GLYCOGEN SYNTHASE KINASE 3 INHIBITORS AND USES THEREOF

[0001] The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63/508,264, filed Jun. 14, 2023, which is incorporated herein by reference.

[0002] The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of extensive study is protein kinases.

[0003] Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).

[0004] In general, protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H₂O₂), cytokines (e.g., interleukin-1 (IL-I), tumor necrosis factor α (TNF-α)), and growth factors (e.g., granulocyte macrophage-colony-stimulating factor (GM-CSF), fibroblast growth factor (FGF)). An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

[0005] Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events as described above. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, metabolic disorders (e.g., diabetes), and hormone-related diseases. Accordingly, there remains a need to find protein kinase inhibitors, particularly glycogen synthase kinase 3 (GSK3) inhibitors, useful as therapeutic agents. GSK3 inhibitors have been reported in, e.g., U.S. patent application publication numbers US-2014-0107141-A1, US-2016-0375006-A1, and US-2020-0109154-A1, each of which is incorporated herein by reference in its entirety.

[0006] The present disclosure relates in part to compounds (e.g., compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof). The compounds provided herein may inhibit GSK3. The compounds provided herein may selectively inhibit GSK3 (e.g., selectively inhibit GSK3α (GSK3a) over GSK3β (GSK3b) or selectively inhibit GSK3β over GSK3α). The compounds provided herein may be advantageous over known GSK3 inhibitors (e.g., non-selective GSK3 inhibitors) at least in part because the former may reduce or eliminate off-target effects. The compounds provided herein may also be advantageous over known GSK3 inhibitors in that the former may be more permeable than the latter (e.g., the former may pass through the blood-brain barrier (BBB) more easily than the latter). The present disclosure also provides pharmaceutical compositions and kits comprising the compounds provided herein. The present disclosure also provides methods of treating or preventing a disease, as well as methods of inhibiting the activity and/or production of a GSK3.

[0007] In one aspect, the present disclosure provides compounds of Formula I:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof.

[0008] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound provided herein and optionally a pharmaceutically acceptable excipient.

[0009] In another aspect, the present disclosure provides kits comprising a compound provided herein or pharmaceutical composition provided herein and instructions for using the compound or pharmaceutical composition.

[0010] In another aspect, the present disclosure provides methods for treating diseases in a subject in need thereof, the methods comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein.

[0011] In another aspect, the present disclosure provides methods for preventing diseases in a subject in need thereof, the methods comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein.

[0012] In another aspect, the present disclosure provides methods of inhibiting the aberrantly high activity and/or production of a GSK3 in a subject in need thereof, cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a compound or pharmaceutical composition provided herein.

[0013] In another aspect, the present disclosure provides methods of inhibiting the aberrantly high activity and/or production of a GSK3 in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound or pharmaceutical composition provided herein, wherein the cell, tissue, or biological sample is in vitro.

[0014] The details of one or more embodiments of the disclosure are set forth herein. Other features, objects, and advantages of the disclosure will be apparent from the Detailed Description, Examples, Figures, and Claims.

[0015] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March's Advanced Organic Chemistry, 7^th Edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987.

[0016] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, in some embodiments, the compounds described herein are in the form of an individual enantiomer, diastereomer or geometric isomer, or are in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. In some embodiments, isomers are isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers are prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0017] The phrases “in certain embodiments” and “in some embodiments” are used interchangeably.

[0018] In a formula, the bond is a single bond, the dashed line is a single bond or absent, and the bond or is a single or double bond.

[0019] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms (e.g., enriched 3-, 10-, 30-, 100-, 300-, 1,000-, 3,000- or 10,000-fold above their natural abundance). For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of ¹⁹F with ¹⁸F, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of the disclosure. In certain embodiments, an isotopically labeled compound comprises one or more deuterium. In certain embodiments, an isotopically labeled compound comprises one or more ¹³C. In certain embodiments, an isotopically labeled compound comprises one or more ¹⁵N or ¹⁸O. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0020] The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.

[0021] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “C_1-6 alkyl” encompasses, C₁, C₂, C₃, C₄, C₅, C₆, C_1-6, C_1-5, C_1-4, C_1-3, C_1-2, C_2-6, C_2-5, C_2-4, C_2-3, C_3-6, C_3-5, C_3-4, C_4-6, C_4-5, and C_5-6 alkyl. The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0022] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C_1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C_1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C_1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C_1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C_1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C_1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C_1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C_1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C_1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C_1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C_1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C_2-6 alkyl”). Examples of C_1-6 alkyl groups include methyl (C₁), ethyl (C₂), propyl (C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C₆) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈), n-dodecyl (C₁₂), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C_1-12 alkyl (such as unsubstituted C_1-6 alkyl, e.g., —CH₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C_1-12 alkyl (such as substituted C_1-6 alkyl, e.g., —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, or benzyl (Bn)).

[0023] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C_1-20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C_1-10 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C_1-9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C_1-8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C_1-7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C_1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C_1-5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C_1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C_1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C_1-2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include —CHF₂, —CH₂F, —CF₃, —CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl, and the like.

[0024] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-20 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-11 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC_1-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC_1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC_1-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC_1-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC₁ alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC_2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC_1-12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC_1-12 alkyl.

[0025] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C_1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C_1-12 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C_1-11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C_1-10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C_1-9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C_1-8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C_1-7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C_1-6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C_1-5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C_1-4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C_1-3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C_1-2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C₁ alkenyl”). In some embodiments, the one or more carbon-carbon double bonds is internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C_1-4 alkenyl groups include methylidenyl (C₁), ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C_1-6 alkenyl groups include the aforementioned C_2-4 alkenyl groups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additional examples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl (C₈), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C_1-20 alkenyl. In certain embodiments, the alkenyl group is a substituted C_1-20 alkenyl. In some embodiments, in an alkenyl group, a C═C double bond for which the stereochemistry is not specified (e.g., —CH═CHCH₃ or

is in the (F)- or (Z)-configuration.

[0026] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-20 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-11 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-10 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-8 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-7 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_1-5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_1-4 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC_1-3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC_1-2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_1-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC_1-20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC_1-20 alkenyl.

[0027] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C_1-20 alkynyl”). In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“C_2-10 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C_1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C_1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C_1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C_1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C_1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C_1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C_1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C_1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“C₁ alkynyl”). In some embodiments, the one or more carbon-carbon triple bonds is internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C_1-4 alkynyl groups include, without limitation, methylidynyl (C₁), ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), and the like. Examples of C_1-6 alkenyl groups include the aforementioned C_2-4 alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and the like. Additional examples of alkynyl include heptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C_1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C_1-20 alkynyl.

[0028] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-20 alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-10 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-8 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_1-6 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_1-5 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and for 2 heteroatoms within the parent chain (“heteroC_1-4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC_1-3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC_1-2 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_1-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC_1-20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC_1-20 alkynyl.

[0029] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C_3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C_3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C_3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C_3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C_3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C_3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C_3-4 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C_3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C_3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C_4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C_5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C_5-10 carbocyclyl”). Exemplary C_3-6 carbocyclyl groups include cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C_3-8 carbocyclyl groups include the aforementioned C_3-6 carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C_3-10 carbocyclyl groups include the aforementioned C_3-8 carbocyclyl groups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), spiro[4.5]decanyl (C₁₀), and the like. Exemplary C_3-8 carbocyclyl groups include the aforementioned C_3-10 carbocyclyl groups as well as cycloundecyl (C₁₁), spiro[5.5]undecanyl (C₁₁), cyclododecyl (C₁₂), cyclododecenyl (C₁₂), cyclotridecane (C₁₃), cyclotetradecane (C₁₄), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and is saturated or contains one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C_3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C_3-14 carbocyclyl.

[0030] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C_3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C_3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C_3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C_3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C_4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C_5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C_5-10 cycloalkyl”). Examples of C_5-6 cycloalkyl groups include cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C_3-6 cycloalkyl groups include the aforementioned C_5-6 cycloalkyl groups as well as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C_3-8 cycloalkyl groups include the aforementioned C_3-6 cycloalkyl groups as well as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C_3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C_3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C═C double bonds in the carbocyclic ring system, as valency permits.

[0031] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In some embodiments, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, a heterocyclyl group is either monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and is either saturated or contains one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0032] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0033] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like. The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C_6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as l-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C_6-14 aryl. In certain embodiments, the aryl group is a substituted C_6-14 aryl.

[0034] “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0035] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In some embodiments, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. In some embodiments, in polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment is on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0036] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0037] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0038] “Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0039] The term “unsaturated bond” refers to a double or triple bond.

[0040] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0041] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds.

[0042] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0043] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any manner by the exemplary substituents described herein.

[0044] Exemplary carbon atom substituents include halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^aa, —ON(R^bb)₂, —N(R^bb)₂, —N(R^bb)₃⁺X⁻, —N(OR^cc)R^bb, —SH, —SR^aa, —SSR^cc, —C(═O)R^aa, —CO₂, —CHO, —C(OR^cc)₂, —CO₂R^aa, —OC(═O)R^aa, —OCO₂R^aa, —C(═O)N(R^bb)₂, —OC(═O)N(R^bb)₂, —NR^bbC(═O)R^aa, —NR^bbCO₂—R^aa, —NR^bbC(═O)N(R^bb)₂, —C(═NR^bb)R^aa, —C(═NR^bb)OR^aa, —OC(═NR^bb)R^aa, —OC(═NR^bb)OR^aa, —C(═NR^bb)N(R^bb)₂, —OC(═NR^bb)N(R^bb)₂, —NR^bbC(═NR^bb)N(R^bb)₂, —C(═O)NR^bbSO₂R^aa, —NR^bbSO₂R^aa, —SO₂N(R^bb)₂, —SO₂R^aa, —SO₂OR^aa, —OSO₂R^aa, —S(═O)R^aa, —OS(═O)R^aa, —Si(R^aa)₃, —OSi(R^aa)₃, —C(═S)N(R^bb)₂, —C(═O)SR^aa, —C(═S)SR^aa, —SC(═S)SR^aa, —SC(═O)SR^aa, —OC(═O)SR^aa, —SC(═O)OR^aa, —SC(═O)R^aa, —P(═O)(R^aa)₂, —P(═O)(OR^cc)₂, —OP(═O)(R^aa)₂, —OP(═O)(OR^cc)₂, —P(═O)(N(R^bb)₂)₂, —OP(═O)(N(R^bb)₂)₂, —NR^bbP(═O)(R^aa)₂, —NR^bbP(═O)(OR^cc)₂, —NR^bbP(═O)(N(R^bb)₂)₂, —P(R^cc)₂, —P(OR^cc)₂, —P(R^cc)₃⁺X⁻, —P(OR^cc)₃⁺X⁻, —P(R^cc)₄, —P(OR^cc)₄, —OP(R^cc)₂, —OP(R^cc)₃⁺X⁻, —OP(OR^cc)₂, —OP(OR^cc)₃⁺X⁻, —OP(R^cc)₄, —OP(OR^cc)₄, —B(R^aa)₂, —B(OR^cc)₂, —BR^aa(OR^cc), C_1-20 alkyl, C_1-20 perhaloalkyl, C_1-20 alkenyl, C_1-20 alkynyl, heteroC_1-20 alkyl, heteroC_1-20 alkenyl, heteroC_1-20 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups;

• • [0045] or two geminal hydrogens on a carbon atom are replaced with the group ═O, ═S, ═NN(R^bb)₂, ═NNR^bbC(═O)R^aa, ═NNR^bbC(═O)OR^aa, ═NNR^bbS(═O)₂R^aa, ═NR^bb, or ═NOR^cc;
  • [0046] wherein:
    • [0047] each instance of R^aa is, independently, selected from C_1-20 alkyl, C_1-20 perhaloalkyl, C_1-20 alkenyl, C_1-20 alkynyl, heteroC_1-20 alkyl, heteroC_1-20 alkenyl, heteroC_1-20alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups;
    • [0048] each instance of R^bb is, independently, selected from hydrogen, —OH, —OR^aa, —N(R^cc)₂, —CN, —C(═O)R^aa, —C(═O)N(R^cc)₂, —CO₂R^aa, —SO₂R^aa, —C(═NR^cc)OR^aa, —C(═NR^cc)N(R^cc)₂, —SO₂N(R^cc)₂, —SO₂R^cc, —SO₂OR^aa, —SOR^aa, —C(═S)N(R^cc)₂, —C(═O)SR^cc, —C(═S)SR^cc, —P(═O)(R^aa)₂, —P(═O)(OR^cc)₂, —P(═O)(N(R^cc)₂)₂, C_1-20 alkyl, C_1-20 perhaloalkyl, C_1-20 alkenyl, C_1-20 alkynyl, heteroC_1-20 alkyl, heteroC_1-20 alkenyl, heteroC_1-20 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups;
    • [0049] each instance of R^cc is, independently, selected from hydrogen, C_1-20 alkyl, C_1-20 perhaloalkyl, C_1-20 alkenyl, C_1-20 alkynyl, heteroC_1-20 alkyl, heteroC_1-20 alkenyl, heteroC_1-20 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups;
    • [0050] each instance of R^dd is, independently, selected from halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^ee, —ON(R^ff)₂, —N(R^ff)₂, —N(R^ff)₃⁺X⁻, —N(OR^ee)R^ff, —SH, —SR^ee, —SSR^ee, —C(═O)R^ee, —CO₂H, —CO₂R^ee, —OC(═O)R^ee, —OCO₂R^ee, —C(═O)N(R^ff)₂, —OC(═O)N(R^ff)₂, —NR^ffC(═O)R^ee, —NR^ffCO₂R^ee, —NR^ffC(═O)N(R^ff)₂, —C(═NR^ff)OR^ee, —OC(═NR^ff)R^ee, —OC(═NR^ff)OR^ee, —C(═NR^ff)N(R^ff)₂, —OC(═NR^ff)N(R^ff)₂, —NR^ffC(═NR^ff)N(R^ff)₂, —NR^ffSO₂R^ee, —SO₂N(R^ff)₂, —SO₂R^ee, —SO₂OR^ee, —OSO₂R^ee, —S(═O)R ee, —Si(R^ee)₃, —OSi(R^ee)₃, —C(═S)N(R^ff)₂, —C(═O)SR^ee, —C(═S)SR^ee, —SC(═S)SR^ee, —P(═O)(OR^ee)₂, —P(═O)(R^ee)₂, —OP(═O)(R^ee)₂, —OP(═O)(OR^ee)₂, C_1-10 alkyl, C_1-10 perhaloalkyl, C_1-10 alkenyl, C_1-10 alkynyl, heteroC_1-10alkyl, heteroC_1-10alkenyl, heteroC_1-10alkynyl, C_3-10 carbocyclyl, 3-10 membered heterocyclyl, C_6-10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gg groups, or two geminal R^dd substituents are joined to form ═O or ═S;
  • [0051] each instance of R^ee is, independently, selected from C_1-10 alkyl, C_1-10 perhaloalkyl, C_1-10 alkenyl, C_1-10 alkynyl, heteroC_1-10 alkyl, heteroC_1-10 alkenyl, heteroC_1-10 alkynyl, C_3-10 carbocyclyl, C_6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gg groups;
    • [0052] each instance of R^ff is, independently, selected from hydrogen, C_1-10 alkyl, C_1-10 perhaloalkyl, C_1-10 alkenyl, C_1-10 alkynyl, heteroC_1-10 alkyl, heteroC_1-10 alkenyl, heteroC_1-10 alkynyl, C_3-10 carbocyclyl, 3-10 membered heterocyclyl, C_6-10 aryl, and 5-10 membered heteroaryl, or two R^ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R⁸ groups;
    • [0053] each instance of R^gg is, independently, halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC_1-6 alkyl, —ON(C_1-6 alkyl)₂, —N(C_1-6 alkyl)₂, —N(C_1-6 alkyl)₃⁺X⁻, —NH(C_1-6 alkyl)₂⁺X⁻, —NH₂(C_1-6 alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC_1-6 alkyl)(C_1-6 alkyl), —N(OH)(C_1-6 alkyl), —NH(OH), —SH, —SC_1-6 alkyl, —SS(C_1-6 alkyl), —C(═O)(C_1-6 alkyl), —CO₂H, —CO₂(C_1-6 alkyl), —OC(═O)(C_1-6 alkyl), —OCO₂(C_1-6 alkyl), —C(═O)NH₂, —C(═O)N(C_1-6 alkyl)₂, —OC(═O)NH(C_1-6 alkyl), —NHC(═O)(C_1-6 alkyl), —N(C_1-6 alkyl)C(═O)(C_1-6 alkyl), —NHCO₂(C_1-6 alkyl), —NHC(═O)N(C_1-6 alkyl)₂, —NHC(═O)NH(C_1-6 alkyl), —NHC(═O)NH₂, —C(═NH)O(C_1-6 alkyl), —OC(═NH)(C_1-6 alkyl), —OC(═NH)OC_1-6 alkyl, —C(═NH)N(C_1-6 alkyl)₂, —C(═NH)NH(C_1-6 alkyl), —C(═NH)NH₂, —OC(═NH)N(C_1-6 alkyl)₂, —OC(NH)NH(C_1-6 alkyl), —OC(NH)NH₂, —NHC(NH)N(C_1-6 alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C_1-6 alkyl), —SO₂N(C_1-6 alkyl)₂, —SO₂NH(C_1-6 alkyl), —SO₂NH₂, —SO₂C_1-6 alkyl, —SO₂OC_1-6 alkyl, —OSO₂C_1-6 alkyl, —SOC_1-6 alkyl, —Si(C_1-6 alkyl)₃, —OSi(C_1-6 alkyl)₃, —C(═S)N(C_1-6 alkyl)₂, —C(═S)NH(C_1-6 alkyl), —C(═S)NH₂, —C(═O)S(C₁-6 alkyl), —C(═S)SC_1-6 alkyl, —SC(═S)SCI-s alkyl, —P(═O)(OC_1-6 alkyl)₂, —P(═O)(C_1-6 alkyl)₂, —OP(═O)(C_1-6 alkyl)₂, —OP(═O)(OC_1-6 alkyl)₂, C_1-10 alkyl, C_1-10 perhaloalkyl, C_1-10 alkenyl, C_1-10 alkynyl, heteroC_1-10 alkyl, heteroC_1-10 alkenyl, heteroC_1-10 alkynyl. C_3-10 carbocyclyl, C_6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal R^gg substituents are joined to form ═O or ═S; and
    • [0054] each X⁻ is a counterion.

[0055] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl, —OR^aa, —SR^aa, —N(R^bb)₂, —CN, —SCN, —NO₂, —C(═O)R^aa, —CO₂R^aa, —C(═O)N(R^bb)₂, —OC(═O)R^aa, —OCO₂R^aa, —OC(═O)N(R^bb)₂, —NR^bbC(═O)R^aa, —NR^bbCO₂R^aa, or —NR^bbC(═O)N(R^bb)₂. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl, —OR^aa, —SR^aa, —N(R^bb)₂, —CN, —SCN, —NO₂, —C(═O)R^aa, —CO₂R^aa, —C(═O)N(R^bb)₂, —OC(═O)R^aa, —OCO₂R^aa, —OC(═O)N(R^bb)₂, —NR^bbC(═O)R^aa, —NR^bbCO₂R^aa, or —NR^bbC(═O)N(R^bb)₂, wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C₁-10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each R^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl, —OR^aa, —SR^aa, —N(R^bb)₂, —CN, —SCN, or —NO₂. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C_1-10 alkyl, —OR^aa, —SR^aa, —N(R^bb)₂, —CN, —SCN, or —NO₂, wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each R^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0056] The term “halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

[0057] The term “hydroxyl” or “hydroxy” refers to the group —OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from —OR^aa, —ON(R^bb)₂, —OC(═O)SR^aa, —OC(═O)R^aa, —OCO₂R^aa, —OC(═O)N(R^bb)₂, —OC(═NR^bb)R^aa, —OC(═NR^bb)OR^aa, —OC(═NR^bb)N(R^bb)₂, —OS(═O)R^aa, —OSO₂R^aa, —OSi(R^aa)₃, —OP(R^cc)₂, —OP(R^cc)₃⁺X⁻, —OP(OR^cc)₂, —OP(OR^cc)₃⁺X⁻, —OP(═O)(R^aa)₂, —OP(═O)(OR^cc)₂, and —OP(═O)(N(R^bb))₂, wherein X⁻, R^aa, R^bb, and R^cc are as defined herein.

[0058] The term “thiol” or “thio” refers to the group —SH. The term “substituted thiol” or “substituted thio,” by extension, refers to a thiol group wherein the sulfur atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from —SR^aa, —S═SR^aa, —SC(═S)SR^aa, —SC(═S)OR^aa, —SC(═S) N(R^bb)₂, —SC(═O)SR^aa, —SC(═O)OR^aa, —SC(═O)N(R^bb)₂, and —SC(═O)R^aa, wherein R^aa and R^cc are as defined herein. The term “amino” refers to the group —NH₂. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

[0059] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from —NH(R^bb), —NHC(═O)R^aa, —NHCO₂R^aa, —NHC(═O)N(R^bb)₂, —NHC(═NR^bb)N(R^bb)₂, —NHSO₂R^aa, —NHP(═O)(OR^cc)₂, and —NHP(═O)(N(R^bb)₂)₂, wherein R^aa, R^bb, and R^cc are as defined herein, and wherein R^bb of the group —NH(R^bb) is not hydrogen.

[0060] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from —N(R^bb)₂, —NR^bbC(═O)R^aa, —NR^bbCO₂R^aa, —NR^bbC(═O)N(R^bb)₂, —NR^bbC(═NR^bb)N(R^bb)₂, —NR^bbSO₂R^aa, —NR^bbP(═O)(OR^cc)₂, and —NR^bbP(═O)(N(R^bb)₂)₂, wherein R^aa, R^bb, and R^cc are as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0061] The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from —N(R^bb)₃ and —N(R^bb)₃⁺X⁻, wherein R^bb and X⁻ are as defined herein.

[0062] The term “sulfonyl” refers to a group selected from —SO₂N(R^bb)₂, —SO₂R^aa, and —SO₂OR^aa, wherein R^aa and R^bb are as defined herein.

[0063] The term “sulfinyl” refers to the group —S(═O)R^aa, wherein R^aa is as defined herein.

[0064] The term “acyl” refers to a group having the general formula —C(═O)R^aa, —C(═O)OR^aa, —C(═O)—O—C(═O)R^aa, —C(═O)SR^aa, —C(═O)N(R^bb)₂, —C(═S)R^aa, —C(═S)N(R^bb)₂, —C(═S)S(R^aa), —C(═NR^bb)R^aa, —C(═NR^bb)OR^aa, —C(═NR^bb)SR^aa, and —C(═NR^bb)N(R^bb)₂, wherein R^aa and R^bb are as defined herein. In some embodiments, the term “acyl” refers to a group having the general formula —C(═O)R^aa, —C(═O)OR^aa, —C(═O)—O—C(═O)R^aa, —C(═O)SR^aa, or —C(═O)N(R^bb)₂.

[0065] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp² hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (—C(═O)R^aa), carboxylic acids (—CO₂H), aldehydes (—CHO), esters (—CO₂R^aa, —C(═O)SR^aa, —C(═S)SR^aa), amides (—C(═O)N(R^bb)₂, —C(═O)NR^bbSO₂R^aa, —C(═S)N(R^bb)₂), and imines (—C(═NR^bb)R^aa, —C(═NR^bb)OR^aa), —C(═NR^bb)N(R^bb)₂), wherein R^aa and R^bb are as defined herein.

[0066] The term “silyl” refers to the group —Si(R^aa)₃, wherein R^aa is as defined herein.

[0067] Nitrogen atoms are substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, —OH, —OR^aa, —N(R^cc)₂, —CN, —C(═O)R^aa, —C(═O)N(R^cc)₂, —CO₂R^aa, —SO₂R^aa, —C(═NR^bb)R^aa, —C(═NR^cc)OR^aa, —C(═NR^cc)N(R^cc)₂, —SO₂N(R^cc)₂, —SO₂R^cc, —SO₂OR^cc, —SOR^cc, —C(═S)N(R^cc)₂, —C(═O)SR^cc, —C(═S)SR^cc, —P(═O)(OR^cc)₂, —P(═O)(R^aa)₂, —P(═O)N(R^cc)₂)₂, C_1-20 alkyl, C_1-20 perhaloalkyl, C_1-20 alkenyl, C_1-20 alkynyl, hetero C_1-20 alkyl, hetero C_1-20 alkenyl, hetero C_1-20 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^d groups, and wherein R^aa, R^bb, R^cc, and R^dd are as defined above.

[0068] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl, —C(═O)R^aa, —CO₂R^aa, —C(═O)N(R^bb)₂, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-20 alkyl, —C(═O)R^aa, —CO₂R^aa, —C(═O)N(R^bb)₂, or a nitrogen protecting group, wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl or a nitrogen protecting group.

[0069] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include —OH, —OR^aa, —N(R^cc)₂, —C(═O)R^aa, —C(═O)N(R^cc)₂, —CO₂R^aa, —SO₂R^aa, —C(═NR^cc)R^aa, —C(═NR^cc)OR^aa, —C(═NR^cc)N(R^cc)₂, —SO₂N(R^cc)₂, —SO₂R^cc, —SO₂OR^aa, —SOR^aa, —C(═S)N(R^cc)₂, —C(═O)SR^cc, —C(═S)SR^cc, C_1-10 alkyl (e.g., aralkyl, heteroaralkyl), C_1-20 alkenyl, C_1-20 alkynyl, hetero C_1-20 alkyl, hetero C_1-20 alkenyl, hetero C_1-20 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups, and wherein R^aa, R^bb, R^cc and R^dd are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0070] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., —C(═O)R^aa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N′-dithiobenzyloxyacylamino)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 derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0071] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., —C(═O)OR^aa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2sulfo)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, r-butyl carbamate (BOC or 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-nitrobenzyl 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, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl 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, and 2,4,6-trimethylbenzyl carbamate.

[0072] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., —S(═O)₂R^aa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxy benzenesulfonamide (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.

[0073] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N′-p-toluenesulfonylaminoacyl derivatives, N′-phenylaminothioacyl derivatives. N-benzovlphenylalanyl derivatives. N-acetylmethionine derivatives, 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-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N—(N′,N′-dimethylaminomethylene)amine, 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 derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]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, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N′-isopropylidenediamine.

[0074] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0075] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl, —C(═O)R^aa, —CO₂R^aa, —C(═O)N(R^bb)₂, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl, —C(═O)R^aa, —CO₂R^aa, —C(═O)N(R^bb)₂, or an oxygen protecting group, wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl or an oxygen protecting group.

[0076] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include —R^aa, —N(R^bb)₂, —C(═O)SR^aa, —C(═O)R^aa, —CO₂R^aa, —C(═O)N(R^bb)₂, —C(═NR^bb)R^aa, —C(═NR^bb)OR^aa, —C(═NR^bb)N(R^bb)₂, —S(═O)R^aa, —SO₂R^aa, —Si(R^aa)₃, —P(R^cc)₂, —P(R^cc)₃⁺X⁻, —P(OR^cc)₂, —P(OR^cc)₃⁺X⁻, —P(═O)(R^cc)₂, —P(═O)(OR^cc)₂, and —P(═O)(N(R^bb)₂)₂, wherein X⁻, R^aa, R^bb, and R^cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0077] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methoxy, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), i-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 (Bn), p-methoxybenzyl (PMB), 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, 4,4′-Dimethoxy-3′″-[N-(imidazolylmethyl)]trityl Ether (IDTr-OR), 4,4′-Dimethoxy-3″-[N-(imidazolylethyl)carbamoyl]trityl Ether (IETr-OR), 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), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, 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 carbonate (MTMEC-OR), 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-(methoxyacyl)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).

[0078] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0079] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl, —C(═O)R^aa, —CO₂R^aa, —C(═O)N(R^bb)₂, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl, —C(═O)R^aa, —CO₂R^aa, —C(═O)N(R^bb)₂, or a sulfur protecting group, wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl or a sulfur protecting group.

[0080] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of —R^aa, —N(R^bb)₂, —C(═O)SR^aa, —C(═O))R^aa, —CO₂R^aa, —C(═O)N(R^bb)₂, —C(═NR^bb)R^aa, —C(═NR^bb)OR^aa, —C(═NR^bb)N(R^bb)₂, —S(═O)R^aa, —SO₂R^aa, —Si(R^aa)₃, —P(R^cc)₂, —P(R^cc)₃⁺X⁻, —P(OR^cc)₂, —P(OR^cc)₃⁺X⁻, —P(═O)(R^aa)₂, —P(═O)(OR^cc)₂, and —P(═O)(N(R^bb)₂)₂, wherein R^aa, R^bb, and R^cc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0081] In certain embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0082] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. In some embodiments, an anionic counterion is monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F⁻, Cl⁻, Br⁻, I⁻), NO₃⁻, ClO₄⁻, OH⁻, H₂PO₄⁻, HCO₃⁻, HSO₄⁻, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF₄⁻, PF₄⁻, PF₆, AsFb⁻, SbFb⁻, B[3,5-(CF₃)₂C₆H₃]₄]⁻, B(C₆F₅)₄⁻, BPh₄⁻, Al(OC(CF₃)₃)₄⁻, and carborane anions (e.g., CB₁₁H₁₂ or (HCB₁₁Me₅Br₆)⁻). Exemplary counterions which may be multivalent include CO₃²⁻, HPO₄²⁻, PO₄³⁻, B₄O₇²⁻, SO₄²⁻, S₂O₃²⁻, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0083] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0084] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0085] The term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C_1-4 alkyl)₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0086] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N⁺(C_1-4 alkyl)₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0087] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. In some embodiments, the compounds provided herein are prepared, e.g., in crystalline form. In some embodiments, the compounds provided herein are prepared, e.g., in crystalline form, and are solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0088] The term “hydrate” refers to a compound, or a salt thereof, that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound, or a salt thereof, is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, in some embodiments, a hydrate of a compound, or a salt thereof, is represented, for example, by the general formula R·x H₂O, wherein R is the compound, or a salt thereof, and x is a number greater than 0. A given compound, or a salt thereof, may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R·0.5 H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2 H₂O) and hexahydrates (R·6 H₂O)).

[0089] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0090] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0091] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. In some embodiments, an enantiomer is characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0092] The term “co-crystal” refers to a crystalline structure comprising at least two different components (e.g., a compound disclosed herein and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound disclosed herein and an acid is different from a salt formed from a compound disclosed herein and the acid. In the salt, a compound disclosed herein is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound disclosed herein easily occurs at room temperature. In the co-crystal, however, a compound disclosed herein is complexed with the acid in a way that proton transfer from the acid to a compound disclosed herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is no proton transfer from the acid to a compound disclosed herein. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound disclosed herein. In some embodiments, co-crystals are useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein.

[0093] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. In some embodiments, various polymorphs of a compound (or a salt, hydrate, or solvate thereof) are prepared by crystallization under different conditions.

[0094] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. In some embodiments. C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkyl esters of the compounds described herein are preferred.

[0095] The terms “composition” and “formulation” are used interchangeably.

[0096] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. In some embodiments, the non-human animal is a male or female at any stage of development. In some embodiments, the non-human animal is a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0097] The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels. In some embodiments, “tissue” is the object to which a compound, particle, and/or composition of the disclosure is delivered. In some embodiments, a tissue is an abnormal or unhealthy tissue, which may need to be treated. A tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented.

[0098] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.

[0099] The term “kinase” represents transferase class enzymes that are able to transfer a phosphate group from a donor molecule to an acceptor molecule, e.g., an amino acid residue of a protein or a lipid molecule. Representative, non-limiting examples of kinases include Abl, ACK, Akt1/PKBα, Akt2/PKBβ, Akt3/PKBγ, ALK1, ALK2, Alk4, AMPKα1/β1/γ1, AMPKα1/β1/γ2, AMPKα1/β1/γ3, AMPKα1/β2/γ1, AMPKα2/β1/γ1, AMPKα2/β2/γ2, Abl2, ARKS, Ask1, Aurora A, Aurora B, Aurora C, Axl, BARK1, Blk, Bmx, B-Raf, Brk, BrSKL, BrSK2, Btk, CaMK1α, CaMK1β, CaMK1γ, CaMK1δ, CAMK2α, CaMK2β, CAMK2δ, CAMK2γ, CAMK4, CAMKK1, CAMKK2, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, CDK1/cyclin B, CDK2/cyclin A, CDK2/cyclin E, CDK3/cyclin E, CDK5/p25, CDK5/p35, CDK6/cyclinD3, CDK7/cyclin H/MAT1, CDK9/cyclin T1, CHK1, CHK2, CK1α, CK1γ, CK1δ, CK1ε, CK1β1, CK1γ1, CK1γ2, CK1γ3, CK2α1, CK2α2, cKit, c-RAF, CLK1, CLK2, CLK3, COT, Csk, DAPK1, DAPK2, DAPK3, DCAMLK2, DDR2, DMPK, DRAK1, DYRKIA, DYRK2, DYRK3, eEF2K, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EphB1, EphB2, EphB3, EphB4, ErbB4, Erk1, Erk2, FAK, Fer, Fes, FGFR1, Flt2, Flt4, FLT3 D835Y, FGFR2, FGFR3, FGFR4, Fgr, Fit1, Flt3, Fms, FRK, FynA, GCK, GPRK5, GRK2, GRK4, GRK6, GRK7, GSK3α, GSK3β, Hck, HER2, HER4, HIPK1, HIPK2, HIPK3, HIPK4, IGFIR, IKKβ, IKKα, IKKε, IR, InsR, IRR, IRAK1, IRAK2, IRAK4, Itk, JAK2, JAK3, JNK1, JNK2, JNK3, KDR, KHS1, Kit, Lck, LIMK1, LKB1, LOK, LRRK2, Lyn A, Lyn B, MAPK1, MAPK2, MAPK12, MAPKAP-K2, MAPKAP-K3, MAPKAPK2, MAPKAPK3, MAPKAPK5, MARK1, MARK2, MARK3, MARK4, MELK, MEK1, MEK2, MEKK2, MEKK3, Mer, Met, MET M1250T, MINK, MKK4, MKK6, MKK7β, MLCK, MLK1, MLK3, MNK1, MNK2, MRCKα, MRCKβ, MSK1, MSK2, MSSK1, STK23, STK4, STK3, STK24, MST1, MST2, MST3, MST4, MUSK, mTOR, MYO3β, MYT1, NDR1, NEK11, NEK2, NEK3, NEK6, NEK7, NEK9, NLK, NUAK2, p38α, p38β, p38δ, p38γ, p70S6K, S6K, SRK, PAK1/CDC42, PAK2, PAK3, PAK4, PAK5, PAK6, PAR-1Bα, PASK, PBK, PDGFRα, PDGFRβ, PDK1, PEK, PHKG2, PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ, Pim1, Pim2, PKAcα, PKAcβ, PKAcγ, PKA(b), PKA, PKBα, PKBβ, PKBγ, PKCα, PKCβ1, PKCβ2, PKCβ11, PKCδ, PKCε, PKCγ, PKCμ, PKCη, PKCt, PKCθ, PKCζ, PKD1, PKD2, PKD3, PKG1α, PKG1B, PKN1, PKN2, PKR, PLK1, PLK2, PLK3, PLK4, Polo, PRAK, PRK2, PrKX, PTK5, PYK2, QIK, Raf1, Ret, RIPK2, RIPK5, ROCK1, ROCK2, RON, ROS, Rse, RSK1, RSK2, RSK3, RSK4, SAPK2a, SAPK2b, SAPK3, SAPK4, SGK1, SGK2, SGK3, SIK, MLCK, SLK, Snk, Src, SRPK1, SRPK2, STK33, SYK, TAK1-TAB1, TAKI, TBK1, TAO1, TAO2, TAO3, TBK1, TEC, TESK1, TGFβR1, TGFβR2, Tie2, TLK2, TrkA, TrkB, TrkC, TSSK1, TSSK2, TTK, TXK, TYK2, TYRO3, ULK1, ULK2, WEE1, WNK2, WNK3, Yes1, YSK1, ZAK, ZAP70, ZC3, and ZIPK.

[0100] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound provided herein, a compound useful in a provided method, or a pharmaceutical composition provided herein, in or on a subject.

[0101] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0102] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment is administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment is administered in the absence of signs or symptoms of the disease. For example, in some embodiments, treatment is administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0103] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0104] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0105] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting the activity and/or production of a GSK3. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting the activity and/or production of a GSK3 and treating a disease.

[0106] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting the activity and/or production of a GSK3. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting the activity and/or production of a GSK3 and preventing a disease.

[0107] The term “inhibit” or “inhibition”, for example, in the context of a GSK3, refers to a reduction in activity or production. In some embodiments, the term refers to a reduction of the level of activity and/or production, e.g., GSK3 activity and/or production, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of activity and/or production. In some embodiments, the term refers to a reduction of the level of activity and/or production, e.g., GSK3 activity and/or production, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of activity and/or production.

[0108] The term “genetic disease” refers to a disease caused by one or more abnormalities in the genome of a subject, such as a disease that is present from birth of the subject. Genetic diseases may be heritable and may be passed down from the parents' genes. A genetic disease may also be caused by mutations or changes of the DNAs and/or RNAs of the subject. In such cases, the genetic disease will be heritable if it occurs in the germline. Exemplary genetic diseases include Aarskog-Scott syndrome, Aase syndrome, achondroplasia, acrodysostosis, addiction, adrenoleukodystrophy, albinism, ablepharon-macrostomia syndrome, alagille syndrome, alkaptonuria, alpha-1 antitrypsin deficiency, Alport's syndrome, Alzheimer's disease, asthma, autoimmune polyglandular syndrome, androgen insensitivity syndrome, Angelman syndrome, ataxia, ataxia telangiectasia, atherosclerosis, attention deficit hyperactivity disorder (ADHD), autism, baldness, Batten disease, Beckwith-Wiedemann syndrome, Best disease, bipolar disorder, brachydactyl), breast cancer. Burkitt lymphoma, chronic myeloid leukemia, Charcot-Marie-Tooth disease, Crohn's disease, cleft lip, Cockayne syndrome, Coffin Lowry syndrome, colon cancer, congenital adrenal hyperplasia, Cornelia de Lange syndrome, Costello syndrome, Cowden syndrome, craniofrontonasal dysplasia, Crigler-Najjar syndrome, Creutzfeldt-Jakob disease, cystic fibrosis, deafness, depression, diabetes, diastrophic dysplasia, DiGeorge syndrome, Down's syndrome, dyslexia, Duchenne muscular dystrophy, Dubowitz syndrome, ectodermal dysplasia Ellis-van Creveld syndrome, Ehlers-Danlos, epidermolysis bullosa, epilepsy, essential tremor, familial hypercholesterolemia, familial Mediterranean fever, fragile X syndrome, Friedreich's ataxia, Gaucher's disease, glaucoma, glucose galactose malabsorption, glutaricaciduria, gyrate atrophy, Goldberg Shprintzen syndrome (velocardiofacial syndrome), Gorlin syndrome, Hailey-Hailey disease, hemihypertrophy, hemochromatosis, hemophilia, hereditary motor and sensory neuropathy (HMSN), hereditary non polyposis colorectal cancer (HNPCC). Huntington's disease, immunodeficiency with hyper-IgM, juvenile onset diabetes, Klinefelter's syndrome, Kabuki syndrome, Leigh's disease, long QT syndrome, lung cancer, malignant melanoma, manic depression, Marfan syndrome, Menkes syndrome, miscarriage, mucopolysaccharide disease, multiple endocrine neoplasia, multiple sclerosis, muscular dystrophy, myotrophic lateral sclerosis, myotonic dystrophy, neurofibromatosis, Niemann-Pick disease. Noonan syndrome, obesity, ovarian cancer, pancreatic cancer, Parkinson's disease, paroxysmal nocturnal hemoglobinuria. Pendred syndrome, peroneal muscular atrophy, phenylketonuria (PKU), polycystic kidney disease, Prader-Willi syndrome, primary biliary cirrhosis, prostate cancer, REAR syndrome, Refsum disease, retinitis pigmentosa, retinoblastoma, Rett syndrome, Sanfilippo syndrome, schizophrenia, severe combined immunodeficiency, sickle cell anemia, spina bifida, spinal muscular atrophy, spinocerebellar atrophy, sudden adult death syndrome, Tangier disease, Tay-Sachs disease, thrombocytopenia absent radius syndrome, Townes-Brocks syndrome, tuberous sclerosis, Turner syndrome, Usher syndrome, von Hippel-Lindau syndrome, Waardenburg syndrome, Weaver syndrome, Werner syndrome, Williams syndrome, Wilson's disease, xeroderma piginentosum, and Zellweger syndrome.

[0109] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0110] The term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and/or is associated with a disease.

[0111] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor's neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0112] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, e.g., Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. The cancer may be a solid tumor. The cancer may be a hematological malignancy. Exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0113] The term “inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, dermatitis (e.g., stasis dermatitis, allergic contact dermatitis, atopic dermatitis, irritant contact dermatitis, neurodermatitis perioral dermatitis, seborrheic dermatitis), hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, necrotizing enterocolitis, inflammatory rosacea. An ocular inflammatory disease includes post-surgical inflammation.

[0114] An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture's disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis/polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0115] A “hematological disease” includes a disease which affects a hematopoietic cell or tissue. Hematological diseases include diseases associated with aberrant hematological content and/or function. Examples of hematological diseases include diseases resulting from bone marrow irradiation or chemotherapy treatments for cancer, diseases such as pernicious anemia, hemorrhagic anemia, hemolytic anemia, aplastic anemia, sickle cell anemia, sideroblastic anemia, anemia associated with chronic infections such as malaria, trypanosomiasis, HTV, hepatitis virus or other viruses, myelophthisic anemias caused by marrow deficiencies, renal failure resulting from anemia, anemia, polycythemia, infectious mononucleosis (EVI), acute non-lymphocytic leukemia (ANLL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL), polycythemia vera, lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia, Wilm's tumor, Ewing's sarcoma, retinoblastoma, hemophilia, disorders associated with an increased risk of thrombosis, herpes, thalassemia, antibody-mediated disorders such as transfusion reactions and erythroblastosis, mechanical trauma to red blood cells such as micro-angiopathic hemolytic anemias, thrombotic thrombocytopenic purpura and disseminated intravascular coagulation, infections by parasites such as Plasmodium, chemical injuries from, e.g., lead poisoning, and hypersplenism.

[0116] The term “neurological disease” refers to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including Alzheimer's disease. Parkinson's disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington's disease. Examples of neurological diseases include headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illness, include bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers' disease; alternating hemiplegia; Alzheimer's disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Amold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing's syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome; Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb's palsy; essential tremor, Fabry's disease; Fahr's syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich's ataxia; frontotemporal dementia and other “tauopathies”; Gaucher's disease; Gerstmann's syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington's disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh's disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig's disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson's disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick's disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen's Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye's syndrome; Saint Vitus Dance; Sandhoff disease; Schilder's disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren's syndrome; sleep apnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd's paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg's syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson's disease; and Zellweger syndrome.

[0117] A “painful condition” includes neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post-operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre-operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and/or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre-term labor, pain associated with withdrawal symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter's arthritis), lumbosacral pain, musculo-skeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache, dental/maxillofacial pain, visceral pain and the like. One or more of the painful conditions contemplated herein can comprise mixtures of various types of pain provided above and herein (e.g. nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular pain can dominate. In other embodiments, the painful condition comprises two or more types of pains without one dominating. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition.

[0118] The term “metabolic disease” refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and/or carbohydrates. Factors affecting metabolism include the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like. Examples of metabolic disorders include diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity.

[0119] The term “psychiatric disorder” refers to a condition or disorder relating to the functioning of the brain and the cognitive processes or behavior. Psychiatric disorders may be further classified based on the type of neurological disturbance affecting the mental faculties. Psychiatric disorders are expressed primarily in abnormalities of thought, feeling, emotion, and/or behavior producing either distress or impairment of function (for example, impairment of mental function such with dementia or senility). The term “psychiatric disorder” is, accordingly, sometimes used interchangeably with the term “mental disorder” or the term “mental illness”.

[0120] A psychiatric disorder is often characterized by a psychological or behavioral pattern that occurs in an individual and is thought to cause distress or disability that is not expected as part of normal development or culture. Definitions, assessments, and classifications of mental disorders can vary, but guideline criteria listed in the International Classification of Diseases and Related Health Problems (ICD, published by the World Health Organization, WHO), or the Diagnostic and Statistical Manual of Mental Disorders (DSM, published by the American Psychiatric Association, APA) and other manuals are widely accepted by mental health professionals. Individuals may be evaluated for various psychiatric disorders using criteria set forth in these and other publications accepted by medical practitioners in the field and the manifestation and severity of a psychiatric disorder may be determined in an individual using these publications.

[0121] Categories of diagnoses in these schemes may include dissociative disorders, mood disorders, anxiety disorders, psychotic disorders, eating disorders, developmental disorders, personality disorders, and other categories. There are different categories of mental disorder, and many different facets of human behavior and personality that can become disordered.

[0122] One group of psychiatric disorders includes disorders of thinking and cognition, such as schizophrenia and delirium. A second group of psychiatric disorders includes disorders of mood, such as affective disorders and anxiety. A third group of psychiatric disorders includes disorders of social behavior, such as character defects and personality disorders. And a fourth group of psychiatric disorders includes disorders of learning, memory, and intelligence, such as mental retardation and dementia. Accordingly, psychiatric disorders encompass schizophrenia, delirium, attention deficit disorder (ADD), schizoaffective disorder, depression (e.g., lithium-resistant depression), mania, attention deficit disorders, drug addiction, dementia, agitation, apathy, anxiety, psychoses, personality disorders, bipolar disorders, unipolar affective disorder, obsessive-compulsive disorders, eating disorders, post-traumatic stress disorders, irritability, adolescent conduct disorder, and disinhibition.

[0123] Some diseases classified as neurodegenerative diseases, for example Alzheimer's disease, also sometimes show aspects of psychiatric disorders as listed herein, for example disorders of memory or dementia. Some neurodegenerative diseases or manifestations thereof can, accordingly, also be referred to as psychiatric disorders. These terms are, therefore, not mutually exclusive.

[0124] The state of anxiety or fear can become disordered, so that it is unusually intense or generalized over a prolonged period of time. Commonly recognized categories of anxiety disorders include specific phobia, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder.

[0125] Relatively long-lasting affective states can also become disordered. Mood disorder involving unusually intense and sustained sadness, melancholia or despair is known as clinical depression (or major depression), and may more generally be described as emotional dysregulation. Milder but prolonged depression can be diagnosed as dysthymia. Bipolar disorder involves abnormally “high” or pressured mood states, known as mania or hypomania, alternating with normal or depressed mood.

[0126] Patterns of belief, language use and perception can become disordered. Psychotic disorders centrally involving this domain include schizophrenia and delusional disorder, schizoaffective disorder is a category used for individuals showing aspects of both schizophrenia and affective disorders. Schizotypy is a category used for individuals showing some of the traits associated with schizophrenia but without meeting cut-off criteria.

[0127] The fundamental characteristics of a person that influence his or her cognitions, motivations, and behaviors across situations and time—can be seen as disordered due to being abnormally rigid and maladaptive. Categorical schemes list a number of different personality disorders, such as those classed as eccentric (e.g., paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder), those described as dramatic or emotional (antisocial personality disorder, Borderline personality disorder, histrionic personality disorder, narcissistic personality disorder) or those seen as fear-related (avoidant personality disorder, dependent personality disorder, obsessive-compulsive personality disorder).

[0129] The present disclosure provides compounds of Formula I, pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof, and pharmaceutical compositions and kits thereof. Also provided herein are methods of treating and/or preventing a disease in a subject in need thereof, as well as methods of inhibiting the activity and/or production GSK3 in a subject in need thereof, cell, tissue, or biological sample in vivo or in vitro.

[0130] In one aspect, provided herein is a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula I:

wherein:

• • [0131] R¹ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • [0132] R² is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • [0133] or R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring, and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring; each of R^3a and R^3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR^A, —SCN, —SR^A, —SSR^A, —N₃, —NO, —N(R^A)₂, —NO₂, —C(═O)R^A, —C(═O)OR^A, —C(═O)SR^A, —C(═O)N(R^A)₂, —C(═NR^A)R^A, —C(═NR^A)OR^A, —C(═NR^A)SR^A, —C(═NR^A)N(R^A)₂, —S(═O)R^A, —S(═O)OR^A, —S(═O)SR^A, —S(═O)N(R^A)₂, —S(═O)₂R^A, —S(═O)₂OR^A, —S(═O)₂SR^A, —S(═O)₂N(R A)₂, —OC(═O)R^A, —OC(═O)OR^A, —OC(═O)SR^A, —OC(═O)N(R^A)₂, —OC(═NR^A)R^A, —OC(═NR^A)OR^A, —OC(═NR^A)SR^A, —OC(═NR^A)N(R^A)₂, —OS(═O)R^A, —OS(═O)OR^A, —OS(═O)SR^A, —OS(═O)N(R^A)₂, —OS(═O)₂R^A, —OS(═O)₂OR^A, —OS(═O)₂SR^A, —OS(═O)₂N(R^A)₂, —ON(R^A)₂, —SC(═O)R^A, —SC(═O)OR^A, —SC(═O)SR^A, —SC(═O)N(R^A)₂, —SC(═NR^A)R^A, —SC(═NR^A)OR^A, —SC(═NR^A)SR^A, —SC(═NR^A)N(R^A)₂, —NR^AC(═O)R^A, —NR^AC(═O)OR^A, —NR^AC(═O)SR^A, —NR^AC(═O)N(R^A)₂, —NR^AC(═NR^A)R^A, —NR^AC(═NR^A)OR^A, —NR^AC(═NR^A)SR^A, —NR^AC(═NR^A)N(R^A)₂, —NR^AS(═O)R^A, —NR^AS(═O)OR^A, —NR^AS(═O)SR^A, —NR^AS(═O)N(R^A)₂, —NR^AS(═O)₂R^A, —NR^AS(═O)₂OR^A, —NR^AS(═O)₂SR^A, —NR^AS(═O)₂N(R^A)₂, —Si(R^A)₃, —Si(R^A)₂OR^A, —Si(R^A)(OR^A)₂, —Si(OR^A)₃, —OSi(R^A)₃, —OSi(R^A)₂OR^A, —OSi(R^A)(OR^A)₂, or —OSi(OR^A)₃;
  • [0134] or R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, or heteroaryl ring, or an optionally substituted phenyl ring;
  • [0135] each instance of R^A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R^A attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring;
  • [0136] R^3c is hydrogen;
  • [0137] X is

• •  or —N(R⁶)—;
  • [0138] each of R^4a, R^4b, R^5a, R^5b, R^6a, and R^6b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • [0139] or R^4a and R^4b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring;
  • [0140] or R^4b and R^5a are taken together with their intervening atoms to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring;
  • [0141] or R^5a and R^5b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring;
  • [0142] or R^5b and R^6a are taken together with their intervening atoms to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring;
  • [0143] or R^6a and R^6b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; and
  • [0144] R⁶ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

[0145] In some embodiments,

are used interchangeably.

[0146] In some embodiments, R¹ is optionally substituted C_1-10 alkyl, optionally substituted C_2-10 alkenyl, or optionally substituted C_2-10 alkynyl.

[0147] In some embodiments, R¹ is optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments, R¹ is optionally substituted C_3-14 carbocyclyl. In some embodiments, R¹ is optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments, R¹ is optionally substituted monocyclic C_3-4 carbocyclyl. In some embodiments, R¹ is optionally substituted monocyclic C_5-7 carbocyclyl. In some embodiments, R¹ is saturated carbocyclyl. In some embodiments, R¹ is carbocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the carbocyclic ring system.

[0148] In some embodiments, R¹ is 3- to 14-membered optionally substituted heterocyclyl. In some embodiments, R¹ is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R¹ is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R¹ is optionally substituted 3-to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R¹ is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R¹ is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R¹ is saturated heterocyclyl. In some embodiments, R¹ is heterocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the heterocyclic ring system.

[0149] In some embodiments, R¹ is optionally substituted aryl. In some embodiments, R¹ is optionally substituted monocyclic aryl. In some embodiments, R¹ is optionally substituted bicyclic aryl. In some embodiments, R¹ is optionally substituted C_6-14 aryl. In some embodiments, R¹ is optionally substituted C_6-10 aryl. In some embodiments, R¹ is optionally substituted phenyl. In some embodiments, R¹ is unsubstituted phenyl. In some embodiments, R¹ is substituted phenyl. In some embodiments, R¹ is ortho mono-substituted phenyl. In some embodiments, R¹ is meta mono-substituted phenyl. In some embodiments, R¹ is para mono-substituted phenyl. In some embodiments, R¹ is di-substituted phenyl. In some embodiments, R¹ is tri-substituted phenyl. In some embodiments, R¹ is optionally substituted naphthyl.

[0150] In some embodiments, R¹ is optionally substituted heteroaryl. In some embodiments, R¹ is optionally substituted monocyclic heteroaryl. In some embodiments, R¹ is optionally substituted bicyclic heteroaryl. In some embodiments, R¹ is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R¹ is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R¹ is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, R¹ is optionally substituted, 2-, 3-, or 4-pyridinyl. In some embodiments, R¹ is mono-substituted, 2-, 3-, or 4-pyridinyl. In some embodiments, R¹ is meta mono-substituted, 2- or 4-pyridinyl. In some embodiments, R¹ is optionally substituted 9- to 10-membered bicyclic heteroaryl.

[0151] In some embodiments, R¹ is optionally substituted aryl fused with optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments, R¹ is optionally substituted C_6-14 aryl fused with optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments, R¹ is optionally substituted C_6-10 aryl fused with optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments, R¹ is optionally substituted phenyl fused with optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments, R¹ is optionally substituted naphthyl fused with optionally substituted monocyclic C_3-7 carbocyclyl.

[0152] In some embodiments, R¹ is optionally substituted aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R¹ is optionally substituted C_6-14 aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R¹ is optionally substituted C_6-10 aryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R¹ is optionally substituted phenyl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R¹ is optionally substituted naphthyl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl.

[0153] In some embodiments, R¹ is optionally substituted heteroaryl fused with optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments, R¹ is optionally substituted 5- to 14-membered heteroaryl fused with optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments, R¹ is optionally substituted 5- to 10-membered heteroaryl fused with optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments, R¹ is optionally substituted 5- to 6-membered monocyclic heteroaryl fused with optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments, R¹ is optionally substituted 9- to 10-membered bicyclic heteroaryl fused with optionally substituted monocyclic C_3-7 carbocyclyl.

[0154] In some embodiments, R¹ is optionally substituted heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R¹ is optionally substituted 5- to 14-membered heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R¹ is optionally substituted 5- to 10-membered heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R¹ is optionally substituted 5- to 6-membered monocyclic heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R¹ is optionally substituted 9- to 10-membered bicyclic heteroaryl fused with optionally substituted monocyclic 3- to 7-membered heterocyclyl.

[0155] In some embodiments, R¹ is

[0156] In certain embodiments, (i) each instance of R⁷ is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR^D, —SCN, —SR^D, —SSR^D, —N₃, —NO, —N(R^D)₂, —NO₂, —C(═O)R^D, —C(═O)OR^D, —C(═O)SR^D, —C(═O)N(R^D)₂, —C(═NR^D)R^D, —C(═NR^D)OR^D, —C(═NR^D)SR^D, —C(═NR^D)N(R^D)₂, —S(═O)R^D, —S(═O)OR^D, —S(═O)SR^D, —S(═O)N(R^D)₂, —S(═O)₂R^D, —S(═O)₂OR^D, —S(═O)₂SR^D, —S(═O)₂N(R^D)₂, —S(═O)(═NR^D)R^D, —S(═O)(═NR^D)OR^D, —S(═O)(═NR^D)SR^D, —S(═O)(═NR^D)N(R^D)₂, —OC(═O)R^D, —OC(═O)OR^D, —OC(═O)SR^D, —OC(═O)N(R^D)₂, —OC(═NR^D)R^D, —OC(═NR^D)OR^D, —OC(═NR^D)SR^D, —OC(═NR^D)N(R^D)₂, —OS(═O)R^D, —OS(═O)OR^D, —OS(═O)SR^D, —OS(═O)N(R^D)₂, —OS(═O)₂R^D, —OS(═O)₂OR^D, —OS(═O)₂SR^D, —OS(═O)₂N(R^D)₂, —OS(═O)(═NR^D)R^D, —OS(═O)(═NR^D)OR^D, —OS(═O)(═NR^D)SR^D, —OS(═O)(═NR^D)N(R^D)₂, —ON(R^D)₂, —SC(═O)R^D, —SC(═O)OR^D, —SC(═O)SR^D, —SC(═O)N(R^D)₂, —SC(═NR^D)R^D, —SC(═NR^D)OR^D, —SC(═NR^D)SR^D, —SC(═NR^D)N(R^D)₂, —NR^DC(═O)R^D, —NR^DC(═O)OR^D, —NR^DC(═O)SR^D, —NR^DC(═O)N(RDN, —NR^DC(═NR^D)R^D, —NR^DC(═NR^D)OR^D, —NR^DC(═NRW)SR^D, —NR^DC(═NR^D)N(R^D)₂, —NR^DS(═O)R^D, —NR^DS(═O)OR^D, —NR^DS(═O)SR^D, —NR^DS(═O)N(R^D)₂, —NR^DS(═O)₂R^D, —NR^DS(═O)₂OR^D, —NR^DS(═O)₂SR^D, —NR^DS(═O)₂N(R^D)₂, —NR^DS(═O)(═NR^D)R^D, —NR^DS(═O)(═NR^D)OR^D, —NR^DS(═O)(═NR^D)NR^DSR^D, —NR^DS(═O)(═NR^D)N(R^D)₂, —Si(R^D)₃, —Si(R^D)₂OR^D, —Si(R^D)(OR^D)₂, —Si(OR^D)₃, —OSi(R^D)₃, —OSi(R^D)₂OR^D, —OSi(R^D)(OR^D)₂, or —OSi(OR^D)₃; or

• • [0157] (ii) two instances of R⁷ on two adjacent carbon atoms are taken together with the two adjacent carbon atoms to form an optionally substituted, monocyclic, aryl, heteroaryl, carbocyclic, or heterocyclic ring, and the remaining instances of R⁷, if present, are as defined in (i).

[0158] n2 is 0, 1, 2, 3, 4, or 5. In some embodiments, n2 is 0, 1, 2, 3, or 4. In some embodiments, n2 is 0, 1, 2, or 3. In some embodiments, n2 is 0, 1, or 2. In some embodiments, n2 is 0 or 1. In some embodiments, n2 is 0. In some embodiments, n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 4. In some embodiments, n2 is 5.

[0159] In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

[0160] In some embodiments, at least one instance of R⁷ is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, —OR^D, —SR^D, or —N(R^D)₂. In some embodiments, at least one instance of R⁷ is optionally substituted C_1-10 alkyl, optionally substituted C_2-10 alkenyl, optionally substituted C_2-10 alkynyl, optionally substituted C_1-10 heteroalkyl, optionally substituted C_1-10 heteroalkenyl, or optionally substituted C_1-10 heteroalkynyl. In some embodiments, at least one instance of R⁷ is optionally substituted alkyl. In some embodiments, at least one instance of R⁷ is unsubstituted C_1-6 alkyl or C_1-6 alkyl substituted with one or more halogen, as valency permits. In some embodiments, at least one instance of R⁷ is C_1-10 haloalkyl. In some embodiments, at least one instance of R⁷ is C_1-4 haloalkyl. In some embodiments, at least one instance of R⁷ is C_1-4 fluoroalkyl (e.g., C_1-4 perfluoroalkyl). In some embodiments, at least one instance of R⁷ is —CF₃.

[0161] In some embodiments, at least one instance of R⁷ is halogen. In some embodiments, at least one instance of R⁷ is bromine, chlorine, or fluorine. In some embodiments, at least one instance of R⁷ is bromine or chlorine. In some embodiments, at least one instance of R⁷ is chlorine or fluorine. In some embodiments, at least one instance of R⁷ is bromine. In some embodiments, at least one instance of R⁷ is chlorine. In some embodiments, at least one instance of R⁷ is fluorine.

[0162] In some embodiments, at least one instance of R⁷ is —OR^D, —SR^D, or —N(R^D)₂ (e.g., wherein R^D is hydrogen, optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R⁷ is —OH. In some embodiments, at least one instance of R⁷ is —SR^D. In some embodiments, at least one instance of R⁷ is —S(optionally substituted alkyl).

[0163] In some embodiments, at least one instance of R⁷ is —S(unsubstituted C_1-6 alkyl or C_1-6 alkyl substituted with one or more halogen). In some embodiments, at least one instance of R⁷ is —SMe or —SCF₃. In some embodiments, at least one instance of R⁷ is —SH. In some embodiments, at least one instance of R⁷ is —NH₂. In some embodiments, at least one instance of R⁷ is —CN, —SCN, —SSR^D, —N₃, —NO, or —NO₂. In some embodiments, at least one instance of R⁷ is —C(═O)R^D, —C(═O)OR^D, —C(═O)SR^D, or —C(═O)N(R^D)₂ (e.g., wherein R^D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R⁷ is —C(═NR^D)R^D, —C(═NR^D)OR^D, —C(═NR^D)SR^D, or —C(═NR^D)N(R^D)₂ (e.g., wherein R^D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R⁷ is —S(═O)R^D, —S(═O)OR^D, —S(═O)SR^D, —S(═O)N(R^D)₂, —S(═O)₂R^D, —S(═O)₂OR^D, —S(═O)₂SR^D, or —S(═O)₂N(R^D)₂ (e.g., wherein R^D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R⁷ is —S(═O)₂R^D. In some embodiments, at least one instance of R⁷ is —S(═O)₂(optionally substituted alkyl). In some embodiments, at least one instance of R⁷ is —S(═O)₂(unsubstituted C_1-6 alkyl or C_1-6 alkyl substituted with one or more halogen). In some embodiments, at least one instance of R⁷ is —S(═O)₂Me or —S(═O)₂CF₃. In some embodiments, at least one instance of R⁷ is —S(═O)(═NR^D)R^D. In some embodiments, at least one instance of R⁷ is —S(═O)(═NR^D)(optionally substituted alkyl). In some embodiments, at least one instance of R⁷ is —S(═O)(═NR^D)(unsubstituted C_1-6 alkyl or C_1-6 alkyl substituted with one or more halogen). In some embodiments, at least one instance of R⁷ is —S(═O)(═NR^D)Me. In some embodiments, at least one instance of R⁷ is —S(═O)(═NH)(optionally substituted alkyl). In some embodiments, at least one instance of R⁷ is —S(═O)(═NH)(unsubstituted C_1-6 alkyl or C_1-6 alkyl substituted with one or more halogen). In some embodiments, at least one instance of R⁷ is —S(═O)(═NH)Me. In some embodiments, at least one instance of R⁷ is —S(═O)(═N(unsubstituted C_1-6 alkyl))(optionally substituted alkyl). In some embodiments, at least one instance of R⁷ is —S(═O)(═N(unsubstituted C_1-6 alkyl))(unsubstituted C_1-6 alkyl or C_1-6 alkyl substituted with one or more halogen). In some embodiments, at least one instance of R⁷ is —S(═O)(═N(unsubstituted C_1-6 alkyl))Me (e.g., —S(═O)(═NMe)Me). In some embodiments, at least one instance of R⁷ is —OC(═O)R^D, —C(═O)OR^D, —OC(═O)SR^D, —OC(═O)N(R^D)₂, —OC(═NR^D)R^D, —OC(═NR^D)OR^D, —OC(═NR^D)SR^D, —OC(═NR^D)N(R^D)₂, —OS(═O)R^D, —OS(═O)OR^D, —OS(═O)SR^D, —OS(═O)N(R^D)₂, —OS(═O)₂R^D, —OS(═O)₂OR^D, —OS(═O)₂SR^D, —OS(═O)₂N(R^D)₂, or —ON(R^D)₂ (e.g., wherein R^D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R⁷ is —SC(═O)R^D, —SC(═O)OR^D, —SC(═O)SR^D, —SC(═O)N(R^D)₂, —SC(═NR^D)R^D, —SC(═NR^D)OR^D, —SC(═NR^D)SR^D, or —SC(═NR^D)N(R^D)₂ (e.g., wherein R^D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R⁷ is —NR^DC(═O)R^D, —NR^DC(═O)OR^D, —NR^DC(═O)SR^D, —NR^DC(═O)N(R^D)₂, —NR^DC(═NR^D)R^D, —NR^DC(═NR^D)OR^D, —NR^DC(═NR^D)SR^D, —NR^DC(═NR^D)N(R^D)₂, —NR^DS(═O)R^D, —NR^DS(═O)OR^D, —NR^DS(═O)SR^D, —NR^DS(═O)N(R^D)₂, —NR^DS(═O)₂R^D, —NR^DS(═O)₂OR^D, —NR^DS(═O)₂SR^D, or —NR^DS(═O)₂N(R^D)₂ (e.g., wherein R^D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, at least one instance of R⁷ is —Si(R^D)₃, —Si(R^D)₂OR^D, —Si(R^D)(OR^D)₃, —Si(OR^D)₃, —OSi(R¹)₃, —OSi(R^D)₂OR^D, —OSi(R^D)(OR^D)₂, or —OSi(OR^D)₃ (e.g., wherein R^D is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0164] In some embodiments, at least one instance of R⁷ is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R⁷ is optionally substituted C_3-14 carbocyclyl. In some embodiments, at least one instance of R⁷ is optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments, at least one instance of R⁷ is optionally substituted monocyclic C_3-4 carbocyclyl. In some embodiments, at least one instance of R⁷ is optionally substituted cyclobutyl. In some embodiments, at least one instance of R⁷ is optionally substituted monocyclic C_5-7 carbocyclyl. In some embodiments, at least one instance of R⁷ is saturated carbocyclyl. In some embodiments, at least one instance of R⁷ is carbocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the carbocyclic ring system.

[0165] In some embodiments, at least one instance of R⁷ is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, at least one instance of R⁷ is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, at least one instance of R⁷ is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, at least one instance of R⁷ is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, at least one instance of R⁷ is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, at least one instance of R⁷ is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, at least one instance of R⁷ is saturated heterocyclyl. In some embodiments, at least one instance of R⁷ is heterocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the heterocyclic ring system.

[0166] In some embodiments, at least one instance of R⁷ is optionally substituted monocyclic aryl. In some embodiments, at least one instance of R⁷ is optionally substituted bicyclic aryl. In some embodiments, at least one instance of R⁷ is optionally substituted C_6-14 aryl. In some embodiments, at least one instance of R⁷ is optionally substituted C_6-10 aryl. In some embodiments, at least one instance of R⁷ is optionally substituted phenyl. In some embodiments, at least one instance of R⁷ is optionally substituted naphthyl.

[0167] In some embodiments, at least one instance of R⁷ is optionally substituted monocyclic heteroaryl. In some embodiments, at least one instance of R⁷ is optionally substituted bicyclic heteroaryl. In some embodiments, at least one instance of R⁷ is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, at least one instance of R⁷ is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, at least one instance of R⁷ is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, at least one instance of R⁷ is optionally substituted heteroaryl comprising one or more nitrogen atoms in the heteroaryl ring system, as valency permits. In some embodiments, at least one instance of R⁷ is at least one instance of R⁷ is optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyrazolyl, or optionally substituted imidazolyl. In some embodiments, at least one instance of R⁷ is optionally substituted 2-pyridinyl, optionally substituted 3-pyridinyl, or optionally substituted 4-pyridinyl. In some embodiments, at least one instance of R⁷ is optionally substituted pyridazinyl. In some embodiments, at least one instance of R⁷ is optionally substituted imidazolyl. In some embodiments, at least one instance of R⁷ is optionally substituted pyrazolyl. In some embodiments, at least one instance of R⁷ is optionally substituted, 5- or 6-membered, monocyclic heteroaryl fused to an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring. In some embodiments, at least one instance of R⁷ is optionally substituted, 5- or 6-membered, monocyclic heteroaryl fused to an optionally substituted, 4- to 7-membered, monocyclic carbocyclic ring. In some embodiments, at least one instance of R⁷ is —S(optionally substituted alkyl), —S(═O)(═NH)(optionally substituted alkyl), —S(═O)(═N(unsubstituted C_1-6 alkyl))(optionally substituted alkyl), —S(═O)₂(optionally substituted alkyl), or —OH. In some embodiments, at least one instance of R⁷ is —CH(CH₃)₂, —CF₃, unsubstituted cyclobutyl, —SCH₃, —SCF₃, —S(═O)(═NH)(CH₃), —S(═O)(═NCH₃)(CH₃), —S(═O)₂CH₃, —S(═O)₂CF₃, or —OH. In some embodiments, R⁷ is not —S(═O)₂CH₃. In some embodiments, R⁷ is not —S(═O)₂CH₃ when

In some embodiments, R⁷ is not —S(═O)₂CH₃ when

[0168] In some embodiments, two instances of R⁷ on two adjacent carbon atoms are taken together with the two adjacent carbon atoms to form an optionally substituted phenyl ring. In some embodiments, two instances of R⁷ on two adjacent carbon atoms are taken together with the two adjacent carbon atoms to form an optionally substituted, monocyclic, 5- or 6-membered heteroaryl ring. In some embodiments, two instances of R⁷ on two adjacent carbon atoms are taken together with the two adjacent carbon atoms to form an optionally substituted, monocyclic, 4- to 7-membered carbocyclic ring. In some embodiments, two instances of R⁷ on two adjacent carbon atoms are taken together with the two adjacent carbon atoms to form an optionally substituted, monocyclic, 5- to 7-membered heterocyclic ring.

[0169] Each instance of R^D is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R^D attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring. In some embodiments, at least one instance of R^D is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R^D is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R^D is independently hydrogen, optionally substituted C_1-10 alkyl, optionally substituted C_2-10 alkenyl, optionally substituted C_2-10 alkynyl, optionally substituted C_3-14 carbocyclyl, or optionally substituted C_6-14 aryl. In some embodiments, at least one instance of R^D is independently hydrogen, optionally substituted C_1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R^D is a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom. In some embodiments, two instances of R^D attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0170] In some embodiments, R² is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R² is optionally substituted C_1-4 alkyl, optionally substituted C_1-4 alkenyl, or optionally substituted C_1-4 alkynyl. In some embodiments, R² is optionally substituted alkyl. In some embodiments, R² is optionally substituted C_1-4 alkyl. In some embodiments, R² is unsubstituted C_1-4 alkyl or C_1-4 alkyl substituted with one or more fluorine, as valency permits. In some embodiments, R² is unsubstituted C₁-C₄ alkyl. In some embodiments, R² is —CH₃. In some embodiments, R² is —C₂H₅. In some embodiments, R² is —CH₂F, —CHF₂, or —CF₃. In some embodiments, R² is —CH₂CH₂F, —CH₂CHF₂, or —CH₂CF₃. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring. In certain embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered carbocyclic ring. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered carbocyclic ring. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered heterocyclic ring. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising one or more oxygen atoms. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring comprising one or more oxygen atoms. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising one or more nitrogen atoms. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring comprising one or more nitrogen atoms. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, 5-membered, monocyclic, heterocyclic ring. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, 6-membered, monocyclic, heterocyclic ring. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, 5-membered, monocyclic, heterocyclic ring, which is fused to an optionally substituted phenyl ring. In some embodiments, R¹ and R² are taken together with their intervening atom to form an optionally substituted, 6-membered, monocyclic, heterocyclic ring, which is fused to an optionally substituted phenyl ring. In some embodiments, R¹ and R² are taken together with their intervening atom to form optionally substituted piperidinyl. In some embodiments, R¹ and R² are taken together with their intervening atom to form

In some embodiments, R¹ and R² are taken together with their intervening atom to form

In some embodiments, R¹ and R² are taken together with their intervening atom to form

In some embodiments, R¹ and R² are taken together with their intervening atom to form

In some embodiments, R¹ and R² are taken together with their intervening atom to form

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

[0171] n3 is 0, 1, 2, 3, or 4. In some embodiments, n3 is 0. In some embodiments, n3 is 1. In some embodiments, n3 is 2. In some embodiments, n3 is 3. In some embodiments, n3 is 4.

[0172] R⁸ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a sulfur protecting group. In some embodiments, R⁸ is hydrogen, optionally substituted C_1-10 alkyl, optionally substituted C_2-10 alkenyl, optionally substituted C_2-10 alkynyl, optionally substituted C_1-10 heteroalkyl, optionally substituted C_1-10 heteroalkenyl, optionally substituted C_1-10 heteroalkynyl, optionally substituted C_3-14 carbocyclyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted C_6-14 aryl, optionally substituted 5-14-membered heteroaryl, or a sulfur protecting group.

[0173] R⁹ is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In some embodiments, R⁹ is optionally substituted C_1-4 alkyl. In some embodiments, R⁹ is unsubstituted C_1-4 alkyl. In some embodiments, R⁹ is —CH₃. In some embodiments, R⁹ is —C₂H₅, —CH₂CH₂CH₃, or —CH(CH₃)₂. In certain embodiments, R⁹ is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0174] In some embodiments, is

In some embodiments,

[0175] In some embodiments, R^3a is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, —OR^A, —SR^A, or —N(R^A)₂. In some embodiments, R is optionally substituted C_1-10 alkyl, optionally substituted C_2-10 alkenyl, optionally substituted C_2-10 alkynyl, optionally substituted C_1-10 heteroalkyl, optionally substituted C_1-10 heteroalkenyl, or optionally substituted C_1-10 heteroalkynyl. In some embodiments, R^3a is C_1-10 haloalkyl. In some embodiments, R^3a is C_1-4 haloalkyl. In some embodiments, R^3a is C_1-4 fluoroalkyl (e.g., C_1-4 perfluoroalkyl). In some embodiments, R^3a is —CH₂F, —CHF₂, or —CF₃. In some embodiments, R^3a is —CF₃. In some embodiments, R^3a is —CH₂CH₂F, —CH₂CHF₂, or —CH₂CF₃. In some embodiments, R^3a is optionally substituted alkyl substituted with optionally substituted carbocyclyl. In some embodiments, R^3a is unsubstituted C_1-6 alkyl substituted with one optionally substituted C_3-7 monocyclic carbocyclyl. In some embodiments, R^3a is —CH₂-(unsubstituted cyclopropyl). In some embodiments, R^3a is hydrogen, optionally substituted C₁-C₆ alkyl, or halogen. In some embodiments, R^3a is hydrogen, fluorine, —CH₃, —CH₂F, —CHF₂, or —CF₃. In some embodiments, R^3a is hydrogen, fluorine, —CH₃, or —CF₃.

[0176] In some embodiments, R^3a is hydrogen or halogen. In some embodiments, R^3a is hydrogen or fluorine. In some embodiments, R^3a is hydrogen or optionally substituted C₁-C₆ alkyl. In some embodiments, R^3a is hydrogen, unsubstituted C₁-C₆ alkyl, or C_1-6 haloalkyl. In some embodiments, R^3a is —CH₃. In some embodiments, R^3a is —C₂H₅. In some embodiments, R^3a is —C₃H₇, —C₄H₉, or —C₅H₁₁. In some embodiments, R^3a is hydrogen. In some embodiments, R^3a is optionally substituted alkenyl (e.g., optionally substituted C_2-6 alkenyl). In some embodiments, R^3a is unsubstituted vinyl.

[0177] In some embodiments, R^3a is halogen. In some embodiments, R^3a is bromine, chlorine, or fluorine. In some embodiments, R^3a is bromine or chlorine. In some embodiments, R^3a is chlorine or fluorine. In some embodiments, R^3a is bromine. In some embodiments, R^3a is chlorine. In some embodiments, R^3a is fluorine.

[0178] In some embodiments, R^3a is —OR^A, —SR^A, or —N(R^Ah (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R³ is —OH.

[0179] In some embodiments, R^3a is —SH. In some embodiments, R³ is —NH₂. In some embodiments, R^3a is —CN, —SCN, —SSR^A, —N₃, —NO, or —NO₂. In some embodiments, R^3a is —CN. In some embodiments, R^3a is —C(═O)R^A, —C(═O)OR^A, —C(═O)SR^A, or —C(═O)N(R^A)₂ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments. R^3a is —C(═NR^A)R^A, —C(═NR^A)OR^A, —C(═NR^A)SR^A, or —C(═NR^A)N(R^A)₂ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R^3a is —S(═O)R^A, —S(═O)OR^A, —S(═O)SR^A, —S(═O)N(R^A)₂, —S(═O)₂R^A, —S(═O)₂OR^A, —S(═O)₂SR^A, or —S(═O)₂N(R^A)₂ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R^3a is —OC(═O)R^A, —OC(═O)OR^A, —OC(═O)SR^A, —OC(═O)N(R^A)₂, —OC(═NR^A)R^A, —OC(═NR^A)OR^A, —OC(═NR^A)SR^A, —OC(═NR^A)N(R^A)₂, —OS(═O)R^A, —OS(═O)OR^A, —OS(═O)SR^A, —OS(═O)N(R^A)₂, —OS(═O)₂R^A, —OS(═O)₂OR^A, —OS(═O)₂SR^A, —OS(═O)₂N(R^A)₂, or —ON(R^A)₂ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R³ is —SC(═O)R^A, —SC(═O)OR^A, —SC(═O)SR^A, —SC(═O)N(R^A)₂, —SC(═NR^A)R^A, —SC(═NR^A)OR^A, —SC(═NR^A)SR^A, or —SC(═NR^A)N(R^A)₂ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R³ is —NR^AC(═O)R^A, —NR^AC(═O)OR^A, —NR^AC(═O)SR^A, —NR^AC(═O)N(R^A)₂, —NR^AC(═NR^A)R^A, —NR^AC(═NR^A)OR^A, —NR^AC(═NR^A)SR^A, —NR^AC(═NR^A)N(R^A)₂, —NR^AS(═O)R^A, —NR^AS(═O)OR^A, —NR^AS(═O)SR^A, —NR^AS(═O)N(R^A)₂, —NR^AS(═O)₂R^A, —NR^AS(═O)₂OR^A, —NR^AS(═O)₂SR^A, or —NR^AS(═O)₂N(R^A)₂ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R^3a is —Si(R^A)₃, —Si(R^A)₂OR^A, —Si(R^A)(OR^A)₂, —Si(OR^A)₃, —OSi(R^A)₃, —OSi(R^A)₂OR^A, —OSi(R^A)(OR^A)₂, or —OSi(OR^A)₃ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0180] In some embodiments, R^3a is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R^3a is optionally substituted C_3-14 carbocyclyl. In some embodiments, R^D is optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments, R^3a is optionally substituted monocyclic C_3-4 carbocyclyl. In some embodiments, R^3a is optionally substituted cyclopropyl. In some embodiments, R^3a is optionally substituted monocyclic C_5-7 carbocyclyl. In some embodiments, R^3a is saturated carbocyclyl. In some embodiments, R^3a is carbocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the carbocyclic ring system.

[0181] In some embodiments, R^3a is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R^3a is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R^3a is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R³ is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more 0 and/S atoms. In some embodiments, R^3a is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R^3a is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R^3a is saturated heterocyclyl. In some embodiments, R^3a is heterocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the heterocyclic ring system.

[0182] In some embodiments, R^3a is optionally substituted monocyclic aryl. In some embodiments, R^3a is optionally substituted bicyclic aryl. In some embodiments, R^3a is optionally substituted C_6-14 aryl. In some embodiments, R^3a is optionally substituted C_6-10 aryl. In some embodiments, R^3a is optionally substituted phenyl. In some embodiments, R^3a is optionally substituted naphthyl.

[0183] In some embodiments, R^3a is optionally substituted monocyclic heteroaryl. In some embodiments, R^3a is optionally substituted bicyclic heteroaryl. In some embodiments, R^3a is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R³ is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R^3a is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0184] In some embodiments, R^3a is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or —CN. In some embodiments, R^3a is halogen; unsubstituted C_1-6 alkyl; C_1-4 alkyl substituted with one or more halogen and/or one or more unsubstituted, monocyclic, 3- to 7-membered carbocyclyl, as valency permits; unsubstituted C_2-6 alkenyl; unsubstituted, monocyclic, 3- to 7-membered carbocyclyl; or —CN. In some embodiments, R^3a is fluorine, chlorine, bromine, —CH₃, —C₂H₅, —CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃, —CH₂-(unsubstituted cyclopropyl), —CH═CH₂, unsubstituted cyclopropyl, unsubstituted cyclobutyl, or —CN. In some embodiments, R^3a is hydrogen; fluorine; chlorine; bromine; C_1-4 alkyl substituted with one or more fluorine, chlorine, and/or bromine; or —CN. In some embodiments, R^3a is fluorine; chlorine; bromine; C_1-4 alkyl substituted with one or more fluorine, chlorine, and/or bromine; or —CN.

[0185] In some embodiments, R^3a is not unsubstituted alkyl. In some embodiments, R^3a is not unsubstituted ≥C₅ alkyl.

[0186] In some embodiments, R^3b is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, —OR^A, —SR^A, or —N(R^A)₂. In some embodiments, R³⁶ is optionally substituted C_1-10 alkyl, optionally substituted C_2-10 alkenyl, optionally substituted C_2-10 alkynyl, optionally substituted C_1-10 heteroalkyl, optionally substituted C_1-10 heteroalkenyl, or optionally substituted C_1-10 heteroalkynyl. In some embodiments, R^3b is C_1-10 haloalkyl. In some embodiments, R^3b is C_1-4 haloalkyl. In some embodiments, R^3b is C_1-4 fluoroalkyl (e.g., C_1-4 perfluoroalkyl). In some embodiments, R^3b is —CH₂F, —CHF₂, or —CF₃. In some embodiments, R^3b is —CF₃. In some embodiments, R^3b is —CH₂CH₂F, —CH₂CHF₂, or —CH₂CF₃. In some embodiments, R^3b is optionally substituted alkyl substituted with optionally substituted carbocyclyl. In some embodiments, R^3b is unsubstituted C_1-4 alkyl substituted with one optionally substituted C_3-7 monocyclic carbocyclyl. In some embodiments, R^3b is —CH₂-(unsubstituted cyclopropyl). In some embodiments, R^3b is hydrogen, optionally substituted C₁-C₆ alkyl, or halogen. In some embodiments, R^3b is hydrogen, fluorine, —CH₃, —CH₂F, —CHF₂, or —CF₃. In some embodiments, R³⁶ is hydrogen, fluorine, —CH₃, or —CF₃. In some embodiments, R^3b is hydrogen or halogen. In some embodiments, R^3b is hydrogen or fluorine. In some embodiments, R^3b is hydrogen or optionally substituted C₁-C₆ alkyl. In some embodiments, R^3b is hydrogen, unsubstituted C₁-C₆ alkyl, or C_1-6 haloalkyl. In some embodiments, R^3b is —CH₃. In some embodiments, R^3b is —C₂H₅. In some embodiments, R^3b is —C₃H₇, —C₄H₉, or —C₅H₁₁. In some embodiments, R^3b is hydrogen. In some embodiments, R^3b is optionally substituted alkenyl (e.g., optionally substituted C_2-6 alkenyl). In some embodiments, R^3b is unsubstituted vinyl.

[0187] In some embodiments, R^A is halogen. In some embodiments, R^3b is bromine, chlorine, or fluorine. In some embodiments, R^3b is bromine or chlorine. In some embodiments, R^3b is chlorine or fluorine. In some embodiments, R^3b is bromine. In some embodiments, R^3b is chlorine. In some embodiments, R^3b is fluorine.

[0188] In some embodiments, R^3b is —OR^A, —SR^A, or —N(R^A)₂ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R^3b is —OH. In some embodiments, R^3b is —SH. In some embodiments, R^3b is —NH₂. In some embodiments, R^3b is —CN, —SCN, —SSR^A, —N₃, —NO, or —NO₂. In some embodiments, R^3b is —CN. In some embodiments, R^3b is —C(═O)R^A, —C(═O)OR^A, —C(═O)SR^A, or —C(═O)N(R^A)₂ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R^3b is —C(═NR^A)R^A, —C(═NR^A)OR^A, —C(═NR^A)SR^A, or —C(═NR^A)N(R^A)₂ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R^3b is —S(═O)R^A, —S(═O)OR^A, —S(═O)SR^A, —S(═O)N(R^A)₂, —S(═O)₂R^A, —S(═O)₂OR^A, —S(═O)₂SR^A, or —S(═O)₂N(R^A)₂ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R^3b is —OC(═O)R^A, —OC(═O)OR^A, —OC(═O)SR^A, —OC(═O)N(R^A)₂, —OC(═NR^A)R^A, —OC(═NR^A)OR^A, —OC(═NR^A)SR^A, —OC(═NR^A)N(R^A)₂, —OS(═O)R^A, —OS(═O)OR^A, —OS(═O)SR^A, —OS(═O)N(R^A)₂, —OS(═O)₂R^A, —OS(═O)₂OR^A, —OS(═O)₂SR^A, —OS(═O)N(R^A)₂, or —ON(R^A)₂ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R^3b is —SC(═O)R^A, —SC(═O)OR^A, —SC(═O)SR^A, —SC(═O)N(R^A)₂, —SC(═NR^A)R^A, —SC(═NR^A)OR^A. —SC(═NR^A)SR^A, or —SC(═NR^A)N(R^A)₂ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R^3b is —NR^AC(═O)R^A, —NR^AC(═O)OR^A, —NR^AC(═O)SR^A, —NR^AC(═O)N(R^A)₂, —NR^AC(═NR^A)R^A, —NR^AC(═NR^A)OR^A, —NR^AC(═NR^A)SR^A, —NR^AC(═NR^A)N(R^A)₂, —NR^AS(═O)R^A, —NR^AS(═O)OR^A, —NR^AS(═O)SR^A. —NR^AS(═O)N(R^A)₂, —NR^AS(═O)₂R^A, —NR^AS(═O)₂OR^A, —NR^AS(═O)₂SR^A, or —NR^AS(═O)₂N(R^A)₂ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R^3b is —Si(R^A)₃, —Si(R^A)₂OR^A, —Si(R^A)(OR^A)₂, —Si(OR^A)₃, —OSi(R^A)₃, —OSi(R^A)₂OR^A, —OSi(R^A)(OR^A)₂, or —OSi(OR^A)₃ (e.g., wherein R^A is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0189] In some embodiments, R^3b is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R^3b is optionally substituted C_3-14 carbocyclyl. In some embodiments, R^3b is optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments, R^3b is optionally substituted monocyclic C_3-4 carbocyclyl. In some embodiments, R^3b is optionally substituted cyclopropyl. In some embodiments, R^3b is optionally substituted cyclobutyl. In some embodiments, R^3b is optionally substituted monocyclic C_5-7 carbocyclyl. In some embodiments, R^3b is saturated carbocyclyl. In some embodiments, R^3b is carbocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the carbocyclic ring system.

[0190] In some embodiments, R^3b is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R^3b is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R^3b is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R^3b is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R^3b is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R^3b is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R^3b is saturated heterocyclyl. In some embodiments, R^3b is heterocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the heterocyclic ring system.

[0191] In some embodiments, R^3b is optionally substituted monocyclic aryl. In some embodiments, R³ is optionally substituted bicyclic aryl. In some embodiments, R^3b is optionally substituted C_1-4 aryl. In some embodiments, R^3b is optionally substituted C_6-10 aryl. In some embodiments, R^3b is optionally substituted phenyl. In some embodiments, R^3b is optionally substituted naphthyl.

[0192] In some embodiments, R^3b is optionally substituted monocyclic heteroaryl. In some embodiments, R^3b is optionally substituted bicyclic heteroaryl. In some embodiments, R^3b is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R^3b is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R^3b is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0193] In certain embodiments, R^3b is halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or —CN. In certain embodiments, R^3b is halogen; unsubstituted C_1-6 alkyl; C_1-6 alkyl substituted with one or more halogen, as valency permits; unsubstituted, monocyclic, 3- to 7-membered carbocyclyl; or —CN. In certain embodiments, R^3b is fluorine, chlorine, bromine, —CH₃, —C₂H₅, —CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃, —CH₂-(unsubstituted cyclopropyl), —CH═CH₂, unsubstituted cyclopropyl, unsubstituted cyclobutyl, or —CN. In certain embodiments, R^3b is fluorine or —CF₃. In some embodiments, R^3b is hydrogen; fluorine; chlorine; bromine; C_1-4 alkyl substituted with one or more fluorine, chlorine, and/or bromine; or —CN. In some embodiments, R^3b is fluorine; chlorine; bromine; C_1-4 alkyl substituted with one or more fluorine, chlorine, and/or bromine; or —CN.

[0194] In some embodiments, R^3b is not unsubstituted alkyl. In some embodiments, R^3b is not unsubstituted ≥C₅ alkyl.

[0195] In some embodiments, each of R³, and R^3b is independently hydrogen; fluorine; chlorine; bromine; C_1-4 alkyl substituted with one or more fluorine, chlorine, and/or bromine; or —CN.

[0196] In some embodiments, each of R^3a and R^3b is independently hydrogen, fluorine, or C_1-2 alkyl substituted with one or more fluorine.

[0197] In some embodiments, at least one of R^3a and R^3b is fluorine; chlorine; bromine; C_1-4 alkyl substituted with one or more fluorine, chlorine, and/or bromine; or —CN. In some embodiments, at least one of R^3a and R^3b is fluorine or C_1-2 alkyl substituted with one or more fluorine.

[0198] In certain embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In certain embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, 3- to 7-membered carbocyclic ring. In certain embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, 5-membered carbocyclic ring.

[0199] In certain embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, 5-membered, monocyclic, heterocyclic ring. In some embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, 6-membered, monocyclic, heterocyclic ring. In some embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, heterocyclic ring comprising one or more oxygen atoms. In some embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, heterocyclic ring comprising one or more nitrogen atoms. In some embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, heterocyclic ring comprising no nitrogen atoms.

[0200] In certain embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted phenyl ring.

[0201] In certain embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, heteroaryl ring. In certain embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, 5-membered, monocyclic, heteroaryl ring. In certain embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, 6-membered, monocyclic, heteroaryl ring. In some embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, heteroaryl ring comprising one or more oxygen and/or sulfur atoms. In some embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, heteroaryl ring comprising one or more nitrogen atoms. In some embodiments, R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, heteroaryl ring comprising no nitrogen atoms.

[0202] In some embodiments, R^3a and R^3b are not taken together with their intervening atoms to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, or heteroaryl ring, or an optionally substituted phenyl ring. In some embodiments, each of R^3a and R^3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR^A, —SCN, —SR^A, —SSR^A, —N₃, —NO, —N(R^A)₂, —NO₂, —C(═O)R^A, —C(═O)OR^A, —C(═O)SR^A, —C(═O)N(R^A)₂, —C(═NR^A)R^A, —C(═NR^A)OR^A, —C(═NR^A)SR^A, —C(═NR^A)N(R^A)₂, —S(═O)R^A, —S(═O)OR^A, —S(═O)SR^A, —S(═O)N(R^A)₂, —S(═O)₂R^A, —S(═O)₂OR^A, —S(═O)₂SR^A, —S(═O)₂N(R^A)₂, —OC(═O)R^A, —OC(═O)OR^A, —OC(═O)SR^A, —OC(═O)N(R^A)₂, —OC(═NR^A)R^A, —OC(═NR^A)OR^A, —OC(═NR^A)SR^A, —OC(═NR^A)N(R^A)₂, —OS(═O)R^A, —OS(═O)OR^A, —OS(═O)SR^A, —OS(═O)N(R^A)₂, —OS(═O)₂R^A, —OS(═O)₂OR^A, —OS(═O)₂SR^A, —OS(═O)₂N(R^A)₂, —ON(R^A)₂, —SC(═O)R^A, —SC(═O)OR^A, —SC(═O)SR^A, —SC(═O)N(R^A)₂, —SC(═NR^A)R^A, —SC(═NR^A)OR^A, —SC(═NR^A)SR^A, —SC(═NR^A)N(R^A)₂, —NR^AC(═O)R^A, —NR^AC(═O)OR^A, —NR⁴C(═O)SR^A, —NR^AC(═O)N(R^A)₂, —NR^AC(═NR^A)R^A, —NR^AC(═NR^A)OR^A, —NR^AC(═NR^A)SR^A, —NR^AC(═NR^A)N(R^A)₂, —NR^AS(═O)R^A, —NR^AS(═O)OR^A, —NR^AS(═O)SR^A, —NR^AS(═O)N(R^A)₂, —NR^AS(═O)₂R^A, —NR^AS(═O)₂OR^A, —NR^AS(═O)₂SR^A, —NR^AS(═O)₂N(R^A)₂, —Si(R^A)₃, —Si(R^A)₂OR^A, —Si(R^A)(OR^A)₂, —Si(OR^A)₃, —OSi(R^A)₃, —OSi(R^A)₂OR^A, —OSi(R^A)(OR^A)₂, or —OSi(OR^A)₃.

[0203] In some embodiments, at least one instance of R^A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R^A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R^A is independently hydrogen, optionally substituted C_1-10 alkyl, optionally substituted C_2-10 alkenyl, optionally substituted C_2-10 alkynyl, optionally substituted C_3-14 carbocyclyl, or optionally substituted C_6-14 aryl. In some embodiments, at least one instance of R^A is independently hydrogen, optionally substituted C_1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R^A is a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom. In some embodiments, two instances of R^A attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0204] In some embodiments, at least one of R^4a and R^4b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one of R⁴ and R^4b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl. In some embodiments, at least one of R^4a and R^4b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R^4a and R^4b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, at least one of R^4a and R^4b is independently hydrogen, halogen, or optionally substituted C_1-4 alkyl. In some embodiments, at least one of R^4a and R^4b is independently hydrogen, fluorine, or optionally substituted C_1-4 alkyl. In some embodiments, at least one of R^4a and R^4b is independently hydrogen or halogen. In some embodiments, at least one of R^4a and R^4b is independently hydrogen or fluorine. In some embodiments, at least one of R^4a and R^4b is independently hydrogen or optionally substituted C_1-4 alkyl. In some embodiments, at least one of R^4a and R^4b is hydrogen. In some embodiments, at least one of R^4a and R^4b is hydrogen. In some embodiments, at least one of R^4a and R^4b is optionally substituted C_1-4 alkyl. In some embodiments, at least one of R^4a and R^4b is unsubstituted methyl. In some embodiments, at least one of R^4a and R^4b is optionally substituted C_1-4 alkyl. In some embodiments, at least one of R^4a and R^4b is unsubstituted methyl. In some embodiments, at least one of R^4a and R^4b is fluorine.

[0205] In some embodiments, R^4a is hydrogen. In some embodiments, R^4b is hydrogen. In some embodiments, R^4b is halogen. In some embodiments, R^b is fluorine. In some embodiments, each of R^4a and R^4b is hydrogen. In some embodiments, R^4a is hydrogen, and R^4b is fluorine. In some embodiments, R^4a is fluorine, and R^4b is hydrogen.

[0206] In some embodiments, R^4s and R^4b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R^4a and R^4b are taken together with their intervening atom to form an optionally substituted, monocyclic, C_3-14 carbocyclic ring. In some embodiments, R^4a and R^4b are taken together with their intervening atom to form an optionally substituted, monocyclic, C_3-7 carbocyclic ring. In certain embodiments, R^4a and R^4b are taken together with their intervening atom to form an optionally substituted, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring. In some embodiments, R^4s and R^4b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R^4A and R^4B are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R^4a and R^4b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising O and/or S heteroatom(s) as the only heteroatoms in the heterocyclic ring. In some embodiments, R^4a and R^4b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising O and/or N heteroatom(s) as the only heteroatoms in the heterocyclic ring. In some embodiments, R^4a and R^4b are taken together with their intervening atom to form optionally substituted oxetane, optionally substituted tetrahydrofuran, optionally substituted tetrahydropyran, or optionally substituted pyrrolidine.

[0207] In certain embodiments,

In certain embodiments,

[0208] In some embodiments, R^4b and R^5a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring. In some embodiments, R^4b and R^5a are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments, R^4b and R^5a are taken together with their intervening atom to form an optionally substituted, monocyclic, C_3-14 carbocyclic ring. In some embodiments, R^4b and RSS are taken together with their intervening atom to form an optionally substituted, monocyclic, C_3-7 carbocyclic ring. In some embodiments, R^4b and R^5a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R^4b and R^5a are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R^4b and R^5a are taken together with their intervening atom to form an optionally substituted, monocyclic, aryl, or heteroaryl ring. In some embodiments, R^4b and R^5a are taken together with their intervening atom to form an optionally substituted phenyl ring. In some embodiments, Re and R⁵ are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- or 6-membered heteroaryl ring.

[0209] In some embodiments, at least one of R^5a and R^5b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one of R^5a and R^5b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, each of R^5a and R^5b is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, at least one of R^5a and R^5b is independently hydrogen, —CH₃, or —CF₃. In some embodiments, at least one of R^5a and R^5b is hydrogen. In some embodiments, at least one of R^5a and R^5b is independently optionally substituted C_1-10 alkyl, optionally substituted C_2-10 alkenyl, or optionally substituted C_2-10 alkynyl. In some embodiments, at least one of R⁵ and R⁵¹ is independently optionally substituted C_1-10 heteroalkyl, optionally substituted C_1-10 heteroalkenyl, or optionally substituted C_1-10 heteroalkynyl. In some embodiments, at least one of R^5a and R^5b is independently optionally substituted C_1-10 alkyl or optionally substituted C_1-10 heteroalkyl. In some embodiments, at least one of R^5a and R^5b is optionally substituted C_1-4 alkyl. In some embodiments, at least one of R^5a and R^5b is —CH₃. In some embodiments, at least one of R^5a and R^5b is —CF₃. In some embodiments, at least one of R^5a and R^5b is optionally substituted C_1-4 heteroalkyl. In some embodiments, at least one of R^5a and R^5b is optionally substituted C_1-4 heteroalkyl comprising an O atom. In some embodiments, at least one of R^5a and R^5b is optionally substituted C_6-14 aryl. In some embodiments, at least one of R^5a and R^5b is optionally substituted C_6-10 aryl. In some embodiments, at least one of R^5a and R^5b is optionally substituted phenyl. In some embodiments, R^5a and R^5b are —CH₃. In some embodiments, R^5a and R^5b are hydrogen.

[0210] In some embodiments, R^5a and R^5b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring. In some embodiments. R^5a and R^5b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring. In some embodiments, R^5a and R^5b are taken together with their intervening atom to form an optionally substituted, monocyclic, C_3-14 carbocyclic ring. In some embodiments, R^5a and R^5b are taken together with their intervening atom to form an optionally substituted, monocyclic, C_3-7 carbocyclic ring. In some embodiments, R^5a and R^5b are taken together with their intervening atom to form an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring. In some embodiments, R^5a and R^5b are taken together with their intervening atom to form an optionally substituted cyclobutyl ring. In some embodiments, R^5a and R^5b are taken together with their intervening atom to form an unsubstituted, monocyclic, 3- to 7-membered carbocyclic ring. In some embodiments, RSS and R^5b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring. In some embodiments, R^5a and R^5b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising O and/or S heteroatom(s) as the only heteroatoms in the heterocyclic ring. In some embodiments, R^5a and R^5b are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring comprising O and/or N heteroatom(s) as the only heteroatoms in the heterocyclic ring. In some embodiments, R^5a and R^5b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 14-membered heterocyclic ring. In some embodiments, R^5a and R^5b are taken together with their intervening atom to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclic ring. In some embodiments, R^5a and R^5b are taken together with their intervening atom to form an optionally substituted, monocyclic, 5- to 6-membered heterocyclic ring. In some embodiments, R^5a and R^5b are taken together with their intervening atom to form optionally substituted oxetane, optionally substituted tetrahydrofuran, optionally substituted tetrahydropyran, or optionally substituted pyrrolidine.

[0211] In some embodiments, R^5a is optionally substituted alkyl. In some embodiments, R^5a is unsubstituted C_1-4 alkyl. In some embodiments, R^5a is —CH₃. In some embodiments, R^5b is optionally substituted alkyl. In some embodiments, R^5b is unsubstituted C_1-4 alkyl. In some embodiments, R^5b is —CH₃.

[0212] In certain embodiments,

In certain embodiments,

[0213] In certain embodiments, R^3c is protium. In certain embodiments, R^3c is deuterium.

[0214] In some embodiments, X is

In certain embodiments,

In certain embodiments,

In some embodiments, X is —N(R⁶)—. In some embodiments, X is —NH—.

[0215] In some embodiments, R⁶ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R⁶ is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In some embodiments, R⁶ is hydrogen. In some embodiments, R⁶ is optionally substituted C_1-10 alkyl, optionally substituted C_2-10 alkenyl, or C_2-10 alkynyl. In some embodiments, R⁶ is optionally substituted alkyl. In some embodiments, R⁶ is optionally substituted C_1-10 alkyl. In some embodiments, R⁶ is optionally substituted C_1-6 alkyl. In some embodiments, R⁶ is optionally substituted C_1-4 alkyl. In some embodiments, R⁶ is unsubstituted methyl. In some embodiments, R⁶ is benzyl.

[0216] In some embodiments, R⁶ is optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments, R⁶ is optionally substituted C_3-14 carbocyclyl. In some embodiments, R⁶ is optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments. R⁶ is optionally substituted monocyclic C_5-7 carbocyclyl. In some embodiments, R⁶ is saturated carbocyclyl. In some embodiments, R⁶ is carbocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the carbocyclic ring system.

[0217] In some embodiments, R⁶ is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R⁶ is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R⁶ is optionally substituted heterocyclyl comprising one or more O and/or S atoms, but no N atoms. In some embodiments, R⁶ is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R⁶ is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R⁶ is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R⁶ is saturated heterocyclyl. In some embodiments, R⁶ is heterocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the heterocyclic ring system.

[0218] In some embodiments, R⁶ is optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R⁶ is optionally substituted monocyclic aryl. In some embodiments, R⁶ is optionally substituted bicyclic aryl. In some embodiments, R⁶ is optionally substituted C_6-14 aryl. In some embodiments, R⁶ is optionally substituted C_6-10 aryl. In some embodiments, R⁶ is optionally substituted phenyl. In some embodiments, R⁶ is optionally substituted naphthyl.

[0219] In some embodiments, R⁶ is optionally substituted monocyclic heteroaryl. In some embodiments, R⁶ is optionally substituted bicyclic heteroaryl. In some embodiments, R⁶ is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R⁶ is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R⁶ is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, R⁶ is optionally substituted heteroaryl comprising one or more N atoms. In some embodiments, R⁶ is optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrimidinyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, or optionally substituted isothiazolyl. In some embodiments, R⁶ is optionally substituted pyridyl, optionally substituted phenyl, or optionally substituted pyrimidinyl.

[0220] In some embodiments, R⁶ is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0221] In some embodiments, R^6a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R^6a is hydrogen. In some embodiments, R^6a is optionally substituted C_1-10 alkyl, optionally substituted C_2-10 alkenyl, or C_2-10 alkynyl. In some embodiments, R^6a is optionally substituted alkyl. In some embodiments, R^6s is optionally substituted C_1-10 alkyl. In some embodiments, R^6s is optionally substituted C_1-6 alkyl. In some embodiments, R^6a is optionally substituted C_1-4 alkyl. In some embodiments, R^6a is unsubstituted methyl. In some embodiments, R^6a is benzyl.

[0222] In some embodiments, R^6a is optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments, R^6a is optionally substituted C_3-14 carbocyclyl. In some embodiments, R^6a is optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments, R^6a is optionally substituted monocyclic C_5-7 carbocyclyl. In some embodiments, R^6a is saturated carbocyclyl. In some embodiments, R^6a is carbocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the carbocyclic ring system.

[0223] In some embodiments, R^6a is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R⁶¹ is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R^6a is optionally substituted heterocyclyl comprising one or more O and/or S atoms, but no N atoms. In some embodiments, R^6a is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R^6a is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R^6a is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R^6a is saturated heterocyclyl. In some embodiments, R^6a is heterocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the heterocyclic ring system.

[0224] In some embodiments, R^6a is optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R^6a is optionally substituted monocyclic aryl. In some embodiments, R^6a is optionally substituted bicyclic aryl. In some embodiments, R^6a is optionally substituted C_6-14 aryl. In some embodiments, R^6a is optionally substituted C_6-10 aryl. In some embodiments, R^6a is optionally substituted phenyl. In some embodiments, R^6a is optionally substituted naphthyl.

[0225] In some embodiments, R^6a is optionally substituted monocyclic heteroaryl. In some embodiments, R^6a is optionally substituted bicyclic heteroaryl. In some embodiments, R^6a is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R^6a is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R^6a is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, R^6a is optionally substituted heteroaryl comprising one or more N atoms. In some embodiments, R^6a is optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrimidinyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, or optionally substituted isothiazolyl. In some embodiments, R^6a is optionally substituted pyridyl, optionally substituted phenyl, or optionally substituted pyrimidinyl.

[0226] In some embodiments, R^6b is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R^6b is hydrogen. In some embodiments, R^6b is optionally substituted C_1-10 alkyl, optionally substituted C_2-10 alkenyl, or C_2-10 alkynyl. In some embodiments, R^6b is optionally substituted alkyl. In some embodiments, R^6b is optionally substituted C_1-10 alkyl. In some embodiments, R^6b is optionally substituted C_1-6 alkyl. In some embodiments, R^6b is optionally substituted C_1-4 alkyl. In some embodiments, R^6b is unsubstituted methyl. In some embodiments, R^6b is benzyl.

[0227] In some embodiments, R^6b is optionally substituted carbocyclyl or optionally substituted heterocyclyl. In some embodiments, R^6b is optionally substituted C_3-14 carbocyclyl. In some embodiments, R^6b is optionally substituted monocyclic C_3-7 carbocyclyl. In some embodiments. R^6b is optionally substituted monocyclic C_5-7 carbocyclyl. In some embodiments, R^6b is saturated carbocyclyl. In some embodiments, R^6b is carbocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the carbocyclic ring system.

[0228] In some embodiments, R^6b is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R^6b is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R^6b is optionally substituted heterocyclyl comprising one or more O and/or S atoms, but no N atoms. In some embodiments, R^6b is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R^6b is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R^6b is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R^6b is saturated heterocyclyl. In some embodiments, R^6b is heterocyclyl comprising only one unsaturated bond (e.g., C═C bond) in the heterocyclic ring system.

[0229] In some embodiments, R^6b is optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R^6b is optionally substituted monocyclic aryl. In some embodiments, R^6b is optionally substituted bicyclic aryl. In some embodiments, R^6b is optionally substituted C_6-14 aryl. In some embodiments, R^6a is optionally substituted C_6-10 aryl. In some embodiments, R^6b is optionally substituted phenyl. In some embodiments, R^6a is optionally substituted naphthyl.

[0230] In some embodiments, R^6b is optionally substituted monocyclic heteroaryl. In some embodiments, R^6b is optionally substituted bicyclic heteroaryl. In some embodiments, R^6b is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R^6b is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R^6b is optionally substituted 5- to 6-membered monocyclic heteroaryl. In some embodiments, R^6b is optionally substituted heteroaryl comprising one or more N atoms. In some embodiments, R^6b is optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrimidinyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, or optionally substituted isothiazolyl. In some embodiments, R^6b is optionally substituted pyridyl, optionally substituted phenyl, or optionally substituted pyrimidinyl.

[0231] In some embodiments, each of R^6a and R^6b is independently hydrogen, halogen, or optionally substituted alkyl.

[0232] In some embodiments, the molecular weight of the compound is not greater than 500 g/mol. In some embodiments, the molecular weight of the compound is between 200 and 300, between 300 and 400, between 400 and 500, between 500 and 600, between 600 and 700, between 700 and 800, or between 800 and 1000, inclusive, g/mol. In certain embodiments, the compound comprises 1, 2, or 3 hydrogen bond donors. In certain embodiments, the compound comprises 1, 2, or 3 hydrogen bond acceptors. In certain embodiments, the compound comprises 2, 3, 4, or 5 hydrogen bond donors and hydrogen bond acceptors as combined.

[0233] In some embodiments, the compound is of Formula I-1:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0234] In some embodiments, the compound is of Formula I-2:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0235] In some embodiments, the compound is of Formula I-3:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0236] In some embodiments, the compound is of Formula I-4:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0237] In some embodiments, the compound is of any one of the formulae shown in Table 1:

	TABLE 1
	No.	Formula
	101R
	101S
	102R
	102S
	103R
	103S
	104R
	104S
	105R
	105S
	107R
	107S
	108R
	108S
	109R
	109S
	110R
	110S
	111R
	111S
	112R
	112S
	113R
	113S
	114R
	114S
	115R
	115S
	116R
	116S
	117R
	117S
	118R
	118S
	119R
	119S
	120R
	120S
	121R
	121S
	122R
	122S
	123R
	123S
	124R
	124S
	125R
	125S
	126R
	126S
	127R
	127S
	128R
	128S
	129R
	129S
	130R
	130S
	131R
	131S
	132R
	132S
	133R
	133S
	134R
	134S
	135R
	135S
	136R
	136S
	137R
	137S
	138R
	138S
	139R
	139S
	140R
	140S
	141R
	141S
	142R
	142S
	143R
	143S
	144R
	144S
	145R
	145S
	146R
	146S
	147R
	147S
	148R
	148S
	149R
	149S
	150R
	150S
	151R
	151S
	152R
	152S
	153R
	153S
	154R
	154S
	155R
	155S
	156R
	156S
	157R
	157S
	158R
	158S
	159R
	159S
	160R
	160S
	161R
	161S
	162R
	162S
	163R
	163S
	164R
	164S
	165R
	165S
	166R
	166S
	167R
	167S
	168R
	168S
	169R
	169S
	170R
	170S
	171R
	171S
	172R
	172S
	173R
	173S
	174R
	174S
	175R
	175S
	176R
	176S

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0238] In some embodiments, the compound is any one of the formulae shown in Table 1A:

TABLE 1A
No.	Formula
501R
501S
502R
502S
503R
503S
504R
504S
505R
505S
506R
506S

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0239] In some embodiments, the compound is any one of the formulae shown in in Table 1B:

TABLE 1B
No.	Formula
601R
601S
602R
602S
603R
603S
604R
604S
605R
605S
606R
606S
607R
607S
608R
608S
609R
609S
610R
610S
611R
611S
612R
612S
613R
613S
614R
614S
615R
615S
616RR
616SR
616RS
616SS
617RR
617SR
617RS
617SS
618R
618S
619R
619S
620R
620S
621R
621S
622R
622S
623R
623S
624R
624S
625R
625S
626R
626S
627R
627S
628R
628S
629R
629S
630R
630S
631R
631S
632R
632S
633RR
633SR
633RS
633SS
634R
634S
635R
635S
636R
636S
637R
637S
638R
638S
639R
639S
640R
640S
641R
641S
642R
642S
643R
643S
644R
644S
645R
645S
646R
646S
647R
647S
648R
648S
649R
649S
650R
650S
651R
651S
652R
652S
653R
653S
654RR
654SR
654RS
654SS
655RS
655SS
655RR
655SR
656R
656S
657R
657S

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0240] In some embodiments, the compound is any one of the formulae shown in Table 2:

TABLE 2
No.	Formula
1002R
1002S
1004R
1004S
1006RR
1006SR
1006RS
1006SS
1007R
1007S
1008R
1008S
1009RR
1009SR
1009RS
1009SS
1010R
1010S
1011R
1011S
1012R
1012S
1014R
1014S
1015R
1015S
1016R
1016S
1017R
1017S
1018R
1018S
1019R
1019S
1020R
1020S
1021R
1021S
1022R
1022S
1023R
1023S
1024R
1024S
1025R
1025S
1027R
1027S
1028R
1028S
1031R
1031S
1032R
1032S
1033R
1033S
1034R
1034S
1035R
1035S
1037R
1037S
1038R
1038S
1039R
1039S

[0241] “A compound of the present disclosure” or “a compound provided herein” refers to a compound of Formula I (e.g., a compound shown in Table 1 or 2), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In some embodiments, a compound of the present disclosure is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled compound thereof. In some embodiments, a compound of the present disclosure is a compound of Formula I, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or isotopically labeled compound thereof. In some embodiments, a compound of the present disclosure is a compound of Formula I, or a pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions. Kits, and Administration

[0242] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound provided herein and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises one or more additional pharmaceutical agents.

[0243] Pharmaceutical compositions can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.

[0244] In some embodiments, pharmaceutical compositions are prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0245] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the pharmaceutical composition is to be administered. The pharmaceutical composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0246] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the pharmaceutical composition.

[0247] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0248] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0249] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers. (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

[0250] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

[0251] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0252] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0253] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0254] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0255] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0256] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0257] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0258] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0259] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0260] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0261] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzil alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor® alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0262] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0263] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0264] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, in some embodiments, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0265] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0266] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0267] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0268] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0269] Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

[0270] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0271] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0272] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0273] Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally, the propellant may constitute 50 to 99.9% (w/w) of the pharmaceutical composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the pharmaceutical composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0274] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0275] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0276] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0277] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

[0278] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the pharmaceutical compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

[0279] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the pharmaceutical compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0280] In some embodiments, the compounds and compositions provided herein are administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0281] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. In some embodiments, an effective amount is included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0282] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. In some embodiments, the amount to be administered to, for example, a child or an adolescent is determined by a medical practitioner or person skilled in the art. In some embodiments, the amount to be administered to, for example, a child or an adolescent is lower or the same as that administered to an adult.

[0283] In some embodiments, a compound or composition, as described herein, is administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). In some embodiments, the compounds or compositions are administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in inhibiting the activity and/or production of a GSK3 in a subject, cell, tissue, or biological sample), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject, cell, tissue, or biological sample. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.

[0284] In some embodiments, the compound or composition is administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents. In some embodiments, the one or more additional pharmaceutical agents are useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease. In some embodiments, each additional pharmaceutical agent is administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0285] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti-pyretics, hormones, and prostaglandins. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds or pharmaceutical compositions described herein are administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.

[0286] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs) comprising a compound or pharmaceutical composition provided herein; and instructions for using the compound or pharmaceutical composition provided herein. In some embodiments, the kit comprises a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0287] In certain embodiments, the kit includes a first container comprising a compound or pharmaceutical composition provided herein. In certain embodiments, the kits are useful for treating a disease in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting the activity (e.g., aberrant activity, such as increased activity) and/or production of a GSK3 in a subject, cell, tissue, or biological sample.

[0288] In certain embodiments, a kit provided herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for inhibiting the activity (e.g., aberrant activity, such as increased activity) and/or production of a GSK3 in a subject, cell, or tissue. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[0289] GSK3 remains a therapeutic target of interest for many diseases, however the development of small molecule inhibitors has been hindered by significant safety concerns related to β-catenin activation and the lack of structural information for the GSK3α paralog.

[0290] Originally identified as a protein kinase involved in the regulation of glycogen metabolism, GSK3 is now known to be a multi-functional protein with key roles in diverse biological processes including cell proliferation, differentiation, apoptosis, embryonic development, and insulin response (Cole A R, 2012; Racaud-Sultan C, Vergnolle N, 2021; Henriksen E J and Dokken B B, 2006). In addition, GSK3 is also of considerable interest as a therapeutic target because of its involvement in core pathophysiologies underlying multiple diseases including Alzheimer's Disease (AD), Fragile X Syndrome, diabetes, and several types of cancer (Bhat R V et al., 2004; Beurel et al., 2015; O'Leary O and Nolan Y, 2015; McCoubrey J A et al., 2014).

[0291] GSK3 has been of particular focus in AD because preclinical data demonstrates that modulation of this kinase has beneficial effects on both hallmark pathological processes in AD: hyperphosphorylation of tau protein and production of amyloid-beta peptides (Phiel, C J et al., 2003; Plattner, F et al., 2006; Ly, P et al., 2013). Based on the therapeutic potential of targeting GSK3 in AD, several GSK3 inhibitors have advanced into clinical trials (Georgievska B et al., 2013; del Ser T et al., 2013), but these compounds have had limited clinical success due to lack of efficacy and/or significant safety concerns. Safety concerns around GSK3 stem from evidence demonstrating a key role for this kinase in regulating the Wnt-β-catenin pathway (Behrens J et al., 1998) and multiple reports have demonstrated that long-term inhibition of GSK3 can induce aberrant proliferation and hyperplasia in several tissues in vivo (Meijer et al., 2004; Sato N et al., 2004; Coghlan et al., 2000; Bhat R et al., 2003).

[0292] GSK3 exists as two paralogs, GSK3α and GSK30, which are encoded from separate genes and are thought to have arisen evolutionarily through gene duplication. The GSK3 paralogs are similar in sequence with 95% identity in the ATP binding site (67% amino acid identity overall) and exhibit a high degree of overlap in both tissue expression patterns and in their phosphorylation substrates (Woodgett, J R 1991; Yao H B et al., 2002; Soutar et al., 2010; Kaidanovich-Beilin O, Woodgett J R 2011). Interestingly, recent studies have highlighted distinct functional roles for GSK3α in several biological processes (Beurel et al., 2015). Notably, loss of GSK3β causes embryonic lethality in mice whereas loss of GSK3α results in relatively modest defects (Kim, W Y et al., 2009; Morgansmith, M et al., 2014). In the context of AD, most of the focus has traditionally been on GSK3β (Hooper C et al., 2008). However, in a study using a mouse model that combines amyloid and tau pathologies, Hurtado et al. (2012) reported that knockdown of either GSKα or GSK3β ameliorated tau hyper-phosphorylation, yet only knockdown of GSK3α additionally reduced amyloid pathology. More recently, selective loss or inhibition of GSK3α, but not GSK30, has been shown to rescue deficits in a mouse model of Fragile x (McCamphill P K et al., 2020) and suppress tumorigenesis in models of acute myeloid leukemia (Wang Y et al., 2019). With respect to safety risks, studies have shown that selective reduction or ablation of either GSK3 paralog circumvents β-catenin stabilization (Doble B W et al., 2007) and that selective genetic suppression of GSK3α impairs leukemia progression in mouse models of AML without increasing β-catenin levels (Banerji V et al., 2012).

[0293] The challenge in discovery of selective GSK3 inhibitors is predominantly due to the high degree of homology in the ATP binding site where the primary difference is an Asp to Glu switch located in the hinge region (Wagner F F et al., 2018). This difference is further complicated by the positioning of corresponding amino acid side chains located outside of the ATP binding site and therefore directed away from potential interactions with ATP competitive inhibitors. Previously a series of oxadiazole inhibitors were identified that were able to achieve ˜3-fold GSK3 selectivity for the −α paralog (Lo Monte et al., 2013) and there have also been reports of imide-based (Palomo V et al., 2012) and thioxoimidazolidine kinase inhibitors that exhibit paralog selectivity up to ˜7-fold (Wang Y et al., 2019). Interestingly, a series of aminopyrazole inhibitors with up to 8-fold selectivity were recently reported by Wagner et al., (2018) and their development was based on the crystal structure of a GSK3β D133E mutant thought to mimic key differences between the two paralogs within the ATP binding site. Further results from this study also identified differential hydrogen bonding networks outside of the hinge Asp/Glu switch.

[0294] The compounds and pharmaceutical compositions provided herein may be useful in a provided method. Compounds useful in a provided method and pharmaceutical compositions provided herein may be useful for the inhibition of a GSK3. Without being bound by any particular theory, the compounds useful in a provided method and the pharmaceutical compositions provided herein being useful as described herein may be at least in part due to their inhibition of the activity and/or production of a GSK3. Compared to known GSK3 inhibitors, the compounds useful in a provided method and the pharmaceutical compositions provided herein may increase the potency, efficacy, and/or selectivity in inhibiting the activity and/or production of a GSK3 in a subject, cell, or tissue. Compared to known GSK3 inhibitors, the compounds useful in a provided method and the pharmaceutical compositions provided herein may increase bioavailability, safety, and/or therapeutic window, reduce toxicity and/or resistance, and/or increase subject compliance, in a subject. In certain embodiments, the compounds useful in a provided method are selective GSK3 inhibitors (e.g., GSK3 inhibitors that selectively inhibit a GSK3 over one or more other kinases). In certain embodiments, the compounds useful in a provided method are selective GSK3α inhibitors (e.g., GSK3α inhibitors that selectively inhibit GSK3α over GSK3β and optionally one or more other kinases). In certain embodiments, the compounds useful in a provided method are selective GSK3β inhibitors (e.g., GSK3β inhibitors that selectively inhibit GSK3β over GSK3α and optionally one or more other kinases).

[0295] In some embodiments, the GSK3 is glycogen synthase kinase 3 α (GSK3α). In some embodiments, the compound provided herein is more selective for inhibiting the activity and/or production of GSK3α than glycogen synthase kinase 3 β (GSK3β) in an in vitro assay. In some embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is determined by the relative K_d values for GSK3α and GSKβ. In certain embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is determined by the quotient of the IC₅₀ value of the compound in inhibiting GSK3β over the IC₅₀ value of the compound in inhibiting GSK3α. In certain embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is at least 1.1, at least 1.3, at least 1.5, at least 1.7, at least 2, at least 3, at least 4, at least 6, at least 8, at least 10, at least 12, at least 15, at least 17, at least 20, at least 30, at least 50, at least 100, at least 1,000, or at least 10,000. In certain embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is at least 3. In certain embodiments, the compound provided herein is at least three times more selective for inhibiting the activity and/or production of GSK3α than GSK3β in an in vitro assay. In certain embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is at least 8. In certain embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is at least 10. In certain embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is at least 12. In certain embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is at least 15. In certain embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is at least 17. In certain embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is at least 20. In certain embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is at least 30. In certain embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is at least 50. In certain embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is at least 100. In certain embodiments, the selectivity of the compound provided herein for GSK3α over GSK3β is between 10 and 1,000, inclusive.

[0296] In some embodiments, the GSK3 is glycogen synthase kinase 3 β (GSK3β). In some embodiments, the compound provided herein is more selective for inhibiting the activity and/or production of GSK3β than glycogen synthase kinase 3 α (GSK3α) in an in vitro assay. In some embodiments, the selectivity of the compound provided herein for GSK3β over GSK3α is determined by the relative K_d values for GSK3β and GSKα. In certain embodiments, the selectivity of the compound provided herein for GSK3β over GSK3α is determined by the quotient of the IC₅₀ value of the compound in inhibiting GSK3α over the IC₅₀ value of the compound in inhibiting GSK3β. In certain embodiments, the selectivity of the compound provided herein for GSK3β over GSK3α is at least 1.1, at least 1.3, at least 1.5, at least 1.7, at least 2, at least 3, at least 4, at least 6, at least 8, at least 10, at least 12, at least 15, at least 17, at least 20, at least 30, at least 50, at least 100, at least 1,000, or at least 10,000. In certain embodiments, the selectivity of the compound provided herein for GSK3β over GSK3α is at least 3. In certain embodiments, the compound provided herein is at least three times more selective for inhibiting the activity and/or production of GSK3β than GSK3α in an in vitro assay. In certain embodiments, the selectivity of the compound provided herein for GSK3β over GSK3α is at least 8. In certain embodiments, the selectivity of the compound provided herein for GSK30 over GSK3α is at least 10. In certain embodiments, the selectivity of the compound provided herein for GSK3β over GSK3α is at least 12. In certain embodiments, the selectivity of the compound provided herein for GSK3β over GSK3α is at least 15. In certain embodiments, the selectivity of the compound provided herein for GSK3β over GSK3α is at least 17. In certain embodiments, the selectivity of the compound provided herein for GSK3D over GSK3α is at least 20. In certain embodiments, the selectivity of the compound provided herein for GSK3β over GSK3α is at least 30. In certain embodiments, the selectivity of the compound provided herein for GSK3β over GSK3α is at least 50. In certain embodiments, the selectivity of the compound provided herein for GSK3β over GSK3α is at least 100. In certain embodiments, the selectivity of the compound provided herein for GSK3β over GSK3α is between 10 and 1,000, inclusive.

[0297] In another aspect, provided herein is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of: a compound useful in a provided method or a pharmaceutical composition provided herein. In another aspect, provided herein is a use a compound useful in a provided method or pharmaceutical composition provided herein for the manufacture of a medicament for treating a disease in a subject in need thereof. In another aspect, provided herein is a compound useful in a provided method or pharmaceutical composition provided herein for use in treating a disease in a subject in need thereof.

[0298] In another aspect, provided herein is a method of preventing a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of; a compound useful in a provided method or a pharmaceutical composition provided herein. In another aspect, provided herein is a use of a compound useful in a provided method or pharmaceutical composition provided herein for the manufacture of a medicament for preventing a disease in a subject in need thereof. In another aspect, provided herein is a compound useful in a provided method or pharmaceutical composition provided herein for use in preventing a disease in a subject in need thereof.

[0299] In some embodiments the effective amount is further effective in inhibiting the activity and/or production of a GSK3. In some embodiments, the effective amount is further effective in inhibiting the aberrantly high activity and/or production of the GSK3. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a GSK3 in a subject, cell, tissue, or biological sample. In certain embodiments, the effective amount is an amount effective for inhibiting the production of a GSK3 in a subject, cell, tissue, or biological sample.

[0300] In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a GSK3 by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a GSK3 by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a GSK3 by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0301] In some embodiments, the term refers to a reduction of the level of production, e.g., GSK3 protein production, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of production. In some embodiments, the term refers to a reduction of the level of production, e.g., GSK3 protein production, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of production.

[0302] In some embodiments, the disease is associated with aberrantly high activity and/or production of a GSK3. In some embodiments, the disease is associated with aberrantly high activity and/or production of catenin beta-1. In some embodiments, the disease is associated with a mutation and/or overexpression of the CTNNB1 gene. In some embodiments, the disease is a central nervous system disease. In some embodiments, the disease is a brain disease. In some embodiments, the disease is Edwards syndrome, gliosis, hyperekplexia, Meckel syndrome, myoclonic epilepsy myopathy sensory ataxia, narcolepsy, prion diseases, serotonin syndrome, or spinal cord disease. In some embodiments, the disease is a mental or behavioral disease. In some embodiments, the disease is CTNNB1 syndrome. In some embodiments, the disease is fragile X syndrome. In some embodiments, the disease is autism. In some embodiments, the disease is schizophrenia. In some embodiments, the disease is bipolar disorder. In some embodiments, the disease is attention deficit hyperactivity disorder. In some embodiments, the disease is a neurological disease. In some embodiments, the disease is seizure. In some embodiments, the disease is Alzheimer's disease. In some embodiments, the disease is Huntington's disease. In some embodiments, the disease is Parkinson's disease. In some embodiments, the disease is amyotrophic lateral sclerosis. In some embodiments, the disease is a cancer. In some embodiments, the disease is a hematological malignancy. In some embodiments, the disease is leukemia. In some embodiments, the disease is acute myeloid leukemia. In some embodiments, the disease is acute lymphoblastic leukemia. In some embodiments, the disease is colon cancer. In some embodiments, the disease is pancreatic cancer. In some embodiments, the disease is a metabolic disease. In some embodiments, the disease is diabetes. In some embodiments, the disease is Type II diabetes. In some embodiments, the disease is obesity.

[0303] In another aspect, provided herein is a method of inhibiting the aberrantly high activity and/or production of a glycogen synthase kinase 3 (GSK3) in a subject in need thereof, cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of: a compound useful in a provided method or a pharmaceutical composition provided herein.

[0304] In another aspect, provided herein is a method of inhibiting the aberrantly high activity and/or production of a glycogen synthase kinase 3 (GSK3) in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of: a compound useful in a provided method or a pharmaceutical composition provided herein, wherein the cell, tissue, or biological sample is in vitro.

[0305] In certain embodiments, the cell, tissue, or biological sample is in vitro. In certain embodiments, the cell, tissue, or biological sample is in vivo.

[0306] In certain embodiments, the subject is an animal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human aged 18 years and older. In some embodiments, the subject is a human aged<2 years. In some embodiments, the subject is a human aged 2-6 years, inclusive. In some embodiments, the subject is a human aged 6-18 years, inclusive. In some embodiments, the subject is a human aged 18-65 years, inclusive. In some embodiments, the subject is a human aged≥65 years. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In some embodiments, the subject is a research animal.

• • [0307] 1. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula I:

wherein:

• • [0308] R¹ is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • [0309] R² is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • [0310] or R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring;
  • [0311] each of R^3a and R^3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR^A, —SCN, —SR^A, —SSR^A, —N₃, —NO, —N(R^A)₂, —NO₂, —C(═O)R^A, —C(═O)OR^A, —C(═O)SR^A, —C(═O)N(R^A)₂, —C(═NR^A)R^A, —C(═NR^A)OR^A, —C(═NR^A)SR^A, —C(═NR^A)N(R^A)₂, —S(═O)R^A, —S(═O)OR^A, —S(═O)SR^A, —S(═O)N(R^A, —S(═O)₂R^A, —S(═O)₂OR^A, —S(═O)₂SR^A, —S(═O)₂N(R^A)₂, —OC(═O)R^A, —OC(═O)OR^A, —OC(═O)SR^A, —OC(═O)N(R^A)₂, —OC(═NR^A)R^A, —OC(═NR^A)OR^A, —OC(═NR^A)SR^A, —OC(═NR^A)N(R^A)₂, —OS(═O)R^A, —OS(═O)OR^A, —OS(═O)SR^A, —OS(═O)N(R^A)₂, —OS(═O)₂R^A, —OS(═O)OR^A, —OS(═O)₂SR^A, —OS(═O)₂N(R^A)₂, —ON(R^A), —SC(═O)R^A, —SC(═O)OR^A, —SC(═O)SR^A, —SC(═O)N(R^A)₂, —SC(═NR^A)R^A, —SC(═NR^A)OR^A, —SC(═NR^A)SR^A, —SC(═NR^A)N(R^A)₂, —NR^AC(═O)R^A, —NR^AC(═O)OR^A, —NR^AC(═O)SR^A, —NR^AC(═O)N(R^A)₂, —NR^AC(═NR^A)R^A, —NR^AC(═NR^A)OR^A, —NR^AC(═NR^A)SR^A, —NR^AC(═NR^A)N(R^A)₂, —NR^AS(═O)R^A, —NR^AS(═O)OR^A, —NR^AS(═O)SR^A, —NR^AS(═O)N(R^A)₂, —NR^AS(═O)₂R^A, —NR^AS(═O)₂OR^A, —NR^AS(═O)₂SR^A, —NR^AS(═O)₂N(R^A)₂, —Si(R^A)₃, —Si(R^A)₂OR^A, —Si(R^A)(OR^A)₂, —Si(OR^A)₃, —OSi(R^A)₃, —OSi(R^A)₂OR^A, —OSi(R^A)(OR^A)₂, or —OSi(OR^A)₃;
  • [0312] or R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, carbocyclic, heterocyclic, or heteroaryl ring, or an optionally substituted phenyl ring;
  • [0313] each instance of R^A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R^A attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.
  • [0314] R^3c is hydrogen;
  • [0315] X is

• •  or —N(R⁶)—;
  • [0316] each of R^4a, R^4b, R^5a, R^5b, R^6a, and R^6b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • [0317] or R^4a and R^4b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring;
  • [0318] or R^4b and R^5a are taken together with their intervening atoms to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring;
  • [0319] or R^5a and R^5b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring;
  • [0320] or R^5b and R^6a are taken together with their intervening atoms to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring;
  • [0321] or R^6a and R^6b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; and
  • [0322] R⁶ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
  • [0323] 2. The compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein

• • [0324] 3. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R¹ is optionally substituted aryl.
  • [0325] 4. The compound of embodiment 3, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R¹ is optionally substituted phenyl.
  • [0326] 5. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R¹ is

• •  wherein:
    • [0327] (i) each instance of R⁷ is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR^D, —SCN, —SR^D, —SSR^D, —N₃, —NO, —N(R^D)₂, —NO₂, —C(═O)R^D, —C(═O)OR^D, —C(═O)SR^D, —C(═O)N(R^D)₂, —C(═NR^D)R^D, —C(═NR^D)OR^D, —C(═NR^D)SR^D, —C(═NR^D)N(R^D)₂, —S(═O)R^D, —S(═O)OR^D, —S(═O)SR^D, —S(═O)N(R^D)₂, —S(═O)₂R^D, —S(═O)₂ORD, —S(═O)₂SR^D, —S(═O)₂N(R^D)₂, —S(═O)(═NR^D)R^D, —S(═O)(═NR^D)ORD, —S(═O)(═NR^D)SR^D, —S(═O)(═NR^D)N(R^D)₂, —OC(═O)R^D, —OC(═O)OR^D, —OC(═O)SR^D, —OC(═O)N(R^D)₂, —OC(═NR^D)R^D, —OC(═NR^D)OR^D, —OC(═NR^D)SR^D, —OC(═NR^D)N(R^D)₂, —OS(═O)R^D, —OS(═O)OR^D, —OS(═O)SR^D, —OS(═O)N(R^D)₂, —OS(═O)₂R^D, —OS(═O)₂OR^D, —OS(═O)₂SR^D, —OS(═O)₂N(R^D)₂, —OS(═O)(═NR^D)R^D, —OS(═O)(═NR^D)OR^D, —OS(═O)(═NR^D)SR^D, —OS(═O)(═NR^D)N(R^D)₂, —ON(R^D)₂, —SC(═O)R^D, —SC(═O)OR^D, —SC(═O)SR^D, —SC(═O)N(R^D)₂, —SC(═NR^D)R^D, —SC(═NR^D)OR^D, —SC(═NR^D)SR^D, —SC(═NR^D)N(R^D)₂, —NR^DC(═O)R^D, —NR^DC(═O)OR^D, —NR^DC(═O)SR^D, —NR^DC(═O)N(R^D)₂, —NR^DC(═NR^D)R^D, —NR^DC(═NR^D)OR^D, —NR^DC(═NR^D)SRD, —NR^DC(═NR^D)N(R^D)₂, —NR^DS(═O)R^D, —NR^DS(═O)OR^D, —NR^DS(═O)SR^D, —NR^DS(═O)N(R^D)₂, —NRDS(═O)₂R^D, —NR^DS(═O)₂OR^D, —NRDS(═O)₂SR^D, —NR^DS(═O)₂N(R^D)₂, —NR^DS(═O)(═NR^D)R^D, —NR^DS(═O)(═NR^D)OR^D, —NR^DS(═O)(═NR^D)NR^DSR^D, —NR^DS(O)(═NR^D)N(R^D)₂, —Si(R^D)₃, —Si(R^D)₂OR^D, —Si(R^D)(OR^D), —Si(OR^D)₃, —OSi(R^D)₃, —OSi(R^D)₂OR^D, —OSi(R^D)(OR^D)₂, or —OSi(OR^D)₃; or
    • [0328] (ii) two instances of R⁷ on two adjacent carbon atoms are taken together with the two adjacent carbon atoms to form an optionally substituted, monocyclic, aryl, heteroaryl, carbocyclic, or heterocyclic ring, and the remaining instances of R⁷, if present, are as defined in (i);
    • [0329] each instance of R^D is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R^D attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring, and
    • [0330] n2 is 0, 1, 2, 3, 4, or 5.
  • [0331] 6. The compound of embodiment 5, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula I-1:

• • [0332] 7. The compound of embodiment 5, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula I-2:

• • [0333] 8. The compound of any one of embodiments 5-7, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein n2 is 0.
  • [0334] 9. The compound of any one of embodiments 5-7, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R¹ is

• • [0335] 10. The compound of embodiment 5, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula I-3:

• • [0336] 11. The compound of embodiment 5, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of Formula I-4:

• • [0337] 12. The compound of any one of embodiments 5-7 and 9-11, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein n2 is 1.
  • [0338] 13. The compound of any one of embodiments 5-7 and 9-12, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is optionally substituted alkyl.
  • [0339] 14. The compound of any one of embodiments 5-7 and 9-13, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is unsubstituted C_1-6 alkyl or C_1-6 alkyl substituted with one or more halogen, as valency permits.
  • [0340] 15. The compound of any one of embodiments 5-7 and 9-14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is optionally substituted carbocyclyl.
  • [0341] 16. The compound of any one of embodiments 5-7 and 9-15, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is optionally substituted monocyclic C_3-7 carbocyclyl.
  • [0342] 17. The compound of any one of embodiments 5-7 and 9-16, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is optionally substituted heteroaryl.
  • [0343] 18. The compound of any one of embodiments 5-7 and 9-17, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is optionally substituted heteroaryl comprising one or more nitrogen atoms in the heteroaryl ring system, as valency permits.
  • [0344] 19. The compound of any one of embodiments 5-7 and 9-18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is optionally substituted, 5- or 6-membered, monocyclic heteroaryl.
  • [0345] 20. The compound of any one of embodiments 5-7 and 9-19, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyrazolyl, or optionally substituted imidazolyl.
  • [0346] 20A. The compound of any one of embodiments 5-7 and 9-20, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is optionally substituted pyridinyl.
  • [0347] 20B. The compound of any one of embodiments 5-7 and 9-20, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is optionally substituted 4-pyridinyl.
  • [0348] 21. The compound of any one of embodiments 5-7 and 9-20B, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is optionally substituted, 5- or 6-membered, monocyclic heteroaryl fused to an optionally substituted, monocyclic, carbocyclic, heterocyclic, aryl, or heteroaryl ring.
  • [0349] 22. The compound of any one of embodiments 5-7 and 9-21, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is optionally substituted, 5- or 6-membered, monocyclic heteroaryl fused to an optionally substituted, 4- to 7-membered, monocyclic carbocyclic ring.
  • [0350] 23. The compound of any one of embodiments 5-7 and 9-22, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is —S(optionally substituted alkyl), —S(═O)(═NH)(optionally substituted alkyl), —S(═O)(═N(unsubstituted C_1-6 alkyl))(optionally substituted alkyl), —S(═O)₂(optionally substituted alkyl), or —OH.
  • [0351] 24. The compound of any one of embodiments 5-7 and 9-23, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R⁷ is —CH(CH₃)₂, —CF₃, unsubstituted cyclobutyl, —SCH₃, —SCF₃, —S(═O)(═NH)(CH₃), —S(═O)(═NCH₃)(CH₃), —S(═O)₂CH₃, —S(═O)₂CF₃, or —OH.
  • [0352] 25. The compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R² is optionally substituted alkyl.
  • [0353] 26. The compound of embodiment 25, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R² is unsubstituted C_1-4 alkyl or C_1-4 alkyl substituted with one or more fluorine, as valency permits.
  • [0354] 27. The compound of embodiment 25, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R² is —CH₃.
  • [0355] 28. The compound of embodiment 25, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R² is —C₂H₅.
  • [0356] 29. The compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring.
  • [0357] 30. The compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R¹ and R² are taken together with their intervening atom to form an optionally substituted, monocyclic, heterocyclic ring, which is optionally fused to an optionally substituted, aryl, heteroaryl, carbocyclic, or heterocyclic ring and/or optionally forms a spiro linkage with an optionally substituted, carbocyclic or heterocyclic ring.
  • [0358] 31. The compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R¹ and R² are taken together with their intervening atom to form an optionally substituted, 5-membered, monocyclic, heterocyclic ring, which is fused to an optionally substituted phenyl ring.
  • [0359] 32. The compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R¹ and R² are taken together with their intervening atom to form

• •  wherein
    • [0360] (i) each instance of R⁷ is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR^D, —SCN, —SR^D, —SSR^D, —N₃, —NO, —N(R^D)₂, —NO₂, —C(═O)R^D, —C(═O)OR^D, —C(═O)SR^D, —C(═O)N(R^D)₂, —C(═NR^D)R^D, —C(═NR^D)OR^D, —C(═NR^D)SR^D, —C(═NR^D)N(R^D)₂, —S(═O)R^D, —S(═O)OR^D, —S(═O)SR^D, —S(═O)N(R^D)₂, —S(═O)₂R^D, —S(═O)₂OR^D, —S(═O)₂SR^D, —S(═O)₂N(R^D)₂, —S(═O)(═NR^D)R^D, —S(═O)(═NR^D)OR^D, —S(═O)(═NR^D)SR^D, —S(═O)(═NR^D)N(R^D)₂, —OC(═O)R^D, —OC(═O)OR^D, —OC(═O)SR^D, —OC(═O)N(R^D)₂, —OC(═NR^D)R^D, —OC(═NR^D)OR^D, —OC(═NR^D)SR^D, —OC(═NR^D)N(R^D)₂, —OS(═O)R^D, —OS(═O)OR^D, —OS(═O)SR^D, —OS(═O)N(R^D)₂, —OS(═O)₂R^D, —OS(═O)OR^D, —OS(═O)₂SR^D, —OS(═O)₂N(R^D)₂, —OS(═O)(═NR^D)R^D, —OS(═O)(═NR^D)OR^D, —OS(═O)(═NR^D)SR^D, —OS(═O)(═NR^D)N(R^D)₂. —ON(R^D)₂, —SC(═O)R^D, —SC(═O)OR^D, —SC(═O)SR^D, —SC(═O)N(R^D)₂, —SC(═NR^D)R^D, —SC(═NR^D)OR^D, —SC(═NR^D)SR^D, —SC(═NR^D)N(R^D)₂, —NR^DC(═O)R^D, —NR^DC(═O)OR^D, —NR^DC(═O)SR^D, —NR^DC(═O)N(R^D)₂, —NR^DC(═NR^D)R^D, —NR^DC(═NR^D)OR^D, —NR^DC(═NR^D)SR^D, —NR^DC(═NR^D)N(R^D)₂, —NR^DS(═O)R^D, —NR^DS(═O)OR^D, —NR^DS(═O)SR^D, —NR^DS(═O)N(R^D)₂, —NR^DS(═O)₂R^D, —NR^DS(═O)OR^D, —NR^DS(═O)₂SR^D, —NR^DS(═O)₂N(R^D)₂, —NR^DS(═O)(═NR^D)R^D, —NR^DS(═O)(═NR^D)OR^D, —NR^DS(═O)(═NR^D)NR^DSR^D, —NR^DS(═O)(═NR^D)N(R^D)₂, —Si(R^D)₃, —Si(R^D)₂OR^D, —Si(R^D)(OR^D)₂, —Si(OR^D)₃, —OSi(R^D)₃, —OSi(R^D)₂OR^D, —OSi(R^D)(OR^D)₂, or —OSi(OR^D)₃; or
    • [0361] (ii) two instances of R⁷ on two adjacent carbon atoms are taken together with the two adjacent carbon atoms to form an optionally substituted, monocyclic, aryl, heteroaryl, carbocyclic, or heterocyclic ring, and the remaining instances of R⁷, if present, are as defined in (i);
    • [0362] each instance of R^D is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R^D attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring;
    • [0363] n3 is 0, 1, 2, 3, or 4; and
    • [0364] R⁹ is hydrogen, optionally substituted alkyl, or a nitrogen protecting group.
  • [0365] 33. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^3a is hydrogen.
  • [0366] 34. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^3a is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, or —CN.
  • [0367] 35. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R³ is halogen; unsubstituted C_1-6 alkyl; C_1-6 alkyl substituted with one or more halogen and/or one or more unsubstituted, monocyclic, 3- to 7-membered carbocyclyl, as valency permits; unsubstituted C_2-6 alkenyl; unsubstituted, monocyclic, 3- to 7-membered carbocyclyl; or —CN.
  • [0368] 36. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R³ is fluorine, chlorine, bromine, —CH₃, —C₂H₅, —CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃, —CH₂-(unsubstituted cyclopropyl), —CH═CH₂, unsubstituted cyclopropyl, unsubstituted cyclobutyl, or —CN.
  • [0369] 37. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^3a is —CF₃.
  • [0370] 37A. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^3a is —CN.
  • [0371] 38. The compound of any one of embodiments 1-37A, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^3b is hydrogen.
  • [0372] 39. The compound of any one of embodiments 1-37A, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^3b is halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or —CN.
  • [0373] 40. The compound of any one of embodiments 1-37A, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^3b is halogen; unsubstituted C_1-6 alkyl; C_1-6 alkyl substituted with one or more halogen, as valency permits; unsubstituted, monocyclic, 3- to 7-membered carbocyclyl; or —CN.
  • [0374] 41. The compound of any one of embodiments 1-37A, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^3b is fluorine, chlorine, bromine, —CH₃, —C₂H₅, —CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃, —CH₂-(unsubstituted cyclopropyl), —CH═CH₂, unsubstituted cyclopropyl, unsubstituted cyclobutyl, or —CN.
  • [0375] 42. The compound of any one of embodiments 1-37A, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^3b is fluorine or —CF₃.
  • [0376] 43. The compound of any one of embodiments 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one of R^3a and R^3b is fluorine or C_1-2 alkyl substituted with one or more fluorine.
  • [0377] 44. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring.
  • [0378] 45. The compound of embodiment 44, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^3a and R^3b are taken together with their intervening atoms to form an optionally substituted, monocyclic, 3- to 7-membered carbocyclic ring.
  • [0379] 46. The compound of any one of embodiments 1-45, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R^4a and R^4b is independently hydrogen, halogen, or optionally substituted alkyl.
  • [0380] 47. The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^4a is hydrogen.
  • [0381] 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^4b is hydrogen.
  • [0382] 49. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^4b is halogen.
  • [0383] 50. The compound of embodiment 49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^4b is fluorine.
  • [0384] 51. The compound of any one of embodiments 1-45, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^4a and R^4b are taken together with their intervening atom to form an optionally substituted, monocyclic, C_3-7 carbocyclic ring.
  • [0385] 52. The compound of any one of embodiments 1-45, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^4a and R^4b are taken together with their intervening atom to form an optionally substituted, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring.
  • [0386] 53. The compound of any one of embodiments 1-50, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein

• • [0387] 54. The compound of any one of embodiments 1-50, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein

• • [0388] 55. The compound of any one of embodiments 1-54, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R^5a and R^5b is independently hydrogen, halogen, or optionally substituted alkyl.
  • [0389] 56. The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^5a is optionally substituted alkyl.
  • [0390] 57. The compound of embodiment 56, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^5a is unsubstituted C_1-4 alkyl.
  • [0391] 58. The compound of embodiment 56, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^5a is —CH₃.
  • [0392] 59. The compound of any one of embodiments 1-58, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^5b is optionally substituted alkyl.
  • [0393] 60. The compound of embodiment 59, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^5b is unsubstituted C_1-4 alkyl.
  • [0394] 61. The compound of embodiment 59, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^5b is —CH₃.
  • [0395] 62. The compound of any one of embodiments 1-54, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^5a and R^5b are taken together with their intervening atom to form an optionally substituted, monocyclic, carbocyclic ring.
  • [0396] 63. The compound of embodiment 62, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^5a and R^5b are taken together with their intervening atom to form an unsubstituted, monocyclic, 3- to 7-membered carbocyclic ring.
  • [0397] 64. The compound of embodiment 62, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^5a and R^5b are taken together with their intervening atom to form an optionally substituted cyclobutyl ring.
  • [0398] 65. The compound of any one of embodiments 1-5, 8, 9, and 12-64, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein X is

• • [0399] 66. The compound of any one of embodiments 1-6, 8-10, and 12-65, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R^6a and R^6b is independently hydrogen, halogen, or optionally substituted alkyl.
  • [0400] 67. The compound of any one of embodiments 1-6, 8-10, and 12-66, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^6a is hydrogen.
  • [0401] 68. The compound of any one of embodiments 1-6, 8-10, and 12-67, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R^6b is hydrogen.
  • [0402] 69. The compound of any one of embodiments 1-5, 8, 9, and 12-64, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein X is —N(R⁶)—.
  • [0403] 70. The compound of any one of embodiments 1-5, 7-9, 11-64, and 69, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R⁶ is hydrogen, optionally substituted alkyl, or a nitrogen protecting group.
  • [0404] 71. The compound of embodiment 70, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R⁶ is hydrogen.
  • [0405] 72. The compound ofany one of embodiments 1-71 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the molecular weight of the compound is not greater than 500 g/mol.
  • [0406] 73. The compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of any one of the formulae: