embodiments, a provided compound has a structure of:703.101.412 r aindependently as described herein.

[0118] In some embodiments, a provided compound has a structure of: ,703.101.412 of,

[0119] In some embodiments, a provided compound has a structure of: r ah variable is independently as described herein.

[0120] In some embodiments, a provided compound has a structure of: -48-703.101.412 ,a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,pendently as described herein.

[0121] In some embodiments, a provided compound has a structure of: ,703.101.412 r a variable isindependently as described herein.

[0122] In some embodiments, a provided compound has a structure of: , r a703.101.412 pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each variable is independently as described herein.

[0123] In some embodiments, a provided compound has a structure of: , e isindependently as described herein.

[0124] In some embodiments, a provided compound has a structure of: er

[0125] In some embodiments, the present disclosure provides compounds comprising hypervalent halogen atoms. In some embodiments, a hypervalent halogen compound is a compound of Formula (Hyper-R*), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:-51-703.101.412 *);wherein: Ring A is C6-C10aryl or 6-20 membered heteroaryl, wherein Ring A is optionally and independently substituted with 1-5 R’; is a single bond or double bond; R1is hydrogen or C1-C6alkyl; R2and R3are each independently hydrogen or a group selected from C1-C6alkyl, C1-C6heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein each group is optionally and independently substituted with 1-20 Rs; or R2and R3are taken together with the nitrogen atom they are attached to form 3-20 membered heterocycloalkyl optionally substituted with 1-20 Rs, or R2and R3are taking together with the nitrogen atom they are attached to for ; R4is -C(=O)R’, -C(=O)OR’, -C(=O)N(R’) , or -B(R’) , –B(R’) X, or 5-6 m2 2 3 embered heteroaryl; 5 -L-NHC(=NPG)NH2, -L-NHC(=NPG)NHPG, or -L-NHC(=NPG)-N=C(R )2; p is 0, 1, 2, or 3; each R7is independently F or radioisotope

[0018] F; m is 1 or 2; each R8is independently hydrogen, PG, C1-C6 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; each X is independently a counterion; each PG is independently a protecting group; -52-703.101.412 L is absent or C1-C6 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’)-; each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, or -S(O)2R; each R is independently hydrogen, halogen, or an optionally substituted group selected from C1- C10 aliphatic, C1-C10 heteroalkyl, C6-C10 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 =O; or two 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; or two 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, C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OC1-C6alkyl, -OC3-C10 cycloalkyl, -OC6-C10 aryl, -O-5-10 membered heteroaryl, -O-3-20 membered heterocycloalkyl, -OC(=O)C1-C6 alkyl, -OC(=O)C3-C10 cycloalkyl, -OC(=O)C6-C10 aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)C1-C6alkyl, -S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, - NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)C(=O)C1-C6 alkyl, -NHS(=O)2C1-C6alkyl, -NHS(=O)2C3-C10cycloalkyl, -NHS(=O)2C6-C10aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(C1- C6alkyl)S(=O)2C1-C6 alkyl, -N(C1-C6alkyl)S(=O)2C3-C10 cycloalkyl, -N(C1- C6alkyl)S(=O)2C6-C10 aryl, -N(C1-C6alkyl)S(=O)25-10 membered heteroaryl, -N(C1- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)C1-C6alkyl, -C(=O)OH, - C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)NHC1-C6 alkyl, -C(=O)N(C1-C6alkyl)2; wherein each C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered -53-703.101.412 heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C3- C10cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl. L*and -L*-R*-

[0126] 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, C1-C10alkyl, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 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, L*is -C(=NR’)O- and R’ is C1-C10alkyl, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 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, L*is -N=C(R’)O-. In some embodiments, L*is -N=C(R’)O- and R’ is hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, C6-C10 aryl, 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-C10alkyl. In some embodiments, L*is -N=C(Me)O-. In some embodiments, -L*-R*- is -N=C(R’)O- R*-. In some embodiments, L*is -N=C(N(R’)2)O-. In some embodiments, L*is - N=C(N(R’)2)O- and each R’ is independently hydrogen, C1-C10alkyl, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 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(N(R’)2)O- and each R’ is independently hydrogen or C1-C10alkyl. 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, C1-C10alkyl, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 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-. -54-703.101.412 In some embodiments, L*is -L-O-. In some embodiments, L*is -L-O- and L is C1-C6 alkylene optionally substituted with 1-12 Rs, wherein 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 some embodiments, L*is -L-O- and L is C1-C6alkylene optionally substituted with 1-6 Rs, wherein each Rsis independently as described herein. In some embodiments, L*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, L*is -CH2-O- and -CH2- 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, orhalomethyl. In some embodiments, L* is . In some embodiments, L* is . Insome embodiments, -L*-R*- is -L-O-R*-, whereinL 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

[0211] 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 Cl-. In some embodiments, X is OAc-. X

[0127] 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. -55-703.101.412

[0128] 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 K+.

[0129] In some embodiments, a provided compound has a structure of: alt, in.

[0130] In some embodiments, a provided compound has a structure of: r ais independently as described herein.

[0131] In some embodiments, a provided compound has a structure of: -56-703.101.412 r a isindependently as described herein.

[0132] In some embodiments, a provided compound has a structure of: , r ae is independently as described herein.

[0133] In some embodiments, a provided compound has a structure of: -57-703.101.412 of,Ring A

[0134] In some embodiments, Ring A is C6-C10 aryl or 5-20 membered heteroaryl, 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 C6-C10aryl optionally and independently substituted with 1-5 R’ and each R’ is independently as described herein. In some embodiments, Ring A is C6-C10 aryl 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’ 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-C4alkyl, C1-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. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is phenyl independently -58-703.101.412 substituted with 1-2 R’ groups independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl (e.g., -CF3), -CN, -NO2, -OH, -O-C1-C4alkyl, -N(RSB)2, -C(O)ORSB, and - S(O)2N(RSB)2, wherein each RSBis independently hydrogen, C1-C4alkyl, C1-C4haloalkyl (e.g., - CF3), or phenyl.

[0135] In some embodiments, Ring A is 5-20 membered heteroaryl, 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 5-20 membered heteroaryl comprising 1-10 heteroatoms from independently selected from nitrogen, oxygen, or sulfur, 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 5-20 membered heteroaryl comprising 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 5-10 membered heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally and independently substituted with 1-3 R’ and each R’ is independently as described herein. In some embodiments, Ring A is 5-6 membered heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally and independently substituted with 1-3 R’ and each R’ is independently as described herein. In some embodiments, Ring A is 5 membered heteroaryl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is 5 membered heteroaryl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally and independently substituted with 1-2 R’ and each R’ is independently as described herein. In some embodiments, Ring A is 5 membered heteroaryl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally and independently substituted with 1-2 R’ groups independently selected from halogen, C1-C4alkyl, C1-C4haloalkyl (e.g., -CF3), -CN, -NO2, -OH, -O-C1-C4alkyl, -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 or-59-703.101.412 , wherein RAis R’ as described herein. In some embodiments, Ring A is ,, wherein RAis a nitrogen protecting group. In someembodiments, RAis Boc. In some embodiments, Ring A is ,or . In some embodiments, Ring A is . In some embodiments, Ring A is. In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is .

[0136] In some embodiments, Ring A is 6 membered heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is 6 membered heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally and independently substituted with 1-3 R’ and each R’ is independently as described herein. In some embodiments, Ring A is 6 membered heteroaryl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally and independently substituted with 1-3 R’ and each R’ is independently as described herein. In some embodiments, Ring A is 6 membered heteroaryl comprising 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally and independently substituted with 1-3 R’ and each R’ is independently as described herein. In some embodiments, Ring A is 6 membered heteroaryl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally and independently substituted with 1-3 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-C4alkyl, C1-C4haloalkyl (e.g., -CF3), or phenyl. In some embodiments, Ring A is 6 membered heteroaryl comprising 1-3 nitrogen atoms, wherein Ring A is optionally and independently substituted with -60-703.101.412 1-3 R’ groups independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl (e.g., -CF3), - CN, -NO2, -OH, -O-C1-C4alkyl, -N(RSB)2, -C(O)ORSB, and -S(O)2N(RSB)2, wherein each RSBis independently hydrogen, C1-C4alkyl, C1-C4haloalkyl (e.g., -CF3), or phenyl. In someembodiments, Ring A is . In some embodiments, RingA i . In some embodiments, Ring A i . In some embodiments, Ring A i .In some embodiments, Rin . In some embodiments, Ring A .

[0137] In some emb Ring A is 9 membered heteroaryl1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is 9 membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally and independently substituted with 1-3 R’ and each R’ is independently as described herein. In some embodiments, Ring A is 9 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally and independently substituted with 1-3 R’ and each R’ is independently as described herein. In some embodiments, Ring A is 9 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally and independently substituted with 1-3 R’ and each R’ is independently as described herein. In some embodiments, Ring A is 9 membered heteroaryl having 1-2 nitrogen atoms, wherein Ring A is optionally and independently substituted with 1-3 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-C4alkyl, C1-C4haloalkyl (e.g., -CF3), or phenyl. In some embodiments, Ring A is A ts,-61-703.101.412 B nts,, wherein each variable isindependently as described herein. In some embodiment , whereineach variable is independently as described herein. In some embodiment isnts, eembodiments, , wherein each variable is independently as-62-703.101.412 described herein. In some embodiment , wherein each variable,wherein each variable is independently as described herein. In some embodimen, wherein each variable is independently as described herein. In someembodiments, , wherein each variable is independently as describedherein. In some embodiments, , wherein each variable isindependently as described herein. In some embodiments , whereineach variable is independently as described herein. In some embodiment is-63-703.101.412 nts, omeembodiments, , wherein each variable is independently as describedherein. In some embodiments, , wherein each variable is independentlyas described herein. In some embodiments , wherein each variable isindependently as described herein. In some embodiments , whereineach variable is independently as described herein. In some embodiment is, wherein each variable is independently as described herein. In some embodiments,-64-703.101.412 , wherein each variable is independently as described herein. In someembodiments, , wherein each variable is independently as describedherein. In some embodiments, , wherein each variable isindependently as described herein. In some embodiments , whereineach variable is independently as described herein. In some embodiment isnts, omeembodiments, , wherein each variable is independently as described-65-703.101.412 herein. In some embodiments , wherein each variable isindependently as described herein. In some embodiments , whereineach variable is independently as described herein. In some embodiment isnts, meembodiments, , wherein each variable is independently as describedherein. In some embodiments , wherein each variable isindependently as described herein. In some embodiments ein-66-703.101.412 each variable is independently as described herein. In some embodimen isnts, meembodiments , wherein each variable is independently as describedherein. In some embodiments, , wherein each variable isindependently as described herein. In some embodiments , whereineach variable is independently as described herein. In some embodiment is, wherein each variable is independently as described herein. In some embodiments,-67-703.101.412 , wherein each variable is independently as described herein. In someembodiments, , wherein each variable is independently as describedherein. In some embodiments, isindependently as described herein. In some embodiments ,wherein each variable is independently as described herein. In some embodimen, wherein each variable is independently as described herein. In some, wherein each variable is independently as describedherein. In some embodiments, , wherein each variable is-68-703.101.412 (OR8)nindependently as described herein. In some embodimentsRB,wherein each variable is independently as described herein. In some embodiment (OR8)nR6B , wherein each variable is independently as described herein. In some(OR8)nRB, wherein each variable is independently as describedherein. In some embodiments, , wherein each variable isindependently as described herein. In some embodiments ,wherein each variable is independently as described herein. In some embodimen, wherein each variable is independently as described herein. In some-69-703.101.412 embodiments , 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 embodimen (OR8)9nR B , wherein each variable is independently as described herein. In somebedindependently as described herein. In some embodiments ein-70-703.101.412 each variable is independently as described herein. In some embodimen is, wherein each variable is independently as described herein. In some, wherein each variable is independently as described(OR8)nN herein. In some embodiments,RB, wherein each variable isindependently as described herein. In some embodiment ,wherein each variable is independently as described herein. In some embodiment, wherein each variable is independently as described herein. In someembodiments , wherein each variable is independently as-71-703.101.412 described herein. In some embodiment , wherein each variableis independently as described herein. In some embodiments ,wherein each variable is independently as described herein. In some embodimen, wherein each variable is independently as described herein. In some(OR8)nN embodiments,RB, wherein each variable is independently as described herein.

[0139] In some embodiments e isindependently as described herein. In some embodiments eineach variable is independently as described herein. In some embodimen is-72-703.101.412 nts,some embodiments, , wherein each variable is independently asdescribed herein. In some embodiments , wherein each variable isindependently as described herein. In some embodiment eineach variable is independently as described herein. In some embodiment is, wherein each variable is independently as described herein. In some-73-703.101.412 embodiments , wherein each variable is independently as describedherein. In some embodiments, , wherein each variable isindependently as described herein. In some embodiment eineach variable is independently as described herein. In some embodiment isnts, Insome embodiments, , wherein each variable is independently as-74-703.101.412 described herein. In some embodiment , wherein each variable isindependently as described herein. In some embodiment , whereineach variable is independently as described herein. In some embodimen isnts, nsome embodiments, , wherein each variable is independently asdescribed herein. In some embodiment , wherein each variable isindependently as described herein. In some embodiment ein-75-703.101.412 each variable is independently as described herein. In some embodimen isnts,some embodiments asdescribed herein. In some embodiment , wherein each variable isOMe F R9H independently as described herein. In some embodiment , whereineach variable is independently as described herein. In some embodimen is-76-703.101.412 OMe F R9nts, nsome embodiments, , wherein each variable is independently asdescribed herein. In some embodiments , wherein each variable isindependently as described herein. In some embodiments eineach variable is independently as described herein. In some embodiment isnts, me-77-703.101.412 embodiments, , wherein each variable is independently as describedherein. In some embodiments, , wherein each variable isindependently as described herein. In some embodiment eineach variable is independently as described herein. In some embodiment is, wherein each variable is independently as described herein. In some embodiments,, wherein each variable is independently as describedherein. In some embodiments, , wherein each variable is-78-703.101.412 independently as described herein. In some embodiments ,wherein each variable is independently as described herein. In some embodiment, wherein each variable is independently as described herein. In someembodiments , wherein each variable is independently asdescribed herein. In some embodiments achvariable is independently as described herein. In some embodiment is, wherein each variable is independently as described herein. In some-79-703.101.412 embodiments, , wherein each variable is independently as describedherein. In some embodiments, isF 9 independently as described herein. In some embodiments ,wherein each variable is independently as described herein. In some embodiment, wherein each variable is independently as described herein. In someembodiments, , wherein each variable is independently as describedherein. In some embodiments, , wherein each variable isindependently as described herein. In some embodiments , wherein-80-703.101.412 each variable is independently as described herein. In some embodimen is, wherein each variable is independently as described herein. In some, wherein each variable is independently as describedherein. In some embodiments, , wherein each variable isindependently as described herein. In some embodiments eineach variable is independently as described herein. In some embodiment is, wherein each variable is independently as described herein. In someembodiments, , wherein each variable is independently as described-81-703.101.412 herein. In some embodiments , wherein each variable isindependently as described herein. In some embodiments ,wherein each variable is independently as described herein. In some embodimen, wherein each variable is independently as described herein. In someembodiments, , wherein each variable is independently asdescribed herein. In some embodiments , wherein each variable isindependently as described herein. In some embodiments ,wherein each variable is independently as described herein. In some embodiment-82-703.101.412 , wherein each variable is independently as described herein. In someembodiments, , wherein each variable is independently asdescribed herein. In some embodiments , wherein each variable isF R9N H independently as described herein. In some embodiments ,wherein each variable is independently as described herein. In some embodimenis , wherein each variable is independently as described herein. In someembodiments, , wherein each variable is independently as describedherein. In some embodiments, , wherein each variable is-83-703.101.412 independently as described herein. In some embodiments ,wherein each variable is independently as described herein. In some embodimen, 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 embodimen, wherein each variable is independently as described herein. In some-84-703.101.412 embodiments, , wherein each variable is independently asdescribed herein. In some embodiments , wherein each variable isindependently as described herein. In some embodiments ,wherein each variable is independently as described herein. In some embodimenth variable is independently as described herein. In some embodiments, , wherein each variable is independently as described herein. In someembodiments, , wherein each variable is independently as describedherein. In some embodiments, , wherein each variable is independently-85-703.101.412 as described herein. In some embodiment , wherein eachvariable is independently as described herein. In some embodiment is, wherein each variable is independently as described herein. In someembodiments asdescribed herein. In some embodiments achvariable is independently as described herein. In some embodiment is, wherein each variable is independently as described herein. In some-86-703.101.412 embodiments , wherein each variable is independently as described her

[0140] In some embodiments e isindependently as described herein. In some embodiments eineach variable is independently as described herein. In some embodimen is, wherein each variable is independently as described herein. In someembodiments , wherein each variable is independently as described, wherein each variable isindependently as described herein. In some embodiments , wherein-87-703.101.412 each variable is independently as described herein. In some embodiment ishrin h ribl i ind ndntl d ribd hrin In m mbdimnts,some embodiments, asdescribed herein. In some embodiments , wherein each variable isindependently as described herein. In some embodiments ,wherein each variable is independently as described herein. In some embodiment, wherein each variable is independently as described herein. In some-88-703.101.412 embodiments , wherein each variable is independently as described, wherein each variable isindependently as described herein. In some embodiments ,wherein each variable is independently as described herein. In some embodimen, wherein each variable is independently as described herein. In someembodiments, , wherein each variable is independently asdescribed herein. In some embodiments , wherein each variable isindependently as described herein. In some embodiments ,-89-703.101.412 wherein each variable is independently as described herein. In some embodiment, wherein each variable is independently as described herein.R1

[0141] In some embodiments, R1is hydrogen or C1-C6alkyl. In some embodiments, R1is hydrogen. In some embodiments, R1is C1-C6 alkyl. In some embodiments, R1is C1-C4 alkyl. In some embodiments, R1is methyl. In some embodiments, R1is ethyl. R2

[0142] In some embodiments, R2is hydrogen or a group selected from C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6alkenyl, and C2-C6alkynyl, wherein each group is optionally and independently substituted with 1-20 Rs; or R2and R3are taken together with the nitrogen atom they are attached to form 3-20 membered heterocycloalkyl optionally substituted with 1-20 Rs, wherein each Rsis independently as described herein, or R2and R3are taking together with the nitrogen atom they are attached to form and each R’ is independently as describedherein. In some embodiments, R2is hydrogen. In some embodiments, R2is C1-C6 alkyl. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is methyl. In some embodiments, R2is ethyl. In some embodiments, R2is isopropyl. R3

[0143] In some embodiments, R3is hydrogen or a group selected from C1-C6alkyl, C1-C6heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein each group is optionally and independently substituted with 1-20 Rs; or R2and R3are taken together with the nitrogen atom they are attached to form 3-20 membered heterocycloalkyl optionally substituted with 1-20 Rs, -90-703.101.412 wherein each Rsis independently as described herein. In some embodiments, R3is hydrogen. In some embodiments, R3is C1-C6alkyl. In some embodiments, R3is C1-C3alkyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is isopropyl. In some embodiments, R2and R3are taken together with the nitrogen atom they are attached to form 3-20 membered heterocycloalkyl optionally substituted with 1-20 Rs, wherein each Rsis independently as described herein. In some embodiments, R2and R3are taken together with the nitrogen atom they are attached to form 3-10 membered heterocycloalkyl optionally substituted with 1-10 Rs, wherein each Rsis independently as described herein. In some embodiments, R2and R3are taken together with the nitrogen atom they are attached to form 3-8 membered heterocycloalkyl optionally substituted with 1-5 Rs, wherein each Rsis independently as described herein. In some embodiments, R2and R3are 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, R2and R3are taken together with the nitrogen atom they are attached to form 3-6 membered heterocycloalkyl optionally substituted with 1-3 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, R2and R3are taken together with the nitrogen atom they are attached to form 3-6 membered heterocycloalkyl. In some embodiments, R2and R3are taken together with the nitrogen atom they are attached to for .

[0144] In some embodiments, R2and R3are taken atom they are attached to form , wherein each R’ is independently as described herein. In some mbodiments, R2e and R3are taking together with the nitrogen atom they are attached to form , wherein each R’ is independently hydrogen, C1-C6 alkyl, or phenyl. In someembodiments, R2and R3are taking together with the nitrogen atom they are attached to form -91-703.101.412 . In some embodiments, R2and R3are taking together with the nitrogen atom they are attached to form .R4

[0145] In some embodiments, R4is -C(=O)R’, -C(=O)OR’, -C(=O)N(R’)2, -B(R’)2, - B(R’)3X wherein X is a counterion, or 5-6 membered heteroaryl, wherein each R’ 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, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R4is -C(=O)R’ and R’ is C1-C6 alkyl. In some embodiments, R4is -C(=O)OR’, wherein R’ is as described herein. In some embodiments, R4is -C(=O)OH. In some embodiments, R4is -C(=O)OR’ and R’ is C1-C10alkyl, C1-C10heteroalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R4is -C(=O)OR’ and R’ is C1-C10 alkyl. In some embodiments, R4is - C(=O)OMe. In some embodiments, R4is -C(=O)OEt. In some embodiments, R4is -C(=O)OiPr. In some embodiments, R4is -C(=O)OBu. In some embodiments, R4is -C(=O)OtBu. In some embodiments, R4is -C(=O)N(R’)2, wherein each R’ is independently as described herein. In some embodiments, R4is -C(=O)N(R’)2and each R’ is independently hydrogen, C1-C10alkyl, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 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’)2and each R’ is independently hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R4is -C(=O)N(R’)2 and each R’ is independently hydrogen or C1-C6alkyl. In some embodiments, R4is -C(=O)NH2. In some embodiments, R4is -C(=O)NHMe. In some embodiments, R4is -C(=O)NMe2. In 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, - -92-703.101.412 CN, -OMe, methyl, or halomethyl. In some embodiments, R4is -C(=O)N(R’)2 and two R’ are taken together with the nitrogen atom they are attached to form 3-6 membered heterocycloalkyl optionally substituted with 1-3 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, R4is -C(=O)N(R’)2 and two R’ are taken together with the nitrogen atom they are attached to form 3-6 membered heterocycloalkyl. In some embodiments, R4,. In some embodiments, R4is -B(R’)2, wherein each R’ is In some embodiments, R4is -B(R’)2 and each R’ isindependently halogen, -OH, -OR, or -OC(=O)R, wherein R is as described herein. In some embodiments, R4is -B(R’)2 and each R’ is independently halogen or -OH. In some embodiments, R4is -BF2. In some embodiments, R4is -B(OH)2. In some embodiments, R4is - B(OR)2and each R is independently C1-C6aliphatic. In some embodiments, R4is -B(OMe)2. In some embodiments, R4is -B(OR)2and two R are taken together with the intervening atoms they are attached to form 3-10 membered heterocycloalkyl optionally substituted with 1-4 halogen, - medescribed herein. In some embodiments, R4is –B(R’)3X and each R’ is independently halogen, - OH, or -OR, wherein X and R are each independently as described herein. In some embodiments, R4is –B(R’)3X and each R’ is independently halogen, wherein X is as described herein. In some embodiments, R4is –BF3K. In some embodiments, R4is 5-6 membered heteroaryl. In some embodiments . In some embodiments, R4.R5

[0146] In some embodiments, R5is hydrogen, -L-C(=O)OH, -L-C(=O)OPG, -L- NHC(=NH)NH2, -L-NHC(=NPG)NH2, -L-NHC(=NPG)NHPG, or -L-NHC(=NPG)-N=C(R’)2. -93-703.101.412 In some embodiments, In some embodiments, R5is -L-C(O)OH, wherein L is as described herein. In some embodiments, R5is -L-C(O)OPG, wherein L is as described herein. In some embodiments, R5is -L-C(O)OPG, wherein L and PG are independently as described herein. In some embodiments, R5is -L-NHC(=NH)NH2, wherein L is as described herein. In some embodiments, R5is L-NHC(=NPG)NH2, wherein L and PG are independently as described herein. In some embodiments, R5is -L-NHC(=NPG)NHPG, wherein L and PG are independently as described herein. In some embodiments, R5is -L-NHC(=NPG)-N=C(R’)2 wherein each variable is independently as described herein. R6

[0147] In some embodiments, R6is a stabilizing group as described herein. In some embodiments, R6stabilizes a radioisotope. In some embodiments, R6is stabilizes a radioisotope of iodine. In some embodiments, R6is stabilizes a radioisotope of astatine. In some embodiments, R6is absent, hydrogen, -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 -L-OH, where each variable is independently as described herein. In some embodiments, R6is hydrogen, -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 -L-OH, where each variable is independently as described herein. In some embodiments, R6is absent. In some embodiments, R6is hydrogen. In some embodiments, R6is -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 -L-OH, wherein each of R’ and L is independently as described herein. In some embodiments, R6is –C(=O)R’, wherein R’ is as described herein. In some embodiments, R6is – C(=O)R’ and R’ is C1-C10alkyl, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R6is – C(=O)OR’ and R’ is hydrogen, C1-C10alkyl, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R6is – C(=O)OR’ and R’ is hydrogen or C1-C6 alkyl. In some embodiments, R6is –C(=O)OH. In some embodiments, R6is –C(=O)OR’ and R’ is C1-C6 alkyl. In some embodiments, R6is – C(=O)OMe. In some embodiments, R6is –C(=O)OEt. In some embodiments, R6is – C(=O)N(R’)2 and each R’ is independently hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, or two -94-703.101.412 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, R6is –C(=O)N(R’)2and each R’ is independently hydrogen or C1-C6 alkyl. In some embodiments, R6is –C(=O)NH2. In some embodiments, R6is – C(=O)NHMe. In some embodiments, R6is –C(=O)NMe2. In some embodiments, R6is – C(=O)N(R’)2and 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, R6is –N(R’)2 and each R’ is independently hydrogen, C1- C10alkyl, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 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, R6is –NR’C(=O)R’, and each R’ is independently hydrogen, C1-C10alkyl, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 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, R6is –NR’C(=O)R’, and each R’ is independently hydrogen or C1-C6 alkyl. In some embodiments, R6is –NHC(=O)Me. In some embodiments, R6is –NR’C(=O)N(R’)2, and each R’ is independently hydrogen, C1-C10alkyl, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 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 heterocycloalkyl optionally substituted with 1-5 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, R6is –NR’C(=O)N(R’)2, and each R’ is independently hydrogen or C1-C6alkyl. In some embodiments, R6is –NHC(=O)NHMe. In some embodiments, R6is –OC(=O)R’, and R’ is hydrogen, C1-C10alkyl, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R6is –OC(=O)R’, and R’ is hydrogen or C1-C6 alkyl. In some embodiments, R6is –OC(=O)Me. In some embodiments, R6is –OC(=O)OR’, and R’ is hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, C6-C10 aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R6is -L-OH, wherein L is as described herein. In some embodiments, R6is -L- OH and L is C1-C6 alkylene optionally substituted with 1-12 Rs, wherein one or more methylene -95-703.101.412 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’)-. In some embodiments, R6is -L-OH and L is C1-C6 alkylene optionally substituted with 1-6 Rs, wherein Rsis as described herein. In some embodiments, R6is -L-OH and L is C1-C3 alkylene optionally substituted with 1-4 Rs, wherein Rsis as described herein. In some embodiments, R6is -CH2-OH and -CH2- is optionally substituted with 1-2 Rs, wherein Rsis as described herein. In some embodiments, R6is -CH2-OH and -CH2- is optionally substituted with 1-2 halogen, -OH, -CN, -OMe, methyl, or halomethyl. In some embodiments, R6is -CH2-OH and -CH2- is substituted with 1-2 halogen, -OH, -CN, - OMe, methyl, or halomethyl. In some embodiments, R6is . In some embodiments, R6is.R7

[0148] In some embodiments, R7is F or radioisotope

[0018] F. In some embodiments, R7is F. In some embodiments, R7is radioisotope

[0018] F. m

[0149] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. R8

[0150] In some embodiments, R8is independently hydrogen, PG, C1-C6alkyl, or C3-C10cycloalkyl. In some embodiments, R8is independently hydrogen or C1-C6 alkyl. In some embodiments, R8is independently C3-C10 cycloalkyl. In some embodiments, R8is hydrogen. In some embodiments, R8is independently Me. n

[0151] 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. -96-703.101.412 p

[0152] In some embodiments, p is 0, 1, 2 or 3. In some embodiments, p is 0. In some embodiments, p is 1. Moreover, p can be 2, or p can be 3, in some embodiments. As described herein, when p is 0, the methylene group to which R5is attached is absent, for example, as shown .R9

[0153] In some embodiments, R9is 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. In some embodiments, each R9is 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, provided that at least one of R7and R9is a radioisotope. In some embodiments, R9is Cl. In some embodiments, R9is Br. In some embodiments, R9is I. In some embodiments, R9is

[0076] Br,

[0077] Br, or

[0082] Br. In some embodiments, R9is

[0123] I,

[0124] I,

[0125] I, or

[0131] I. In some embodiments, R9is

[0210] At or

[0211] At. In some embodiments, R7is

[0018] F and R9is Cl, Br, or I. In some embodiments, R7is F and R9is

[0076] Br,

[0077] Br,

[0082] Br,

[0123] I,

[0124] I,

[0125] I,

[0131] I,

[0210] At, or

[0211] At.

[0154] In some embodiments, neither of R7and R9is a radioisotope. In some embodiments, at least one of R7and R9is radioisotope. In some embodiments, at least one of R7and R9is not radioisotope. In some embodiments, one of R7and R9is a radioisotope and one of R7and R9is not a radioisotope. In some embodiments, R7is a radioisotope and R9is not a radioisotope. In some embodiments, R7is not a radioisotope and R9is a radioisotope. PG -97-703.101.412

[0155] In some embodiments, a nitrogen protecting group is Boc. In some embodiments, a nitrogen protecting group is Fmoc. In some embodiments, a protected amino group i . Insome embodiments, a protected amino group is . R’

[0156] 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(R)2, wherein R as described herein. In some embodiments, R’ is -S(O)2R, wherein R as described herein. R

[0157] 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’).

[0158] In some embodiments, R is hydrogen. In some embodiments, R is not hydrogen.

[0159] In some embodiments, each R is independently hydrogen, halogen, or an optionally substituted group selected from C1-C10 aliphatic, C1-C10 heteroaliphatic, C6-C10 aryl, 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-C10aliphatic, C1-C10heteroaliphatic 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-C1-C6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C1-C6aliphatic. In some embodiments, each R is independently hydrogen, halogen, or an optionally substituted group selected from C1-C10 aliphatic, C1-C10 heteroalkyl having 1-3 heteroatoms, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 -98-703.101.412 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-C10alkyl, C1-C10heteroalkyl having 1-3 heteroatoms, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl having 1-6 heteroatoms, and 3-20 membered heterocycloalkyl having 1-6 heteroatoms.

[0160] In some embodiments, R is optionally substituted C1-6aliphatic. In some embodiments, R is optionally substituted C1-6 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.

[0161] In some embodiments, R is optionally substituted C1-C6heteroaliphatic 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 C1-C6 heteroaliphatic having 1-3 (e.g., 1, 2, or 3) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur.

[0162] 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, R is cyclohexyl. In some embodiments, R is cycloheptyl.

[0163] 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.) -99-703.101.412 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 heterocycloalkyl 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 partially 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.

[0164] In some embodiments, R is optionally substituted C6-C10 (e.g., C6, C10, etc.) aryl. In some embodiments, R is optionally substituted C6-C10aryl. 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.

[0165] 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 -100-703.101.412 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.

[0166] In some embodiments, R is optionally substituted C6-C10aryl-C1-C6aliphatic, wherein the aryl and aliphatic are independently as described herein. In some embodiments, R is optionally substituted C6-C10 aryl-C1-C6 alkyl.

[0167] In some embodiments, R is optionally substituted 5-10 membered heteroaryl having 1-6 (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms-C1-C6aliphatic 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-C1-C6 aliphatic. In some embodiments, R is optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms-C1- C6 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-C1-C6 alkyl 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-C1-6alkyl. In some embodiments, R is optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms-C1-C6 alkyl. Various suitable heteroaryl and aliphatic groups are as described herein.

[0168] 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 -101-703.101.412 (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

[0169] 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, 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) 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 -102-703.101.412 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.

[0170] 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 unsubstituted. 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 for their 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 hydrocarbon group. 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 -103-703.101.412 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

[0171] In some embodiments, an optional substituent on a substitutable group is Rsas described herein. In some embodiments, Rsis halogen, -NO2, -CN, -OH, C1-C6alkyl, C1-C6heteroalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OC1-C6alkyl, -OC3-C10cycloalkyl, -OC6-C10aryl, -O-5-10 membered heteroaryl, -O-3-20 membered heterocycloalkyl, -OC(=O)C1-C6alkyl, -OC(=O)C3-C10cycloalkyl, -OC(=O)C6-C10 aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, - S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=O)C1-C6alkyl, -N(C1- C6 alkyl)C(=O)C1-C6 alkyl, -NHS(=O)2C1-C6 alkyl, -NHS(=O)2C3-C10 cycloalkyl, - NHS(=O)2C6-C10 aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(C1-C6alkyl)S(=O)2C1-C6alkyl, -N(C1-C6alkyl)S(=O)2C3-C10cycloalkyl, - N(C1-C6alkyl)S(=O)2C6-C10 aryl, -N(C1-C6 alkyl)S(=O)25-10 membered heteroaryl, -N(C1- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)NHC1-C6alkyl, or -C(=O)N(C1-C6alkyl)2; wherein each C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.

[0172] 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 -104-703.101.412 substituent on a substitutable group (e.g., Ring A, R, etc.) is independently halogen, C1-4 alkyl, C1-4haloalkyl, or –OH. In some embodiments, each optional substituent on a substitutable group (e.g., Ring A, R, etc.) is independently halogen, C1-4alkyl or C1-4haloalkyl. In some embodiments, each halogen is -F.

[0173] 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.

[0174] 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, 18O, 17O, 35S, 18F, 36Cl, respectively. However, additional isotopes for iodine, bromine, and astatine are also included herein. 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 -CD2-.

[0175] 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.

[0176] In some embodiments, a provided compound has a structure of: -105-703.101.412 , , , , , ,703.101.412 , , , , , ,703.101.412 , , , , , , ,703.101.412 , , , , ,703.101.412 , , , , or a124]I,

[0125] I, or

[0131] I.

[0177] In some embodiments, a provided compound has a structure of: -110-703.101.412 , , , , , ,-111-703.101.412 , , , , ,703.101.412 , , , , , , ,703.101.412 , , , , , ,703.101.412 , , or, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,At or

[0211] At.

[0178] In some embodiments, a provided compound has a structure of: , ,703.101.412 or, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,*I is

[0125] I, or

[0131] I.

[0179] In some embodiments, a provided compound has a structure of: , , or

[0180] In some embodiments, a provided compound has a structure of: -116-703.101.412 or, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

[0124] I,

[0125] I, or

[0131] I.

[0181] In some embodiments, a provided compound has a structure of: , t or

[0211] At.

[0182] In some embodiments, a provided compound has a structure of: , , ,703.101.412 , , H , , , , ,703.101.412 , , 4]I,

[0125] I, or

[0131] I and X is as described herein.

[0183] In some embodiments, a provided compound has a structure of: , , ,703.101.412 , , , , , ,703.101.412 , , , , , ,703.101.412 a pharmaceutically acceptable salt, 11]At and X is as described herein.

[00184] In some embodiments, a provided compound has a structure of: , ,703.101.412 , ndF I OMe76Br OMe H2,703.101.412 HO2C CO2H 76, ,H,-124-703.101.412 O NMe2124I F , ,

[0186] In some embodiments, a provided compound has a structure of: F 131I OMe ,703.101.412 ,703.101.412 ,Methods of Preparing

[0187] 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-life (t1 / 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).

[0188] 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. O2free, 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. -127-703.101.412

[0189] Method B. Direct C-O bond conversion: Transition metal catalysis and concerted SNAr methods have been utilized for the direct fluorination of activated C–O 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.

[0190] Method C. Direct C-X (X = F, Cl, Br, I, NO2) 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.

[0191] In some embodiments, compounds of Formula (I) comprising radioisotopes of iodine (i.e.,

[0123] I,

[0124] I,

[0125] I and

[0131] I), 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.

[0192] 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:the method comprising: (a) obtaining a compound of Formula (INT-a) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: -128-703.101.412 ,wherein: Ring A is C6-C10 aryl or 5-20 membered heteroaryl, wherein Ring A is optionally and independently substituted with 1-5 R’; R1is hydrogen or C1-C6alkyl; R2and R3are each independently hydrogen or a group selected from C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein each group is optionally and independently substituted with 1-20 Rs; or R2and R3are taken together with the nitrogen atom they are attached to form 3-20 membered heterocycloalkyl optionally substituted with 1-20 Rs; R4is -C(=O)R’, -C(=O)OR’, -C(=O)N(R’)2, -B(R’)2, –B(R’)3X, or 5-6 membered heteroaryl; R5is hydrogen, -L-C(=O)OH, -L-C(=O)OPG, -L-NHC(=NH)NH2, -L-NHC(=NPG)NH2, -L- NHC(=NPG)NHPG, or -L-NHC(=NPG)-N=C(R’)2; p is 0, 1, 2 or 3; R6is absent, hydrogen, -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 -L-OH; each R7is independently F or radioisotope

[0018] F; m is 1 or 2; each R8is independently hydrogen, PG, C1-C6alkyl, or C3-C10cycloalkyl; n is 0, 1, or 2; R9is 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; )3;each PG is independently a protecting group; L is absent or C1-C6alkylene 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)-, - -129-703.101.412 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’)-; each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, or -S(O)2R; each R is independently hydrogen, halogen, or an optionally substituted group selected from C1- C10 aliphatic, C1-C10 heteroalkyl, C6-C10 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 =O; or two 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; or two 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, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OC1-C6 alkyl, -OC3-C10 cycloalkyl, -OC6-C10 aryl, -O-5-10 membered heteroaryl, -O-3-20 membered heterocycloalkyl, -OC(=O)C1-C6alkyl, -OC(=O)C3-C10cycloalkyl, -OC(=O)C6-C10aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, - NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=O)C1-C6alkyl, -N(C1-C6alkyl)C(=O)C1-C6alkyl, -NHS(=O)2C1-C6alkyl, -NHS(=O)2C3-C10cycloalkyl, -NHS(=O)2C6-C10aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(C1- C6alkyl)S(=O)2C1-C6alkyl, -N(C1-C6alkyl)S(=O)2C3-C10cycloalkyl, -N(C1- C6alkyl)S(=O)2C6-C10aryl, -N(C1-C6alkyl)S(=O)25-10 membered heteroaryl, -N(C1- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1- C6 alkyl, -C(=O)NH2, -C(=O)NHC1-C6 alkyl, -C(=O)N(C1-C6alkyl)2; wherein each C1-C6 alkyl, C1-C6heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more -130-703.101.412 halogen, -NO2, -CN, -OH, C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 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).

[0193] In some embodiments, the present disclosure provides a method of method for the preparation of a compound of Formula (I-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:the method comprising: (a) obtaining a compound of Formula (INT-a-a) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:), wherein: Ring A is C6-C10 aryl or 5-20 membered heteroaryl, wherein Ring A is optionally and independently substituted with 1-5 R’; R1is hydrogen or C1-C6alkyl; R2and R3are each independently hydrogen or a group selected from C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein each group is optionally and independently substituted with 1-20 Rs; or R2and R3are taken together with the nitrogen atom they are attached to form 3-20 membered heterocycloalkyl optionally substituted with 1-20 Rs; R4is -C(=O)R’, -C(=O)OR’, -C(=O)N(R’)2, -B(R’)2, –B(R’)3X, or 5-6 membered heteroaryl; -131-703.101.412 R5is hydrogen, -L-C(=O)OH, -L-C(=O)OPG, -L-NHC(=NH)NH2, -L-NHC(=NPG)NH2, -L- NHC(=NPG)NHPG, or -L-NHC(=NPG)-N=C(R’)2; R6is absent, hydrogen, -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 -L-OH; each R7is independently F or radioisotope

[0018] F; m is 1 or 2; each R8is independently hydrogen, PG, C1-C6 alkyl, or C3-C10 cycloalkyl; n is 0, 1, or 2; R9is 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; R10is Cl Br I -B(R’)2 -B(R’)3X -Sn(R’)3 -Ge(R’)3 or -Si(R’)3;each PG is independently a protecting group; L is absent or C1-C6 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’)-; each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, or -S(O)2R; each R is independently hydrogen, halogen, or an optionally substituted group selected from C1- C10 aliphatic, C1-C10 heteroalkyl, C6-C10 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 =O; or two 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; or two 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; -132-703.101.412 each Rsis independently halogen, -NO2, -CN, -OH, C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OC1-C6alkyl, -OC3-C10cycloalkyl, -OC6-C10aryl, -O-5-10 membered heteroaryl, -O-3-20 membered heterocycloalkyl, -OC(=O)C1-C6 alkyl, -OC(=O)C3-C10 cycloalkyl, -OC(=O)C6-C10 aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, - NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)C(=O)C1-C6 alkyl, -NHS(=O)2C1-C6 alkyl, -NHS(=O)2C3-C10 cycloalkyl, -NHS(=O)2C6-C10 aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(C1- C6alkyl)S(=O)2C1-C6alkyl, -N(C1-C6alkyl)S(=O)2C3-C10cycloalkyl, -N(C1- C6alkyl)S(=O)2C6-C10 aryl, -N(C1-C6alkyl)S(=O)25-10 membered heteroaryl, -N(C1- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)OC1- C6alkyl, -C(=O)NH2, -C(=O)NHC1-C6alkyl, -C(=O)N(C1-C6alkyl)2; wherein each C1-C6alkyl, C1-C6 heteroalkyl, C6-C10 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, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 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).

[0194] 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:, the method comprising: subjecting a compound of Formula (INT-b) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: -133-703.101.412to appropriate conditions, wherein R10is -B(R)2, -B(R )3X and X is a counterion, -Sn(R’)3, - Ge(R’)3, 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.

[0195] 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 multistep 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:the method comprising: (1) subjecting a compound of Formula (INT-b) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:under appropriate conditions to provide a compound of Formula (INT-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:703.101.412 Formula (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.

[0196] 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, p, R4, R5, R6, R7, R8, R9, L, R’, R, Rs, L*, and R*, etc. for the same variable group described in the “Methods of Preparing” section. R10

[0197] In some embodiments, R10is Cl, Br, I, -B(R’)2, -B(R’)3X wherein X is a counterion, -Sn(R’)3, -Ge(R’)3, or -Si(R’)3, wherein each variable is independently as described herein. In some embodiments, R10is Cl. In some embodiments, R10is Br. In some embodiments, R10is I. In some embodiments, each R10is -B(R’)2, -B(R’)3X wherein X is a counterion, -Sn(R’)3, -Ge(R’)3, or -Si(R’)3and each R’ is independently as described herein. In some embodiments, R10is –B(R’)2, wherein each R’ is independently as described herein. In some embodiments, R10is –B(R’)2 and each R’ is independently halogen, -OH, -OR, or - OC(=O)R wherein each R is independently as described herein. In some embodiments, R10is - B(OH)2. In some embodiments, R10is -B(OR)2and each R is independently C1-C6aliphatic. In some embodiments, R10is -B(OMe)2. In some embodiments, R10is -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 some embodiment . In some embodiments, R10is –B(R’)3X and each R’ is independently halog, , , wherein X and R are each independently as described herein. In some embodiments, R10is –B(R’)3X and each R’ is independently halogen, wherein X is as described herein. In some embodiments, R10is –BF3K. In some embodiments, -135-703.101.412 R10is -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 embodiment . In some embodiments, R10in the compound of Formula (IN o R9in the compoundfor Formula (I) in a method as described herein. Oxidant

[0198] 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 CuO2. Base Activator

[0199] 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.

[0200] 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)

[0201] 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%. In some -136-703.101.412 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%. In 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%.

[0202] 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%.

[0203] 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%, 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 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 diastereomeric 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 -137-703.101.412 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 diastereomeric 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%.

[0204] 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 diastereomers, including diastereomeric salts, and separation thereof (Jean Jacques, Andre 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.

[0205] 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 -138-703.101.412 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%.

[0206] 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 at least 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 -139-703.101.412 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. Pharmaceutical Composition and Administration

[0207] In some embodiments, the present disclosure provides a pharmaceutical composition that comprise a provided compound 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, a pharmaceutical composition is suitable for radiotherapy (e.g., alpha-particle therapy, beta-particle therapy). In -140-703.101.412 some embodiments, the present disclosure provides a pharmaceutical composition that can deliver a provided compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, a compound is provided in a pharmaceutically acceptable salt form.

[0208] Various technologies, e.g., routes, modes, dosage regimens, etc. may be utilized to administer and / or deliver provided compounds 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.

[0209] 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. Suitable excipients may include stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. -141-703.101.412

[0210] 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 cetylpyridinium chloride.

[0211] 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-1- carboxylic acid, glucoheptonic acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, 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.

[0212] In some embodiments, salts are more soluble in aqueous or other protonic solvents than corresponding, free acid or base forms. In some embodiments, a pharmaceutical composition may be a lyophilized powder. In some embodiments, a pharmaceutical composition comprises a provided compound, e.g., a compound of Formula (I) or a pharmaceutically -142-703.101.412 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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, a suspension may also contain suitable stabilizers or agents which increase solubility to allow for the preparation of highly concentrated solutions. -143-703.101.412

[0217] Co-solvents and adjuvants may be added to compositions and formulations. Non- limiting 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.

[0218] 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.

[0219] 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.

[0220] In some embodiments, the present disclosure provides methods for delivering provided compounds 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 compound, e.g., a compound of formula I or a salt thereof, or a composition thereof.

[0221] A compound 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 skilled artisan will appreciate factors that may influence dosage and timing required to provide an amount sufficient for providing a therapeutic or prophylactic benefit.

[0222] 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 -144-703.101.412 disease treated, any host immune response to administered compound or composition, stability of administered compound or composition, etc. Generally, an agent, such as a compound of Formula (I) disclosed herein, 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.

[0223] 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.

[0224] The dosing and administration regimes of radionuclide-based compositions containing compounds of Formula (I) to be administered is based on various factors such as the type of radionuclide present in the compound of Formula (I), 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 compound of Formula (I). The amount of radioactivity of a radioactive compound of Formula (I) 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] I) 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 at doses encompassed by, but not limited to, the above-mentioned ranges depending on the type of therapy (alpha-particle vs. beta-particle).

[0225] 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 -145-703.101.412 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.

[0226] In some embodiments, pharmaceutical compositions comprise or deliver active ingredients, e.g., compounds of Formula (I) 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.

[0227] 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.

[0228] 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 pharmaceutical compositions 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 -146-703.101.412 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 solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0229] 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.

[0230] 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.

[0231] In some embodiments, the present disclosure encompasses a prodrug or a metabolite of a provided compound as understood by those skill in the art. In some embodiments, a prodrug of a provided compound is administered. Active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. Methods of Treatment

[0232] 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 (LAT1).

[0233] 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 -147-703.101.412 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 0.01% 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.

[0234] 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 compound or composition. 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 compound or composition. 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 compound or composition. In some embodiments, the disease is selected from a disease associated with expression of cellular targets involved in amino acid metabolism (e.g., LAT1), aberrant expression, overexpression and / or activity (e.g. cancer). In certain embodiments, the disease is mediated by cellular targets involved in amino acid 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 compound or composition. -148-703.101.412

[0235] 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 compound or composition.

[0236] 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 compound or composition, 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).

[0237] In some embodiments, a condition, disorder or disease is neurological diseases, cardiovascular diseases, and / or an infection.

[0238] 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, 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, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, -149-703.101.412 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, hematologic 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, Oligodendroglioma, Craniopharyngioma, Pituitary adenoma, Brainstem glioma, Schwannoma, 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.

[0239] 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, -150-703.101.412 Craniopharyngioma, Pituitary adenoma, Brainstem glioma, Schwannoma, Vestibular schwannoma, Anaplastic astrocytoma, Primary central nervous system lymphoma, Germ cell tumor, Primitive neuroectodermal tumor, Pilocytic astrocytoma, Mixed glioma, Chordoma, Optic nerve glioma and diffuse Astrocytomas.

[0240] In some embodiments, a cancer is pancreatic cancer. In some embodiments, a cancer is breast cancer.

[0241] In some embodiments, the compound 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.

[0242] In some embodiments, a subject who is suitable for a method described herein has been diagnosed as having acute myeloid leukemia, 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, 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 -151-703.101.412 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, 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, 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 diabetes. 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).

[0243] 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 compound or composition. In some embodiments, a condition, disorder or disease is neurological diseases, cardiovascular diseases, and / or an infection.

[0244] 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 compound or composition. In some embodiments, 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).

[0245] In some embodiments, a provided compound or composition 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 -152-703.101.412 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.

[0246] 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.

[0247] In some embodiments, a provided compound or composition is administered in combination with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof.

[0248] In another embodiment, a provided compound or composition is administered in combination with another therapeutic agent capable of inhibiting BRAF, MEK, KRAS, SOS1, CDK4 / 6, SHP-2, HDAC, EGFR, MET, mTOR, PI3K or AKT, or anti-PD1 drugs such as Nivolumab, Prembolamab, Cemiplimab, or anti-PDL1 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.

[0249] 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 compound is administered or delivered concurrently with another therapeutic agent. In some embodiments, a provided compound is administered or delivered in a single composition with another therapeutic agent. In some embodiments, a provided compound is administered or delivered concurrently with another therapeutic agent but in different compositions. In some embodiments, a provided compound 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 -153-703.101.412 therapeutic agent). In some embodiments, a provided compound 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 compound is administered or delivered when a subject is under the therapeutic effect of another therapeutic agent. Method of Use

[0250] 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 diagnose 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 LAT1.

[0251] Thus, one aspect of the present disclosure is that provided compounds or compositions 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.

[0252] 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).

[0253] 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 compound containing no radioisotopes. In such embodiments, a second theranostic agent is a provided compound comprising a radionuclide generally known to be used in PET and SPECT imaging modalities (e.g.,

[0018] F,

[0124] I,

[0075] Br,

[0076] Br, and

[0077] Br,

[0123] I,

[0125] I,

[0131] I,

[0210] At or

[0211] At).

[0254] In an alternate embodiment, a first theranostic agent is a radiolabeled-based therapy agent and is a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or -154-703.101.412 stereoisomer thereof containing a radioisotope generally known to be used in radiolabeled-based therapy agents (e.g.,

[0131] I and / or

[0211] At). In such embodiments, a second theranostic agent is a compound of Formula (I) 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

[0211] At).

[0255] 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.

[0256] Thus, one aspect of the present disclosure is to employ a provided compound 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.

[0257] In some embodiments, a provided compound 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 compounds wherein R9is 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

[0211] At; or R7is

[0018] F. In some embodiments, the compounds employed in the methods disclosed herein are compounds wherein R9is a radioisotope selected from the group consisting of

[0123] I,

[0124] I,

[0131] I,

[0210] At and

[0211] At; or R7is

[0018] F.

[0258] 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.

[0259] 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 pharmaceutically acceptable excipients or carriers will vary depending on the mode of -155-703.101.412 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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 drugs, 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 compound is not radioactive (e.g., neither of R7and R9are radioisotopes). In some embodiments, a provided compound is radioactive (and thus contains a radionuclide).

[0264] 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, -156-703.101.412 Trifluridine / Tipracil, Aldesleukin (IL-2), Denileukin Diftitox, Interferon Gamma, Belinostat, Panobinostat, Romidepsin, Vorinostat, Antiandrogens: 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, Ivosidenib, 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, Ixabepilone, Lenalidomide, Mitotane, Omacetaxine, Pomalidomide, Selinexor, Tagraxofusp, Tazemetostat, Tebentafusp, Telotristat, Temsirolimus, Thalidomide, and Venetoclax.

[0265] 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 I-131 (Hicon®), lobenguane iodine-131 (Azedra®), lutetium-177 (Lutathera® and Pluvicto®) and yttrium-90 (Zevalin®).

[0266] In some embodiments, the therapeutic agent is administered prior to administration of the imaging agent disclosed herein. -157-703.101.412 EXAMPLES Example 1: Synthesis of Poly Halogenated Amino Acid Derivatives and Radiolabeling of Amino Acid Derivatives.

[0267] Enantioenriched (e.g., enantiopure) poly halogenated amino acid derivatives as described herein have exhibited high tumor uptake and tumor-to-normal organ contrast.

[0268] In some embodiments, the present Example demonstrates an enantioselective multi-step synthesis of amino acid derivatives and radiolabeling of amino acid derivatives. As shown in Scheme 1, both D- and L- isomers of amino acid derivatives will be obtained with >95% optical purity, which will be measured by chiral HPLC. Scheme 1. Enantioselective Synthesis of Amino Acid Derivatives and Radiolabeling of Amino Acid Derivatives, wherein each variable is independently as described herein.synthesis of amino acid derivatives and radiolabeling of amino acid derivatives. Scheme 2: Synthesis of Amino Acid Derivatives and Radiolabeling of Amino Acid Derivatives, wherein each variable is independently as described herein. -158-703.101.412 18F DiagnosticH2N CO2H ling

[0270] Amino acid metabolism represents an important class of pathways in cancer progression. It has been shown that active transportation of amino acids plays a role during the energy metabolism reprogramming in PDAC. LAT1 is responsible for transporting amino acids. High LAT1 expression has been found to predict poor prognosis of PDAC and resistance to therapy. Elevated expressions of LAT1 in PDAC are associated with tumor size and disease stages.

[0271] A library of fluorinated amino acid derivatives was constructed using the methods described in e.g., Science 2019, 364, 1170-1174; Nature Catalysis 2020, 3, 734-742; Nature Chem 2022, 14, 216-223, each of which is herein incorporated by reference. Those skilled in the art will appreciate substrates with ring systems other than phenyl ring (e.g., heteroaryl rings as described herein) and / or with other substituent patterns on a ring system (e.g., those comprising -159-703.101.412 R6, R7, R9or other groups as described herein) can be radiolabeled according to methods described in the present Example. The present Example demonstrates that compounds and methods described herein can be used in imaging to assess LAT1-mediated uptake and / or binding. Example 3: Radiolabeling of Amino Acid Derivatives and Initial Evaluation of the Same

[0272] [18F] labeling: Amino acid derivatives will be labeled with

[0018] F according to methods described in Example 1 or reported in literature. See, e.g., Nature Chem.2022, 14, 216- 223.

[0273] Amino acid transporter assay: To investigate the involvement of amino acid transporters in the cellular uptake of the provided compounds, cellular uptake assay in MIA Paca-2 PDAC cancer cell lines will be performed. In brief, cells will be plated onto 6-well tissue culture plates (2 × 105 cells / well) and incubated with

[0018] F-labeled compounds as described herein (8 μCi / well) for 0–2 h. After incubation, cells will be washed with ice-cold PBS twice, detached, and collected. The radioactivity will be measured with a γ-counter. Data will be expressed in mean ± SD percentage of cellular uptake (%Uptake). To determine the specificity of the disclosed

[0018] F-labeled compounds to L-amino acid transporter (LAT), additional assays will be performed: the cellular uptake assay will be performed in the presence of an excess amount of L-Phe or LAT1 inhibitors as a competitor to investigate whether cell uptake of

[0018] F- labeled compounds is mediated by LAT1.

[0274] Serum stability, in vivo stability, pharmacokinetics, and tissue distribution of the PET agents. Priority

[0018] F-labeled compounds will be incubated with serum solution for 5, 15, 30, 60, 120, and 240 min, then analyzed by radio-HPLC to determine compound stability. In vivo metabolic study will be determined by tissue homogenization, extraction, and radioHPLC analysis. The pharmacokinetics and tissue distribution of these PET agents will be determined by bioD at 30min, 1, 2, and 4 h post injection.

[0275] 131I / 211At labeling: Amino acid derivatives will be labeled with

[0131] I /

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

[0131] I /

[0211] At will be preferentially used for radionuclide-based therapy.

[0276] Enantioenriched agents (e.g., optical pure) (D and L) will be synthesized and radiolabeled in accordance with the present disclosure. Agents with low pancreatic uptake are preferred due to the low background of a normal organ. -160-703.101.412 Example 4: PET imaging and biodistribution in PDAC tumor model

[0277] In the present Example, in vivo tumor targeting efficacy and pharmacokinetics of radiolabeled compounds prepared above will be assessed using pancreatic tumor models. In addition, the uptake in the normal pancreas will be assessed to ensure the selected radiolabeled have a high tumor to background ratio.

[0278] The constructed library of analogs will first be evaluated in MIA Paca-2 and PANC-1 orthotopic xenograft models to select promising agents with prominent tumor uptake, high contrast and relatively low pancreas uptake. In brief, 100 μCi of the PET agent will be injected and the animal will be scanned at 1, 2, 4, and 6 h post injection (p.i.). Region of interest will be drawn at the tumor and major organ area. Bio-D will be performed after the last time point is finished. The uptake and clearance profile will be compared among different

[0018] F labeled compunds. The selected agent should have tumor uptake > 5%ID / g, labeling yield > 5%, tumor retention >60% from 1 to 4 h p.i. and >50% at 6h p.i., and tumor to muscle ratio > 3. After initial screening, two selected lead agents will be tested in a syngeneic orthotopic PDAC model, which was established from genetically engineered KPC (KRasLSL.G12D / +; p53LSL.R172H / +; PdxCre on a C57Bl / 6 background, using static scans at 1, 2, 4 and 6h p.i.. IHC and autoradiography would be performed to study LAT1 expression level and localization of the PET agent within the tumor region. After initial imaging screening,

[0131] I /

[0211] At-labeled analogs will be prepared for biodistribution study to further confirm in vivo distribution of the therapeutic agents at late time points. In brief, the KPC orthotopic xenograft models will be injected with ~100μCi of

[0131] I /

[0211] At-labeled amino acids and will be sacrificed at 1,4, 24, 48, 72 and 96 h post-injection.

[0279] Lead agents will be evaluated in an orthotopic PDAC model established from KPC cells. Because the KPC model recapitulates many of the salient clinical and histopathological features (including poor vascularity, fibrosis, etc.) of human disease, in a future study, one would evaluate the lead agent in KPC tumors that arise spontaneously to determine uptake of lead agents in primary tumor and metastasis. Example 5: Synthesis of Methyl 2-((tert-butoxycarbonyl)amino)-3-(3-carbamoyl-5-fluoro-4- iodo-2-methoxyphenyl)propanoate -161-703.101.412 Scheme 3: Representation of methyl 2-((tert-butoxycarbonyl)amino)-3-(3-carbamoyl-5-fluoro-4- iodo-2-methoxyphenyl)propanoateScheme 4: Representative synthetic route for methyl 2-((tert-butoxycarbonyl)amino)-3-(3- carbamoyl-5-fluoro-4-iodo-2-methoxyphenyl)propanoateTo a solution 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 Na2SO4and 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-methylbenzaldehyde To a mixture of 5-fluoro-2-methoxy-3-methylbenzaldehyde (10.0 g, 59.5 mmol) in DCE (240 mL) was added N-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 -162-703.101.412 at 60 ℃ 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 Na2SO4and concentrated under reduced pressure. The crude residue was purified by reverse flash chromatography (C18 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+H]+. STEP 3: 3-fluoro-2-iodo-6-methoxy-5-methylbenzoic acid To 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 NaH2PO4(1.80 g, 15.0 mmol) in H2O (12 mL), NaClO2(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 (C18 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-methylbenzoate To 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 ℃ for 2 h, the mixture was cooled to rt, 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 Na2SO4and 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 (EI, m / z): 365.90 [M]. STEP 5: tert-butyl 3-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoate To a mixture of tert-butyl 3-fluoro-2-iodo-6-methoxy-5-methylbenzoate (1.80 g, 4.92 mmol) in CCl4(18 mL) was added N-bromosuccinimide (1.31 g, 7.38 mmol) and benzoyl peroxide (75% aq, 59 mg, 0.49 mmol). After heating at 70 ℃ 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 tert-butyl 3-(bromomethyl)-5-fluoro-6- iodo-2-methoxybenzoate (700 mg, 32%) as a colorless oil. GCMS (EI, m / z): 443.90 [M] -163-703.101.412 STEP 6: tert-butyl 3-(2-((diphenylmethylene)amino)-3-methoxy-3-oxopropyl)-5-fluoro-6- iodo-2-methoxybenzoate To a solution of tert-butyl 3-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoate (700 mg, 1.58 mmol) in ACN (7 mL) was added K2CO3 (870 mg, 6.31 mmol), TBAB (203 mg, 0.63 mmol) and methyl 2-(diphenylmethyleneamino)acetate (400 mg, 1.58 mmol). After 16 h, the mixture was purified by reverse flash chromatography (C18 silica gel, ACN-water, 0-80% with 10 mM NH4HCO3) to afford tert-butyl 3-(2-((diphenylmethylene)amino)-3-methoxy-3-oxopropyl)-5- fluoro-6-iodo-2-methoxybenzoate (400 mg, 41%) as a white solid. LCMS (ES, m / z): 618.05 [M+H]+. STEP 7: 3-(2-amino-3-methoxy-3-oxopropyl)-5-fluoro-6-iodo-2-methoxybenzoic acid To a solution of tert-butyl 3-(2-((diphenylmethylene)amino)-3-methoxy-3-oxopropyl)-5-fluoro- 6-iodo-2-methoxybenzoate (400 mg, 0.65 mmol) in DCM (6 mL) was added TFA (3 mL). After 2 h, the mixture was concentrated under reduced pressure, whereupon EtOH / H2O (4:1, 5 mL) was added, followed by hydroxylamine hydrochloride (582 mg, 8.43 mmol). After heating at 50 ℃ for 4 h, the mixture was purified by reverse flash chromatography (C18 silica gel, ACN- water, 0-20% with 10 mM NH4HCO3) to afford 3-(2-amino-3-methoxy-3-oxopropyl)-5-fluoro-6- iodo-2-methoxybenzoic acid (200 mg, 77%) as a white solid. LCMS (ES, m / z): 397.85 [M+H]+. STEP 8: 3-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-5-fluoro-6-iodo-2- methoxybenzoic acid To a mixture of 3-(2-amino-3-methoxy-3-oxopropyl)-5-fluoro-6-iodo-2-methoxybenzoic acid (200 mg, 0.50 mmol) in MeOH (2 mL) was added a solution of NaHCO3 (210 mg, 2.50 mmol) in H2O (1 mL) followed by di-tert-butyl dicarbonate (164 mg, 0.75 mmol). After 4 h, the mixture was purified by reverse flash chromatography (C18 silica gel, ACN-water, 0-50% with 10 mM NH4HCO3) to afford 3-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-5-fluoro-6- iodo-2-methoxybenzoic acid (200 mg, 80%) as a white solid. LCMS (ES, m / z): 496.00 [M-H]-. STEP 9: methyl 2-((tert-butoxycarbonyl)amino)-3-(3-carbamoyl-5-fluoro-4-iodo-2- methoxyphenyl)propanoate To a mixture of 3-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-5-fluoro-6-iodo-2- methoxybenzoic acid (100 mg, 0.20 mmol) in DMF (1 mL) was added DIEA (130 mg, 1.00 mmol), HATU (114 mg, 0.30 mmol) followed by NH3Cl (21 mg, 0.40 mmol). After 2 h, the mixture was purified by reverse flash chromatography (C18 silica gel, ACN-water, 0-50% with -164-703.101.412 10 mM NH4HCO3) to afford the title compound (61.1 mg, 61%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.68 (s, 1H), *7.36 (d, J = 8.4 Hz, 0.9H), *7.21 (br d, J = 8.6 Hz, 0.2H), 7.16 (d, J = 8.8 Hz, 0.8H), 6.98 (br d, J = 7.7, 0.1H), *4.28-4.19 (m, 0.8H), *4.18- 4.09 (m, 0.2H), 3.74 (s, 3H), 3.65 (s, 3H), 3.13-2.99 (m, 1H), 2.79 (dd, J = 14.2, 10.4 Hz, 1H), 1.40-1.22 (m, 9H). *Partial integration due to presence of rotamers.19F NMR (376 MHz, DMSO-d6) δ -98.68 (minor rotamer), -98.77 (major rotamer). LCMS (ES, m / z): 396.95 [M- Boc+H]+; 98.3% purity (254 nm). Example 6: Synthesis of 2-amino-3-(3-carbamoyl-5-fluoro-4-iodo-2 methoxyphenyl)propanoic acid Scheme 5: Representation of 2-amino-3-(3-carbamoyl-5-fluoro-4-iodo-2 methoxyphenyl)propanoic acid Scheme 5a: Representative synthoyl-5-fluoro-4-iodo-2 methoxyphenyl)propanoic acid A suspensiono-4-iodo-2- methoxyphenyl)propanoate (10 mg, 0.020 mmol) in HCl (6 M, 1 mL) was heated at 100 °C for 10 min, whereupon the mixture was cooled to room temperature and purified by reverse flash chromatography column (C18 silica gel, ACN-water, 0-80% with 0.1% FA) followed by Prep- HPLC (Column: XBridge Prep OBD C185 μm, 30 x 150 mm; Mobile Phase: ACN-water, 2- 19% with 0.1% FA; Flow rate: 60 mL / min; Wavelength: 254 / 220 nm) to affording the title compound (1.2 mg, 16%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.72-7.74 (m, 1H), 7.68 (br s, 1H), 7.64-7.25 (m, 1H), 7.21 (d, J = 8.8 Hz, 1H), 3.72 (s, 3H), 3.49-3.40 (m, 1H), 3.19 -165-703.101.412 (d, J = 14.5, 4.8, 1H), 2.77 (dd, J = 14.7, 8.2 Hz, 1H).19F NMR (376 MHz, DMSO-d6) δ -98.56. LCMS (ES, m / z): 382.90 [M+H]+; 99.6% purity (254 nm). Example 7: Synthesis of Methyl 2-((tert-butoxycarbonyl)amino)-3-(5-fluoro-4-iodo-2-methoxy- 3-(methylcarbamoyl)phenyl)propanoate Scheme 6: Representation of methyl 2-((tert-butoxycarbonyl)amino)-3-(5-fluoro-4-iodo-2- methoxy-3-(methylcarbamoyl)phenyl)propanoate The title compound (59 mg) wa toxycarbonyl)amino)-3-methoxy-3-oxopropyl)-5-fluoro-6-iodo-2-methoxybenzoic acid according to analogous methods described for Example 5.1H NMR (400 MHz, DMSO-d6) δ 8.40-8.32 (m, 1H), *7.36 (d, J = 8.3 Hz, 0.9H), *7.26-7.21 (m, 0.1H), *7.21-7.14 (m, 0.9H), *7.01-6.94 (m, 0.1H), *4.28-4.18 (m, 0.9H), *4.17- 4.09 (m, 0.2H), 3.76-3.68 (m, 3H), 3.64 (s, 3H), 3.14-2.98 (m, 1H), 2.85-2.72 (m, 4H), 1.43-1.21 (m, 9H). *Partial integration due to presence of rotamers.19F NMR (376 MHz, DMSO) δ -98.96 (major rotamer), -98.88 (minor rotamer). LCMS (ES, m / z): 410.95 [M-Boc+H]+. Example 8: Synthesis of Methyl 3-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3- oxopropyl)-5-fluoro-6-iodo-2-methoxybenzoate Scheme 7: Representation of methyl 3-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3- oxopropyl)-5-fluoro-6-iodo-2-methoxybenzoate Scheme 8: Representativeethyl 3-(3-(tert-butoxy)-2-((tert- butoxycarbonyl)amino)-3-oxopropyl)-5-fluoro-6-iodo-2-methoxybenzoate -166-703.101.412To a mixture of 3-fluoro-2-iodo-6-methoxy-5-methylbenzoic acid (1.50 g, 4.84 mmol) in DMF (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 Na2SO4and 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-methoxybenzoate To a solution of methyl 3-fluoro-2-iodo-6-methoxy-5-methylbenzoate (1.30 g, 4.01 mmol) in CCl4 (13 mL) was added N-bromosuccinimide (1.07 g, 6.02 mmol) and benzoyl peroxide (96.8 mg, 0.40 mmol). After heating the mixture at 70 ℃ for 16 h, it was cooled to rt poured into ice- water (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 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-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoate (800 mg, 49%) as a colorless oil. GCMS (EI, m / z): 401.90 [M]. STEP 3: methyl 3-(3-(tert-butoxy)-2-((diphenylmethylene)amino)-3-oxopropyl)-5-fluoro-6-i odo-2-methoxybenzoate To a solution of methyl 3-(bromomethyl)-5-fluoro-6-iodo-2-methoxybenzoate (800 mg, 1.99 mmol) in MeCN (8 mL) was added K2CO3 (1.10 g, 7.96 mmol), TBAB (256 mg, 0.80 mmol) and tert-butyl 2-[(diphenylmethylidene)amino] acetate (587 mg, 1.99 mmol). After 16 h, the mixture was poured into ice-water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel -167-703.101.412 chromatography (EA-Petroleum ether, 10%) to afford methyl 3-(3-(tert-butoxy)-2- ((diphenylmethylene)amino)-3-oxopropyl)-5-fluoro-6-iodo-2-methoxybenzoate (700 mg, 57%) as a white solid. LCMS (ES, m / z): 618.10 [M+H]+. STEP 4: methyl 3-(2-amino-3-(tert-butoxy)-3-oxopropyl)-5-fluoro-6-iodo-2- methoxybenzoate To a stirred mixture of methyl 3-(3-(tert-butoxy)-2-((diphenylmethylene)amino)-3-oxopropyl)-5- fluoro-6-iodo-2-methoxybenzoate (700 mg, 1.14 mmol) in EtOH (10 mL) / H2O (3 mL) was added hydroxylamine hydrochloride (1.03 g, 14.8 mmol). After heating at 50 ℃ for 4 h, the mixture directly purified by reverse flash chromatography (C18 silica gel, ACN-water, 0-70% with 0.1% FA), affording methyl 3-(2-amino-3-(tert-butoxy)-3-oxopropyl)-5-fluoro-6-iodo-2- methoxybenzoate (400 mg, 77%) as a colorless oil. LCMS (ES, m / z): 454.05 [M+H]+. STEP 5: methyl 3-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)-5-fluoro-6- iodo-2-methoxybenzoate To a solution of methyl 3-(2-amino-3-(tert-butoxy)-3-oxopropyl)-5-fluoro-6-iodo-2- methoxybenzoate (400 mg, 0.88 mmol) in DCM (6 mL) at 0 ℃ was added TEA (268 mg, 2.65 mmol) followed by di-tert-butyl dicarbonate (289 mg, 1.33 mmol). After 4 h, mixture was concentrated under reduced pressure and purified by silica gel chromatography (EA-Petroleum ether, 15%) to afford the title compound (400 mg, 81%) as a white solid.1H NMR (400 MHz, DMSO-d6 / D2O) δ 7.32-7.20 (m, 1H), 4.14-3.97 (m, 1H), 3.95-3.83 (m76-3.66 (s, 3H), 3.08-2.94 (m, 1H), 2.83-2.69 (m, 1H), 1.41-1.20 (m, 18H).19F NMR (376 MHz, DMSO-d6 / D2O) δ -99.00 (minor rotamer), -99.12 (major rotamer). LCMS (ES, m / z): 397.90 [M-tBu- Boc+2H]+; 98.1% purity (254 nm). Example 9: Synthesis of Methyl 3-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3- oxopropyl)-5-(4-chlorophenoxy)-2-iodobenzoate Scheme 9: Representation of methyl 3-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3- oxopropyl)-5-(4-chlorophenoxy)-2-iodobenzoate703.101.412 Scheme 10: Representative synthetic route for methyl 3-(3-(tert-butoxy)-2-((tert- butoxycarbonyl)amino)-3-oxopropyl)-5-(4-chlorophenoxy)-2-iodobenzoateTo 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-nitrobenzoate To 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 -169-703.101.412 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 (EI, m / z): 213.10 [M] STEP 3: methyl 5-(4-chlorophenoxy)-3-methyl-2-nitrobenzoate A 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 (EI, m / z): 321.10 [M] STEP 4: methyl 2-amino-5-(4-chlorophenoxy)-3-methylbenzoate To 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 (C18 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-methylbenzoate To a solution of methyl 2-amino-5-(4-chlorophenoxy)-3-methylbenzoate (4.00 g, 13.7 mmol) in HCl (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. 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-(methoxycarbonyl)benzoic acid -170-703.101.412 To 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 Na2SO4 and concentrated under reduced pressure. The crude residue was purified by reverse flash chromatography (C18 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-iodobenzoate To 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.1H NMR (400 MHz, DMSO-d6) δ 7.51-7.45 (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). STEP 8: methyl 3-(bromomethyl)-5-(4-chlorophenoxy)-2-iodobenzoate To 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 PBr3 (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.1H NMR (400 MHz, DMSO) δ 7.52-7.46 (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]+; 99.8% purity (254 nm). STEP 9: methyl 3-(3-(tert-butoxy)-2-((diphenylmethylene)amino)-3-oxopropyl)-5-(4- chlorophenoxy)-2-iodobenzoate To a mixture of methyl 3-(bromomethyl)-5-(4-chlorophenoxy)-2-iodobenzoate (600 mg, 1.25 mmol) in ACN (4 mL) was added tert-butyl 2-((diphenylmethylene)amino)acetate (552 mg, 1.86 mmol), tetrabutylammonium bromide (40 mg, 0.12 mmol) and K2CO3 (517 mg, 3.75 mmol). -171-703.101.412 After 16 h, the mixture was filtered, 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 (C18 silica gel, ACN-water, 5-100% with 10 mM NH4HCO3), affording methyl 3-(3-(tert-butoxy)-2-((diphenylmethylene)amino)-3-oxopropyl)-5-(4-chlorophenoxy)-2- iodobenzoate (350 mg, 40%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.50-7.35 (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 10: methyl 3-(2-amino-3-(tert-butoxy)-3-oxopropyl)-5-(4-chlorophenoxy)-2- iodobenzoate To a mixture of methyl 3-[3-(tert-butoxy)-2-[(diphenylmethylidene)amino]-3-oxopropyl]-5-(4- chlorophenoxy)-2-iodobenzoate (350 mg, 0.50 mmol) in EtOH / water (4:1, 5 mL) was added hydroxylamine hydrochloride (454 mg, 6.53 mmol). After heating at 50 °C for 4 h, the mixture was cooled to rt and directly purified by reverse flash chromatography (C18 silica gel, ACN- water, 5-100% with 10 mM NH4HCO3) to afford methyl 3-[2-amino-3-(tert-butoxy)-3- oxopropyl]-5-(4-chlorophenoxy)-2-iodobenzoate (200 mg, 74%) as a white solid. LCMS (ES, m / z): 532.10 [M+H]+. STEP 11: methyl 3-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)-5-(4- chlorophenoxy)-2-iodobenzoate To a mixture of methyl 3-[2-amino-3-(tert-butoxy)-3-oxopropyl]-5-(4-chlorophenoxy)-2- iodobenzoate (200 mg, 0.37 mmol) in DCM (2 mL) was added TEA (115 mg, 1.13 mmol) and di-tert-butyl decarbonate (99 mg, 0.45 mmol). After 1 h, the mixture was concentrated under reduced pressure and purified by silica gel chromatography (EA-Petroleum ether, 50%) to afford the title compound (200 mg, 84%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.49-7.43 (m, 2H), 7.26 (d, J = 8.4 Hz, 0.8H), *7.22-7.19 (m, 0.2H), *7.17 (d, J = 2.9 Hz, 0.8H), 7.10-7.04 (m, 3H), *6.89-6.84 (m, 0.2H), *4.22-4.14 (m, 0.2), *4.13 (m, 0.8H), 3.82 (s, 3H), 3.21 (dd, J = 13.7, 4.9 Hz, 1H), 3.03-2.85 (m, 1H), 1.45-1.36 (m, 9H), *1.33 (s, 7H), *1.24 (s, 2H). *Integration values due to presence of rotamers. LCMS (ES, m / z): 654.00 [M+Na]+; 99.8% purity (254 nm). -172-703.101.412 Example 10: Synthesis of tert-Butyl 2-((tert-butoxycarbonyl)amino)-3-(3-carbamoyl-5-(4- chlorophenoxy)-2-iodophenyl)propanoate Scheme 11: Representation of tert-butyl 2-((tert-butoxycarbonyl)amino)-3-(3-carbamoyl-5-(4- chlorophenoxy)-2-iodophenyl)propanoate Scheme 12: Representative synt ert-butoxycarbonyl)amino)-3-(3-carbamoyl-5-(4-chlorophenoxy)-2-iodophenyl)propanoateSTEP 1: 3-[3-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl]-5-(4- chlorophenoxy)-2-iodobenzoic acid To a mixture of methyl 3-[3-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl]-5-(4- chlorophenoxy)-2-iodobenzoate (150 mg, 0.24 mmol) in MeOH / THF (1:1, 2 mL) was added LiOH•H2O (100 mg, 2.38 mmol) in water (1 mL). After 1 h, the mixture was cooled to 0 °C, neutralized with HCl (1 M) and extracted with EA (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by reverse flash chromatography (C18 silica gel, ACN-water, 5-100% with 10 mM NH4HCO3) to afford 3-[3-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl]-5-(4- chlorophenoxy)-2-iodobenzoic acid (50 mg, 34%) as a white solid. LCMS (ES, m / z): 616.10 [M- H]-. STEP 2: tert-butyl 2-[(tert-butoxycarbonyl)amino]-3-[3-carbamoyl-5-(4-chlorophenoxy)-2- iodophenyl]propanoate To a mixture of 3-[3-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl]-5-(4- chlorophenoxy)-2-iodobenzoic acid (40 mg, 0.06 mmol) in DMF (1.5 mL) was added HATU (37 -173-703.101.412 mg, 0.10 mmol), DIEA (42 mg, 0.32 mmol) and NH3Cl (7 mg, 0.13 mmol). After 16 h, the mixture was purified by reverse flash chromatography (C18 silica gel, ACN-water, 5-80% with 10 mM NH4HCO3) to afford the title compound (31.7 mg, 79%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.87-7.79 (m, 1H), 7.54 (s, 1H), 7.48-7.41 (m, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.15-7.08 (m, 1H), 7.07-7.02 (m, 2H), 6.81 (d, J = 2.9 Hz, 1H), 4.15-4.00 (m, 1H), 3.22-3.11 (m, 1H), 3.00-2.83 (m, 1H), 1.47-1.21 (m, 18H). LCMS (ES, m / z): 505.00 [M-2tBu+2H]+; 99.1% purity (254 nm). Example 11: Synthesis of tert-Butyl 2-((tert-butoxycarbonyl)amino)-3-(5-(4-chlorophenoxy)-2- iodo-3-(methylcarbamoyl)phenyl)propanoate Scheme 13: Representation of tert-butyl 2-((tert-butoxycarbonyl)amino)-3-(5-(4-chlorophenoxy)- 2-iodo-3-(methylcarbamoyl)phenyl)propanoate Scheme 14: Representative synthetic method for tert-butyl 2-((tert-butoxycarbonyl)amino)-3-(5- (4-chlorophenoxy)-2-iodo-3-(methylcarbamoyl)phenyl)propanoate tert-butyl 2-[((methylcarbamoyl)phenyl]propanoate To a mixture of 3-[3-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl]-5-(4- chlorophenoxy)-2-iodobenzoic acid (40 mg, 0.06 mmol) and MeNH3Cl (9 mg, 0.13 mmol) in ACN (1 mL) at 0 °C was added TCFH (54 mg, 0.19 mmol) and 1-methyl-1H-imidazole (53 mg, 0.65 mmol). After 1 h, the mixture was directly purified by reverse flash chromatography (C18 silica gel, ACN-water, 5-80% with 10 mM NH4HCO3) to afford the title compound (30.1 mg, 73%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.33-8.24 (m, 1H), 7.48-7.41 (m, 2H), *7.28 (d, J = 8.4 Hz, 0.87H), 7.16-7.09 (m, 1H), 7.08-7.01 (m, 2H), *6.92-6.86 (m, 0.15 H), 6.79 (d, J = 2.9 Hz, 1H), 4.15-4.00 (m, 1H), 3.22-3.10 (m, 1H), 3.00-2.83 (m, 1H), *2.72 (s, 1.5H), *2.71 (s, 1.5H), 1.46-1.37 (m, 9H), 1.37-1.21 (m, 9H). *Partial integration due to presence of rotamers. LCMS (ES, m / z): 629.05 [M-H]-; 99.9% purity (254 nm). Example 12: Synthesis of 5-(4-chlorophenoxy)-3-(hydroxymethyl)-2-iodo-N-methylbenzamide -174-703.101.412 Scheme 15: Representation of 5-(4-chlorophenoxy)-3-(hydroxymethyl)-2-iodo-N- methylbenzamide Scheme 16: Representative syntheti phenoxy)-3-(hydroxymethyl)-2-iodo-N-methylbenzamideSTEP 1: 5-(4-chlorophenoxy)-3-(hydroxymethyl)-2-iodobenzoic acid To a mixture of methyl 5-(4-chlorophenoxy)-3-(hydroxymethyl)-2-iodobenzoate (200 mg, 0.48 mmol) in THF (2 mL) was added a solution of LiOH (115 mg, 4.80 mmol) in H2O (2 mL). After 16 h, the mixture was acidified to pH~7, concentrated under reduced pressure and purified by reverse flash chromatography (C18 silica gel, ACN-water, 0-60% with 0.1% FA) to afford 5-(4- chlorophenoxy)-3-(hydroxymethyl)-2-iodobenzoic acid (100 mg, 51%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 13.47 (br s, 1H), 7.52-7.44 (m, 2H), 7.19 (d, J = 3.0 Hz, 1H), 7.15-7.05 (m, 3H), 5.61 (br s, 1H), 4.42 (s, 2H). LCMS (ES, m / z): 402.80 [M-H]-. STEP 2: 5-(4-chlorophenoxy)-3-(hydroxymethyl)-2-iodo-N-methylbenzamide To a mixture of 5-(4-chlorophenoxy)-3-(hydroxymethyl)-2-iodobenzoic acid (100 mg, 0.25 mmol) in DMF (1 mL) was added DIEA (161 mg, 1.25 mmol) and HATU (143 mg, 0.38 mmol) and methylamine hydrochloride (34 mg, 0.50 mmol). After 16 h, the mixture was directly purified by reverse flash chromatography (C18 silica gel, ACN-water, 0-50% with 10 mM NH4HCO3) to afford the title compound (80 mg, 77%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.33-8.25 (m, 1H), 7.51-7.44 (m, 2H), 7.11 (d, J = 3.0 Hz, 1H), 7.10-7.05 (m, 2H), 6.83 (d, J = 2.9 Hz, 1H), 5.59 (t, J = 5.5 Hz, 1H), 4.39 (d, J = 5.5 Hz, 2H), 2.72 (d, J = 4.6 Hz, 3H). LCMS (ES, m / z): 417.90 [M+H]+. -175-703.101.412 Example 13: Synthesis of 4-carbamoyl-6-(4-chlorophenoxy)-3-iodopicolinic acid Scheme 17: Representation of 4-carbamoyl-6-(4-chlorophenoxy)-3-iodopicolinic acid Scheme 18: Representative syntheti yl-6-(4-chlorophenoxy)-3-iodopicolinicacidTo a stirred mixture of ethyl 3-amino-3-iminopropanoate hydrochloride (75.0 g, 452 mmol) in water (250 mL) at ~15 ℃ was added NaOH (50% aq, 38.0 g, 474 mmol). After 3 h at 25 ℃, the mixture was cooled to 0 ℃, whereupon EtOH (500 mL) and ethyl 2,4-dioxopentanoate (71.4 g, 452 mmol) were added. After 30 min, NaOH (50% aq, 18.1 g, 226 mmol) was added. After 1 h at 0 ℃, the mixture was heated at 45 ℃ for 2 h, whereupon it was cooled to rt and partially concentrated under reduced pressure, diluted with ice-water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA- Petroleum ether, 50%) to afford ethyl 2-amino-6-methylpyridine-4-carboxylate (23 g, 28%) as a brown solid. LCMS (ES, m / z): 181.05 [M+H]+. STEP 2: ethyl 6-amino-3-iodo-2-methylpyridine-4-carboxylate To a solution of ethyl 2-amino-6-methylpyridine-4-carboxylate (6.50 g, 36.1 mmol) in DMF (65 mL) was added NIS (8.93 g, 39. 7 mmol). After 16 h, the mixture was diluted with ice-water -176-703.101.412 (200 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude residue was purified by reverse phase flash chromatography (C18 silica gel, ACN-water, 0-70% with 10 mM NH4HCO3) to afford ethyl 6-amino-3-iodo-2-methylpyridine-4-carboxylate (8.6 g, 78%) as a light yellow solid. LCMS (ES, m / z): 307.10 [M+H]+. STEP 3: ethyl 6-fluoro-3-iodo-2-methylpyridine-4-carboxylate To a mixture of ethyl 6-amino-3-iodo-2-methylpyridine-4-carboxylate (7.00 g, 22.0 mmol) in tetrafluoroboric acid (40% aq, 70 mL) at -10 ℃ was added a solution of NaNO2 (1.66 g, 24.0 mmol) in H2O (3 mL), dropwise. The mixture was circulated through a flow reactor with irradiation by low-pressure mercury lamp at rt for 16 h, whereupon the it was diluted with ice- water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude residue was purified by reverse flash chromatography (C18 silica gel, ACN-water, 0- 40% with 10 mM NH4HCO3) to afford ethyl 6-fluoro-3-iodo-2-methylpyridine-4-carboxylate (2.5 g, 35%) as a white solid. LCMS (ES, m / z): 310.10 [M+H]+. STEP 4: ethyl 6-(4-chlorophenoxy)-3-iodo-2-methylisonicotinate A mixture of ethyl 6-fluoro-3-iodo-2-methylisonicotinate (2.00 g, 6.45 mmol), 4-chlorophenol (1.25 g, 9.68 mmol) and Cs2CO3 (5.27 g, 16.2 mmol) in DMF (20 mL) was heated at 80 ℃ for 16 h. Upon cooling to rt, it was diluted with ice-water (150 mL) and extracted with EA (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 material was purified by reverse flash chromatography (C18 silica gel, ACN-water, 0-80% with 10 mM NH4HCO3) to afford ethyl 6-(4-chlorophenoxy)-3-iodo-2-methylisonicotinate (1.2 g, 44%) as a brown oil. LCMS (ES, m / z): 417.90 [M+H]+. STEP 5: 6-(4-chlorophenoxy)-3-iodo-2-methylisonicotinamide To a flask charged with ethyl 6-(4-chlorophenoxy)-3-iodo-2-methylisonicotinate (900 mg, 2.16 mmol) was added NH3 / MeOH (7M, 50 mL). After 16 h, the solvent was removed under reduced pressure and the crude residue was purified by reverse flash chromatography (C18 silica gel, ACN-water, 0-70% with 10 mM NH4HCO3) to afford 6-(4-chlorophenoxy)-3-iodo-2- methylisonicotinamide (600 mg, 71%) as a white solid. LCMS (ES, m / z): 389.05 [M+H]+. STEP 6: 4-carbamoyl-6-(4-chlorophenoxy)-3-iodopicolinic acid -177-703.101.412 To a mixture of 6-(4-chlorophenoxy)-3-iodo-2-methylisonicotinamide (600 mg, 1.54 mmol) in t- BuOH / H2O (1:1, 30 mL) was added KMnO4(1.22 g, 7.72 mmol), whereupon it was heated at 80 ℃. After 16 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 dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by reverse flash chromatography (C18 silica gel, ACN-water, 0-40% with 0.1% FA) followed by Prep-HPLC (Column: Xselect CSH Prep C18 OBD 5 μm, 30 x 150 mm; Mobile Phase: ACN-water 22-52% with 0.1% FA; Flow rate: 60 mL / min; Wavelength: 254 / 220 nm), affording the title compound (43.7 mg, 7%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 13.86 (br s, 1H), 8.09 (s, 1H), 7.86 (s, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 7.08 (s, 1H). LCMS (ES, m / z): 418.90 [M+H]+. Example 14: Synthesis of tert-Butyl 2-((tert-butoxycarbonyl)amino)-3-(3-(dimethylcarbamoyl)- 5-fluoro-2-iodophenyl)propanoate Scheme 19: Representation of tert-butyl 2-((tert-butoxycarbonyl)amino)-3-(3- (dimethylcarbamoyl)-5-fluoro-2-iodophenyl)propanoate Scheme 20: Representative sy((tert-butoxycarbonyl)amino)-3-(3- (dimethylcarbamoyl)-5-fluoro-2-iodophenyl)propanoate703.101.412 STEP 1: 2-amino-3-bromo-5-fluoro-N,N-dimethylbenzamide To 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 Na2SO4and 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-N,N- dimethylbenzamide (40 g, 89%) as a yellow solid. LCMS (ES, m / z): 261.05 [M+H]+. STEP 2: 2-amino-5-fluoro-N,N-dimethyl-3-vinylbenzamide A mixture of 2-amino-3-bromo-5-fluoro-N,N-dimethylbenzamide (40.0 g, 153 mmol), 2-ethenyl- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (35.4 g, 229 mmol), K2CO3 (63.5 g, 459 mmol) and Pd(dppf)Cl2•CH2Cl2(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 Na2SO4 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-N,N- dimethylbenzamide (26 g, 81%) as a yellow solid. LCMS (ES, m / z): 209.00 [M+H]+. STEP 3: 5-fluoro-2-iodo-N,N-dimethyl-3-vinylbenzamide To a solution of 2-amino-3-ethenyl-5-fluoro-N,N-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 NH4Cl (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 Na2SO4and 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-N,N- 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-dimethylbenzamide To a mixture of 3-ethenyl-5-fluoro-2-iodo-N,N-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 -179-703.101.412 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 Na2SO4and 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-N,N-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-dimethylbenzamide To a solution of 5-fluoro-3-formyl-2-iodo-N,N-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-N,N-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-dimethylbenzamide To a stirred solution of 5-fluoro-3-(hydroxymethyl)-2-iodo-N,N-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- (bromomethyl)-5-fluoro-2-iodo-N,N-dimethylbenzamide (850 mg, 79%) as a yellow solid. LCMS (ES, m / z): 385.85, 387.85 [M+H]+. STEP 7: tert-butyl 3-(3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl)-2- ((diphenylmethylene)amino)propanoate A mixture of 3-(bromomethyl)-5-fluoro-2-iodo-N,N-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: tert-butyl 2-amino-3-[3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl]propanoate A mixture of tert-butyl 3-[3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl]-2- [(diphenylmethylidene)amino]propanoate (400 mg, 0.67 mmol) hydroxylamine hydrochloride -180-703.101.412 (277 mg, 3.99 mmol) in EtOH / H2O (4:1, 5 mL) was heated at 50 ℃ for 4 h. Upon cooling to rt, the mixture purified by reverse flash chromatography (C18 silica gel, ACN-water, 5-70% with 10 mM NH4HCO3), affording tert-butyl 2-amino-3-[3-(dimethylcarbamoyl)-5-fluoro-2- iodophenyl]propanoate (300 mg, 80% purity, 82% yield) as a yellow solid. LCMS (ES, m / z): 381.00 [M-tBu+H]+. STEP 9: tert-butyl 2-[(tert-butoxycarbonyl)amino]-3-[3-(dimethylcarbamoyl)-5-fluoro-2- iodophenyl]propanoate To a solution of tert-butyl 2-amino-3-[3-(dimethylcarbamoyl)-5-fluoro-2-iodophenyl]propanoate (300 mg, 80%, 0.55 mmol) in DCM (5 mL) was added TEA (167 mg, 1.65 mmol) and di-tert- butyl dicarbonate (144 mg, 0.66 mmol). After 1 h, the mixture was concentrated under reduced pressure and the crude residue was purified by reverse phase chromatography (C18 silica gel, ACN-water, 5-100% with 10 mM NH4HCO3) to afford the title compound (250 mg, 84%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.39-7.12 (m, 2H), 7.12-6.87 (m, 1H), *4.31-4.20 (m, 0.5H), *4.19-4.06 (m, 0.5H), 3.18 (td, J = 13.9, 5.8 Hz, 1H), 3.05-2.97 (m, 3H), 2.97-2.86 (m, 1H), 2.77-2.64 (m, 3H), 1.47-1.20 (m, 18H). *Partial integration due to presence of rotamers.19F NMR (376 MHz, DMSO-d6) δ -114.60 (minor rotamer), -114.65 (major rotamer), -115.01. LCMS (ES, m / z): 537.20 [M+H]+; 99.8% purity (220 nm). Example 15: Synthesis of 5-fluoro-3-(2-hydroxypropan-2-yl)-2-iodobenzoic acid Scheme 21: Representation of 5-fluoro-3-(2-hydroxypropan-2-yl)-2-iodobenzoic acid Scheme 22: Representative synthetic3-(2-hydroxypropan-2-yl)-2-iodobenzoic acid -181-703.101.412A mixture of 5-fluoro-1,3-dimethyl-2-nitrobenzene (4.80 g, 28.3 mmol) and Pd on carbon (10%, 4.8 g) in t-BuOH (80 mL) was degassed and backfilled with H2(3x). After 16 h, the system was vented and flushed with N2. The suspension was filtered over celite and the filter cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated under reduced pressure to afford 4-fluoro-2,6-dimethylaniline (3.2 g, 82%) as a yellow solid. LCMS (ES, m / z): 140.05 [M+H]+. STEP 2: 5-fluoro-2-iodo-1,3-dimethylbenzene To a mixture of 4-fluoro-2,6-dimethylaniline (3.20 g, 22.9 mmol) in HCl (6 M, 70 mL) at 0 °C was added a solution of NaNO2(1.75 g, 25.2 mmol) in water (2 mL), dropwise. After 30 min at 0 °C, the mixture was cooled to -15 °C and a solution of potassium iodide (19.1 g, 114 mmol) in water (8 mL) was added, dropwise. The mixture was allowed to warm to rt, stirred for 1 h, then slowly poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA- Petroleum ether, 9%) to afford 5-fluoro-2-iodo-1,3-dimethylbenzene (3.2 g, 55%). GCMS (EI, m / z): 250 [M]. STEP 3: 5-fluoro-2-iodobenzene-1,3-dicarboxylic acid A mixture of 5-fluoro-2-iodo-1,3-dimethylbenzene (2.20 g, 8.80 mmol) and KMnO4 (6.95 g, 44.0 mmol) in t-BuOH / H2O (1:1, 26 mL) was heated at 70 °C. After 16 h, the mixture was cooled to rt and filtered. The filter cake was washed with water (2 x 50 mL) and the filtrate was acidified to pH 2 with HCl (2 M) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 5-fluoro-2-iodobenzene-1,3-dicarboxylic acid (2.2 g, crude) as a yellow solid. LCMS (ES, m / z): 309.10 [M-H]-. -182-703.101.412 STEP 4: 1,3-dimethyl 5-fluoro-2-iodobenzene-1,3-dicarboxylate To a mixture of 5-fluoro-2-iodobenzene-1,3-dicarboxylic acid (2.20 g, crude) in DMF (20 mL) was added CH3I (5.00 g, 35.2 mmol) and K2CO3(6.07 g, 44.0 mmol). After 1 h, the mixture was diluted with 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 material was purified by silica gel chromatography (EA-Petroleum ether, 16%) to afford 1,3-dimethyl 5-fluoro-2-iodobenzene-1,3-dicarboxylate (1.4 g, 47%, 2- steps) as an oil. GCMS (EI, m / z): 338 [M]. STEP 5: methyl 5-fluoro-3-(2-hydroxypropan-2-yl)-2-iodobenzoate To a dried flask equipped with a reflux condenser and stirring magnesium turnings (688 mg, 28.6 mmol) was slowly added a solution of iodine (cat, a few crystals) and CH3I (2.94 g, 20.7 mmol) in diethyl ether (5 mL) dropwise over 15 minutes, maintaining a gentle reflux throughout. After 1 h, the resulting MeMgI solution was transferred by syringe to a dry 3-neck flask, equipped with addition funnel and condenser. To the freshly prepared solution at 0 °C was added a solution of 1,3-dimethyl 5-fluoro-2-iodobenzene-1,3-dicarboxylate (1.40 g, 4.14 mmol) in diethyl ether (3 mL), dropwise. After warming to rt, the resulting mixture was stirred for 1 h then cooled to 0 °C, whereupon a solution of iodine (3.10 g, 12.2 mmol) in diethyl ether (3 mL) was added. After 16 h at rt, the mixture was cooled to 0 °C and quenched with NH4Cl (satd, aq, 8 mL), followed by water (8 mL), diethyl ether (8 mL) and Na2S2O3(3 M, aq, 8 mL). The resulting mixture was stirred at rt for 1 h then filtered and the filter cake was washed with diethyl ether (3 x 20 mL). The filtrate was extracted with diethyl ether (3 x 100 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 33%) to afford methyl 5-fluoro-3-(2-hydroxypropan-2-yl)-2-iodobenzoate (210 mg, 15%). LCMS (ES, m / z): 321.05 [M-OH]+. STEP 6: 5-fluoro-3-(2-hydroxypropan-2-yl)-2-iodobenzoic acid To a mixture of methyl 5-fluoro-3-(2-hydroxypropan-2-yl)-2-iodobenzoate (200 mg, 0.59 mmol) in THF (1.5 mL) was added a solution of LiOH•H2O (248 mg, 5.91 mmol) in water (1.5 mL). The mixture was heated at 50 °C for 2 h then cooled to 0 °C, acidified to pH 6 with HCl (2 M) and extracted with EA (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 -183-703.101.412 was purified by reverse flash chromatography (C18 silica gel, ACN-water, 5-80% with 0.1% FA), affording 5-fluoro-3-(2-hydroxypropan-2-yl)-2-iodobenzoic acid (130 mg, 68%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 13.61 (br s, 1H), 7.63 (d, J = 11.1 Hz, 1H), 7.16 (d, J = 5.4 Hz, 1H), 5.42 (br s, 1H), 1.67 (s, 6H). LCMS (ES, m / z): 322.85 [M-H]-. Example 16: Synthesis of 1,1,1,3,3,3-hexafluoro-2-(5-fluoro-3-(hydroxymethyl)-2- iodophenyl)propan-2-ol Scheme 23: Representation of 1,1,1,3,3,3-hexafluoro-2-(5-fluoro-3-(hydroxymethyl)-2- iodophenyl)propan-2-ol Scheme 24: Representative s 1,1,1,3,3,3-hexafluoro-2-(5-fluoro-3-(hydroxymethyl)-2-iodophenyl)propan-2-ol STEP 1: 2-2-ol To a mixture of 4-fluoro-2-methylaniline (5.00 g, 40.0 mmol) was added hexafluoroacetone trihydrate (21.1 g, 96.0 mmol) and PTSA (69 mg, 0.40 mmol), whereupon the mixture was heated at 100 °C. After for 16 h, the mixture was cooled to rt, poured into ice-water (150 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EA-Petroleum ether, 20%) to afford 2-(2- amino-5-fluoro-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.95 g, 17%) as a yellow oil. LCMS (ES, m / z): 292.00 [M+H]+. STEP 2: 1,1,1,3,3,3-hexafluoro-2-(5-fluoro-2-iodo-3-methylphenyl)propan-2-ol -184-703.101.412 To a stirred mixture of 2-(2-amino-5-fluoro-3-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.50 g, 5.15 mmol) in ACN (20 mL) at 0 °C was added KI (1.03 g, 6.19 mmol) and CuI (1.18 g, 6.19 mmol) and I2 (1.57 g, 6.19 mmol) and isoamyl nitrite (1.21 g, 10.3 mmol). After 30 min, the cold bath was removed. After 16 h at rt, the mixture was poured into ice-water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA-Petroleum ether, 10%), affording 1,1,1,3,3,3- hexafluoro-2-(5-fluoro-2-iodo-3-methylphenyl)propan-2-ol (400 mg, 19%) as a yellow oil. GCMS (EI, m / z): 401.90 [M]. STEP 3: 5-fluoro-3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-iodobenzoic acid To a mixture of 1,1,1,3,3,3-hexafluoro-2-(5-fluoro-2-iodo-3-methylphenyl)propan-2-ol (400 mg, 1.00 mmol) in t-BuOH (4 mL) was added a solution of KMnO4(790 mg, 5.00 mmol) in H2O (4 mL), whereupon it was heated at 80 °C. After 16 h the mixture was cooled to rt, diluted with water (80 mL) and extracted with EA (3 x 80 mL). The combined organic layers were concentrated under reduced pressure and the crude residue was purified by reverse flash chromatography (C18 silica gel, ACN-water, 0-60% with 0.1% FA) to afford 5-fluoro-3- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-iodobenzoic acid (40 mg, 9%). LCMS (ES, m / z): 430.85 [M-H]-. STEP 4: 1,1,1,3,3,3-hexafluoro-2-(5-fluoro-3-(hydroxymethyl)-2-iodophenyl)propan-2-ol To a mixture of 5-fluoro-3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-iodobenzoic acid (30 mg, 0.07 mmol) in THF (1 mL) at 0 °C was added borane-tetrahydrofuran complex (1 M in THF) (0.40 mL, 0.35 mmol) dropwise. After 16 h at rt, MeOH (5 mL) was added and the resulting mixture was heated at 70 °C for 1 h, cooled to rt and concentrated under reduced pressure. The crude material was purified by Prep-HPLC (Column: Xselect CSH Prep C18 OBD 5 μm, 30 x 150 mm; Mobile Phase ACN-water: 31-61% with 0.1% FA; Flow Rate: 60 mL / min; Wavelength: 254 / 220 nm), affording the title compound (11.6 mg, 40%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 9.02 (br s, 1H), 7.51 (dd, J = 9.3, 2.6 Hz, 1H), 7.19 (d, J = 10.0 Hz, 1H), 5.78 (t, J = 5.2 Hz, 1H), 4.51 (s, 2H).19F NMR (376 MHz, DMSO-d6) δ -71.27, - 114.38. LCMS (ES, m / z): 416.80 [M-H]-; 98.5% purity (254 nm). -185-703.101.412 Examples 17 and 18: Syntheses of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-iodo-1H- imidazol-5-yl)propanoate and methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2,4-diiodo-1H- imidazol-5-yl)propanoate Scheme 25: Representation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-iodo-1H- imidazol-5-yl)propanoate Scheme 26: Representation of m oxycarbonyl)amino)-3-(2,4-diiodo-1H-imidazol-5-yl)propanoate Scheme 27: Representative synthd methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2,4-diiodo-1H-imidazol-5-yl)propanoate To a solution of methyl (tert-butoxycarbonyl)-L-histidinate (500 mg, 1.86 mmol) in DMF (5 mL) was added NIS (314 mg, 1.39 mmol). After 16 h, the mixture was purified by reverse flash chromatography (C18 silica gel, ACN-water, 0-30% with 0.1% FA) to afford methyl (S)-2-((tert- butoxycarbonyl)amino)-3-(4-iodo-1H-imidazol-5-yl)propanoate (20.8 mg, 2%) and methyl (S)-2- ((tert-butoxycarbonyl)amino)-3-(2,4-diiodo-1H-imidazol-5-yl)propanoate (200 mg, 20%) as white solids. methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-iodo-1H-imidazol-5-yl)propanoate:1H NMR (400 MHz, DMSO-d6) δ *12.47 (s, 0.2H), *12.14 (s, 0.8H), *7.76 (s, 0.2H), 7.61 (s, 0.8H), *7.29 (d, J = 7.2 Hz, 0.7H), *7.12-7.00 (m, 0.15H), *6.97-6.85 (m, 0.15H), 4.30-4.01 (m, 1H), -186-703.101.412 3.65-3.52 (m, 3H), 2.97-2.87 (m, 1H), 2.87-2.76 (m, 1H), 1.43-1.25 (m, 9H). *Partial integration due to presence of rotamers. LCMS (ES, m / z): 396.00 [M+H]+; 98.3% purity (220 nm). methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2,4-diiodo-1H-imidazol-5-yl)propanoate:1H NMR (400 MHz, DMSO-d6) δ *12.90 (s, 0.2H), *12.73 (s, 0.8H), *7.27 (d, J = 7.6 Hz, 0.6H), *7.05 (d, J = 7.7 Hz, 0.2H), *7.05 (br d, J = 5.8 Hz, 0.2H), *4.25-4.11 (m, 0.8H), *4.05-4.00 (m, 0.2H), 3.67-3.53 (m, 3H), 2.92 (dd, J = 14.9, 7.2 Hz, 1H), 2.88-2.71 (m, 1H), 1.47-26 (m, 9H). *Partial integration due to presence of rotamers. LCMS (ES, m / z): 521.95 [M+H]+; 99.8% purity (254 nm). Example 19: Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2,4-diiodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)propanoate Scheme 28: Representation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2,4-diiodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)propanoate Scheme 29: Representative synthe-((tert-butoxycarbonyl)amino)-3-(2,4- diiodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)propanoate To a mixture°C under a N2 atmosphere was added a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2,4-diiodo- 1H-imidazol-5-yl)propanoate (500 mg, 0.96 mmol) in THF (4 mL) dropwise. To the mixture after 30 min at 0 °C was added SEM-Cl (192 mg, 1.15 mmol) dropwise, whereupon the cold bath was removed. After 2 h, the mixture was poured into ice-water (60 mL) and extracted with DCM (3 x 40 mL). The combined organic layers were washed with brine (40 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 the title compound (260 mg, 41%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ *7.08 (d, J = 8.0 Hz, 0.8H), *6.78 (br d, J = 6.3 Hz, 0.2H), 5.21 (s, 2H), *4.28-4.18 (m, 0.8H), *4.17-4.08 (m, 0.2H), 3.62-3.50 (m, -187-703.101.412 5H), 2.90-2.75 (m, 2H), 1.42-1.28 (m, 9H), 0.91-0.82 (m, 2H), -0.02 (s, 9H). *Partial integration due to presence of rotamers. LCMS (ES, m / z): 652.00 [M+H]+; 98.2% purity (254 nm). Example 20: Synthesis of di-tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(5-(4- chlorophenoxy)-3-(dimethylcarbamoyl)-2-iodobenzyl)pentanedioate Scheme 30: Representat...

Claims

703. 101.412 CLAIMS 1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein: Ring A is C6-C10 aryl or 5-20 membered heteroaryl, wherein Ring A is optionally and independently substituted with 1-5 R’; R1is hydrogen or C1-C6alkyl; R2and R3are each independently hydrogen or a group selected from C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein each group is optionally and independently substituted with 1-20 Rs; or R2and R3are taken together with the nitrogen atom they are attached to form 3-20 membered heterocycloalkyl optionally substituted with 1-20 Rs, or R2and R3are taking together with the nitrogen atom they are attached to for ; R4is -C(=O)R’, -C(=O)OR’, -C(=O)N(R’)2, -B(R’)2, –B(R’)3X, or 5-6 membered heteroaryl; 2, -L-NHC(=NPG)NH2, -L-NHC(=NPG)NHPG, or -L-NHC(=NPG)-N=C(R )2; p is 0, 1, 2 or 3; R6is absent, hydrogen, -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 -L-OH; each R7is independently F or radioisotope [18]F; m is 1 or 2; each R8is independently hydrogen, PG, C1-C6alkyl, or C3-C10cycloalkyl; n is 0, 1, or 2; R9is 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 [211]At; X is a counterion; -210-703.101.412 each PG is independently a protecting group; L is absent or C1-C6alkylene 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’)-; each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, or -S(O)2R; each R is independently hydrogen, halogen, or an optionally substituted group selected from C1- C10 aliphatic, C1-C10 heteroalkyl, C6-C10 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 =O; or two 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; or two 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, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OC1-C6 alkyl, -OC3-C10 cycloalkyl, -OC6-C10 aryl, -O-5-10 membered heteroaryl, -O-3-20 membered heterocycloalkyl, -OC(=O)C1-C6alkyl, -OC(=O)C3-C10cycloalkyl, -OC(=O)C6-C10aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)C1-C6alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, - NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=O)C1-C6alkyl, -N(C1-C6alkyl)C(=O)C1-C6alkyl, -NHS(=O)2C1-C6alkyl, -NHS(=O)2C3-C10cycloalkyl, -NHS(=O)2C6-C10aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(C1- C6alkyl)S(=O)2C1-C6 alkyl, -N(C1-C6alkyl)S(=O)2C3-C10 cycloalkyl, -N(C1- C6alkyl)S(=O)2C6-C10aryl, -N(C1-C6alkyl)S(=O)25-10 membered heteroaryl, -N(C1- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1- C6 alkyl, -C(=O)NH2, -C(=O)NHC1-C6 alkyl, -C(=O)N(C1-C6alkyl)2; wherein each C1-C6 -211-703.101.412 alkyl, C1-C6 heteroalkyl, C6-C10 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, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.

2. The compound of claim 1, wherein Ring A is C6-C10 aryl.

3. The compound of claim 1, wherein Ring A is phenyl.

4. The compound of claim 1, wherein p is 0 or 1.

5. The compound of claim 1, wherein at least one of R7and R9comprises the radioisotope.

6. The compound of claim 1, wherein p is 2 or 3.

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

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

9. The compound of claim 4, wherein the compound has a structure of Formula (II-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:703.101.412 10. The compound of claim 4, wherein the compound has a structure of Formula (II-c), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: .

11. The compound of claim 4, wherein the compound has a structure of Formula (II-d), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

12. The compound of claim 4, wherein the compound has a structure of Formula (II-e), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

13. The compound of claim 4, wherein the compound has a structure of Formula (II-f), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:.

14. The compound of claim 4, wherein the compound has a structure of Formula (II-g), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: -213-703.101.41215. The compound of claim 1, wherein Ring A is 5-20 membered heteroaryl.

16. The compound of claim 1, wherein Ring A is 5-20 membered heteroaryl having 1-10 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

17. The compound of claim 1, wherein Ring A is 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

18. The compound of claim 1, wherein Ring A is 5 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

19. The compound of claim 1, wherein Ring A , or, wherein RAis R’.

20. The compound of claim 19, wherein Ring A i , , or.The compound of claim 19, wherein the compound has a structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:.

22. The compound of claim 19, wherein the compound has a structure of Formula (III-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: -214-703.101.412 .

23. The compound of claim 19, wherein the compound has a structure of Formula (III-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

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

25. The compound of claim 19, wherein the compound has a structure of Formula (IV-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:.

26. The compound of claim 19, wherein the compound has a structure of Formula (IV-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:). -215-703.101.412 27. The compound of claim 19, wherein the compound has a structure of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

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

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

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

31. The compound of claim 19, wherein the compound has a structure of Formula (VI-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: -216-703.101.412 ).

32. The compound of claim 19, wherein the compound has a structure of Formula (VI-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: ).

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

34. The compound of claim 19, wherein the compound has a structure of Formula (VII-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:.

35. The compound of claim 19, wherein the compound has a structure of Formula (VII-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:. -217-703.101.412 36. The compound of any one of claims 20-35, wherein RAis hydrogen.

37. The compound of claim 1, wherein Ring A is 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen.

38. The compound of claim 1, wherein Ring A is 6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen.

39. The compound of claim 1, wherein Ring A i .

40. The compound of claim 39, wherein the co I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

41. The compound of claim 39, wherein the compound has a structure of Formula (IX), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: (OR8)5n R1R9R R4R342. The compound of claim 39, wherein the compound has a structure of Formula (X), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:.

43. The compound of claim 39, wherein the compound has a structure of Formula (X-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: -218-703.101.412 .

44. The compound of claim 39, wherein the compound has a structure of Formula (X-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

45. The compound of claim 39, wherein the compound has a structure of Formula (XI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

46. The compound of claim 39, wherein the compound has a structure of Formula (XI-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 5 (OR8)nR R1R6R4R347. The compound of claim 39, wherein the compound has a structure of Formula (XI-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:. -219-703.101.412 48. The compound of claim 39, wherein the compound has a structure of Formula (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

49. The compound of claim 39, wherein the compound has a structure of Formula (XII-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

50. The compound of claim 39, wherein the compound has a structure of Formula (XII-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:.

51. The compound of claim 39, wherein the compound has a structure of Formula (XIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:.

52. The compound of claim 39, wherein the compound has a structure of Formula (XIII-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: -220-703.101.41253. The compound of claim 39, wherein the compound has a structure of Formula (XIII-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: ).

54. The compound of claim 39, wherein the compound has a structure of Formula (XIV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

55. The compound of claim 39, wherein the compound has a structure of Formula (XIV-a), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:).

56. The compound of claim 39, wherein the compound has a structure of Formula (XIV-b), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: .703.101.412 57. The compound of claim 39, wherein the compound has a structure of Formula (XIV-c), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: .

58. The compound of claim 39, wherein Ring A is 9 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

59. The compound of claim 1, wherein Ring A i , wherein RBisR’.

60. The compound of claim 1, wherein Ring A .

61. The compound of claim 1, wherein the com, , ,703.101.412 , , r a62. The compound of claim 1, wherein the compound has a structure of: , , ,703.101.412 , , alt,63. The compound of claim 1, wherein the compound has a structure of: , , ,of.703.101.412 64. The compound of claim 1, wherein the compound has a structure of: , , , or a65. The compound of claim 1, wherein the compound has a structure of: , ,703.101.412 , a66. The compound of claim 5, wherein the compound has a structure of: O I* O , , Bu ,703.101.412 , ora pharmaceutically acceptable salt, solvate, or stereoisomer67. A compound of Formula (Hyper-R*), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:*), wherein: Ring A is C6-C10 aryl or 6-20 membered heteroaryl, wherein Ring A is optionally and independently substituted with 1-5 R’; is a single bond or double bond; R1is hydrogen or C1-C6 alkyl; R2and R3are each independently hydrogen or a group selected from C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, and C2-C6alkynyl, wherein each group is optionally and -227-703.101.412 independently substituted with 1-20 Rs; or R2and R3are taken together with the nitrogen atom they are attached to form 3-20 membered heterocycloalkyl optionally substituted with 1-20 Rs, or R2and R3are taking together with the nitrogen atom they are attached to form ; R4is -C(=O)R’, -C(=O)OR’, -C(=O)N(R’)2, -B(R’)2, –B(R’)3X, or 5-6 memberedryl; R5is hydrogen, -L-C(=O)OH, -L-C(=O)OPG, -L-NHC(=NH)NH2, -L-NHC(=NPG)NH2, -L- NHC(=NPG)NHPG, or -L-NHC(=NPG)-N=C(R’)2; p is 0, 1, 2 or 3; each R7is independently F or radioisotope [18]F; m is 1 or 2; each R8is independently hydrogen, PG, C1-C6alkyl, or C3-C10cycloalkyl; 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 [123]I, [124]I, [125]I, [131]I, [210]At, and [211]At; each X is independently a counterion; each PG is independently a protecting group; L is absent or C1-C6 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’)-; each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, or -S(O)2R; each R is independently hydrogen, halogen, or an optionally substituted group selected from C1- C10aliphatic, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 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 =O; or two 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; or -228-703.101.412 two 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, C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OC1-C6alkyl, -OC3-C10 cycloalkyl, -OC6-C10 aryl, -O-5-10 membered heteroaryl, -O-3-20 membered heterocycloalkyl, -OC(=O)C1-C6 alkyl, -OC(=O)C3-C10 cycloalkyl, -OC(=O)C6-C10 aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)C1-C6alkyl, -S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, - NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)C1-C6 alkyl, -N(C1-C6 alkyl)C(=O)C1-C6 alkyl, -NHS(=O)2C1-C6alkyl, -NHS(=O)2C3-C10cycloalkyl, -NHS(=O)2C6-C10aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(C1- C6alkyl)S(=O)2C1-C6 alkyl, -N(C1-C6alkyl)S(=O)2C3-C10 cycloalkyl, -N(C1- C6alkyl)S(=O)2C6-C10 aryl, -N(C1-C6alkyl)S(=O)25-10 membered heteroaryl, -N(C1- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)OC1- C6 alkyl, -C(=O)NH2, -C(=O)NHC1-C6 alkyl, -C(=O)N(C1-C6alkyl)2; wherein each C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 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, C1-C6 alkyl, C1-C6 heteroalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.

68. The compound of claim 67, wherein p is 0 or 1.

69. The compound of claim 67, wherein p is 2 or 3. * is hydrogen, C1-C10 alkyl,teroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 Rs.

74. The compound of claim 67, wherein L*is -C(=NH)O-. -229-703.101.412 75. The compound of claim 67, wherein L*is -C(=NR’)O- and R’ is C1-C10 alkyl, C1-C10 heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 halogen, -OH, -CN, -OMe, methyl, or halomethyl.

76. The compound of claim 67, wherein -L*-R*- is -C(=NR’)O-R*-.

77. The compound of claim 67, wherein L*is -N=C(R’)O-.

78. The compound of claim 67, wherein L*is -N=C(R’)O- and R’ is hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 Rs.

79. The compound of claim 67, wherein L*is -N=C(R’)O- and R’ is C1-C10alkyl.

80. The compound of claim 67, wherein L*is -N=C(Me)O-.

81. The compound of any one of claims 105-108, wherein -L*-R*- is -N=C(R’)O-R*-.

82. The compound of claim 67, wherein L*is -N=C(N(R’)2)O-.

83. The compound of claim 67, wherein L*is -N=C(N(R’)2)O- and each R’ is independently hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 Rs.

84. The compound of claim 67, wherein L*is -N=C(N(R’)2)O- and each R’ is independently hydrogen or C1-C10 alkyl.

85. The compound of claim 67, wherein L*is -N=C(NHMe)O-.

86. The compound of any one of claims 110-113, wherein -L*-R*- is --N=C(N(R’)2)O-R*-.

87. The compound of claim 67, wherein L*is -NR’C(=O)NR’-.

88. The compound of claim 67, wherein L*is -NR’C(=O)NR’- and each R’ is independently hydrogen, C1-C10alkyl, C1-C10heteroalkyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl, optionally substituted with 1-20 Rs.

89. The compound of claim 67, wherein L*is -NR’C(=O)NR’- and each R’ is independently hydrogen or C1-C3alkyl.

90. The compound of claim 67, wherein L*is -NHC(=O)NH-.

91. The compound of claim 67, wherein L*is -OC(=O)O-.

92. The compound of claim 67, wherein L*is -L-O-.

93. The compound of claim 67, wherein L*is -L-O- and L is C1-C6 alkylene optionally substituted with 1-12 Rs, wherein one or more methylene units of L are optionally and -230-703.101.412 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’)-.

94. The compound of claim 67, wherein L*is -L-O- and L is C1-C6 alkylene optionally substituted with 1-6 Rs.

95. The compound of claim 67, wherein L*is -L-O- and L is C1-C3alkylene optionally substituted with 1-4 Rs.

96. The compound of claim 67, wherein L*is -CH2-O- and --CH2- is optionally substituted with 1-2 Rs.

97. The compound of claim 67, wherein L*is -CH2-O- and -CH2- is optionally substituted with 1-2 halogen, -OH, -CN, -OMe, methyl, or halomethyl.

98. The compound of claim 67, wherein L*is -CH2-O- and -CH2- is substituted with 1-2 halogen, -OH, -CN, -OMe, methyl, or halomethyl.

99. The compound of claim 67, wherein L*is .

100. The compound of claim 67, wherein L*i .

101. The compound of claim 1, wherein the cs: , ,703.101.412 , , H , , , ,703.101.412 , , , , , ,703.101.412 , , , , , , ,703.101.412 , , , , ,703.101.412 , , or a124]I, [125]I, or [131]I.

102. The compound of claim 1, wherein the compound is: ONO H , , ,703.101.412 OOHO *At H , , H , , , ,703.101.412 O F OH , , , , H , , ,703.101.412 , , , , , , ,703.101.412 , , , , ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,[211]At.

103. The compound of claim 67, wherein the compound is: -240-703.101.412 , , , , , , ,703.101.412 , , , ,3]I, [124]I, [125]I, or [131]I and X is a counterion. -242-

Images