Small molecule protein synthesis modulators

Abstract

The present disclosure provides compounds, and pharmaceutically acceptable salts thereof, which are useful for modulating protein synthesis. The present disclosure also provides pharmaceutical compositions and kits comprising the compounds, or pharmaceutically acceptable salts thereof, and methods of treating or preventing diseases or disorders (e.g., diseases or disorders associated with BCL- 2, MYC, CCND1, MCL-1, ALK, KRAS-G12D) by administering to a subject in need thereof the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

Description

[0001] SMALL MOLECULE PROTEIN SYNTHESIS MODULATORS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003]

[0001] This application claims the benefit of and priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 63 / 696,620, filed September 19, 2024, and U.S. Provisional Application Number 63 / 774,401, filed March 19, 2025, the contents of each of which are incorporated herewith by reference in their entireties.

[0004] BACKGROUND OF THE INVENTION

[0005]

[0002] Small molecule therapeutics have for decades largely focused on binding to the target protein of interest to inhibit its action, or to induce activation of its function. In the case of inhibition, the net effect of the drug binding to its target is to sequester the target, making it unable to effectively perform its native (or in the case of certain pathologic states, aberrant) function. More recently, small molecule therapeutics have also been developed which alter protein homeostasis. Protein homeostasis refers to the equilibrium between protein synthesis and protein turnover, or degradation. In one instance, the existing pool of a given protein inside the cell may be diminished by accelerating the induction of its degradation. This can be achieved by small molecules that bind to a target and / or an E3 ligase, whereby the net result of binding is the induction of the target’s degradation by native cellular machinery, as is the case for both molecular glues and PROteolysis TArgeting ChimeraS (PROTACS).

[0006] SUMMARY OF THE INVENTION

[0007]

[0003] The present disclosure relates to small molecules that modulate protein synthesis by inhibiting the translation machinery. These compounds demonstrate therapeutic utility, including but not limited to, in their ability to kill cancer cells.

[0008]

[0004] In one aspect, the present disclosure provides compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein:

[0009] R1is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, each instance of Rlais independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two instances of Rlaare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; R3is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0010] R4is hydrogen or optionally substituted alkyl;

[0011] R5aand R5bare each hydrogen, or R5aand R5bare joined together with their intervening atom to form optionally substituted carbocyclyl; each instance of Y is independently -C(RY)2-, -O-, or -N(Rla)-, or two instances of Y are taken together to form -C(RY)=C(RY)- or -C=C-; each instance of RYis independently hydrogen or halogen, or two instances of RYare taken together to form =0; and n is 0, 1, 2, 3, 4, or 5; provided that: if n is 0, then R1is not optionally substituted aryl, optionally substituted heteroaryl, -ORla, or

[0012] - N(Rla)2; if n is 1, 2, 3, 4, or 5, the Y attached to the oxygen atom of the moiety and if R1is -ORlaor -N(Rla)2, then the Y attached to R1is -C(RY)2-

[0013]

[0005] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein. In some embodiments, the pharmaceutical composition comprises an excipient.

[0014]

[0006] In another aspect, the present disclosure provides methods of modulating protein synthesis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a provided compound, or a pharmaceutical composition thereof.

[0015]

[0007] In another aspect, the present disclosure provides methods of decreasing protein synthesis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a provided compound, or a pharmaceutical composition thereof.

[0016]

[0008] In another aspect, the present disclosure provides methods comprising administering to a subject a provided compound, or a pharmaceutical composition thereof.

[0017]

[0009] In another aspect, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a provided compound, or a pharmaceutical composition thereof.

[0018]

[0010] In another aspect, the present disclosure provides kits comprising a provided compound or pharmaceutical composition and instructions for its use.

[0019] [Oil] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments.

[0020] DEFINITIONS

[0021]

[0012] 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, 75thEd., 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, 7thEdition, 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, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0022]

[0013] 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, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be 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 can be 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 present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0023]

[0014] 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.

[0024]

[0015] 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. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C- enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0025]

[0016] 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

[0026]

[0017] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0018] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci^t alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., zz-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertamyl), and hexyl (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include zz-hcptyl (C7), n-octyl (Cs), zz-dodccyl (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 C1-12 alkyl (such as unsubstituted C1-6alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (z'-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted zz-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted .vec-butyl (sec- Bu or s-Bu), unsubstituted isobutyl (z'-Bu)). In certain embodiments, the alkyl group is a substituted C1-12 alkyl (such as substituted C1-6alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0027]

[0019] 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 (“C1-20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C1-10 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1-9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1-7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1-5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“Ci^t haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 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, -CCI3, -CFQ2, -CF2CI, and the like.

[0028]

[0020] 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 (“heteroC1-20 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 (“heteroC1-12 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 (“heteroC1-n 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 (“heteroC1-10 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 (“heteroC1-9 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 (“heteroC1-s 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 (“heteroC1-7 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 (“heteroC1-6alkyl”). 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 (“heteroC1-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“hctcroCi 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 (“heteroC1-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi 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 (“heteroC26 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 heteroC1-12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-12 alkyl.

[0029]

[0021] 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 (“C1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1-12 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C1-11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1-10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1-9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1-8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1-7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1-6alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1-5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“Ci^t alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1-3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1-2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“Ci alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of Ci 4 alkenyl groups include methylidenyl (Ci), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C1-6alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), 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 C1-20 alkenyl. In certain embodiments, the alkenyl group is a substituted C1-20 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g.,

[0030] -CH=CHCH3 or may be in the (E)- or (Z)-configuration.

[0031]

[0022] 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 (“heteroC1-20 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 (“heteroC1-12 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 (“heteroC1-n 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 (“heteroC1-10 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 (“heteroC1-9 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 (“heteroC1-s 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 (“heteroC1-7 alkenyl”). In some embodiments, a heteroalkenyl group has Ito 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1-6alkenyl”). 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 (“heteroC1-5 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 (“hctcroCi 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 (“heteroC1-3 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 (“heteroC1-2 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 (“heteroC1-6alkenyl”). 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 heteroC1-20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC1-20 alkenyl.

[0032]

[0023] 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) (“C1-20 alkynyl”). In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“C1-10 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8 alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“Cm alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“Ci alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of CM alkynyl groups include, without limitation, methylidynyl (Ci), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C1-6 alkenyl groups include the aforementioned C24 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), 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 C1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl.

[0033]

[0024] 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 (“heteroC1-20 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 (“heteroC1-10alkynyl”). 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 (“heteroC1-9 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 (“heteroC1-8 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 (“heteroC1-7 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 (“heteroC1-6alkynyl”). 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 (“heteroC1-5 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“hctcroCi 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 (“heteroC1-3 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 (“heteroC1-2 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 (“heteroC1-6alkynyl”). 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 heteroC1-20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC1-20 alkynyl.

[0034]

[0025] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non- aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3 -13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3 -11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3 -10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3 -7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (Cn), spiro[5.5]undecanyl (Cn), 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 (“bicyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or tiple 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 C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0035]

[0026] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3 -10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). 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 C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0036]

[0027] 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 heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be 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 can be saturated or can contain 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.

[0037]

[0028] 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.

[0038]

[0029] 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, lH-benzo[e][l,4]diazepinyl, 1,4,5,7-tetrahydro- pyrano[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-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0039]

[0030] 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 n electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce -14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Cu 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 Ce-i4 aryl. In certain embodiments, the aryl group is a substituted Ce u aryl.

[0040]

[0031] “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.

[0041]

[0032] 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 n 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 heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be 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. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be 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.

[0042]

[0033] 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.

[0043]

[0034] 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.

[0035] “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.

[0036] The term “unsaturated bond” refers to a double or triple bond.

[0044]

[0037] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0045]

[0038] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., only contains single bonds.

[0046]

[0039] 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.

[0047]

[0040] 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.

[0048]

[0041] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X-, -N(ORcc)Rbb, -SH, -SRaa, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)2, -CO2R", -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, heteroC1-2o alkenyl, heteroC1-2o alkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce i4aryl, 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 Rddgroups; wherein X“ is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; wherein: each instance of Raais, independently, selected from C1-2o alkyl, C1-20 perhaloalkyl, C1-2o alkenyl, C1-2o alkynyl, heteroC1-2o alkyl, heteroC1-2oalkenyl, heteroC1-2oalkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce i4aryl, and 5-14 membered heteroaryl, or two Raagroups 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 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, -OH, -OR311, -N(RCC)2, membered heterocyclyl, Ce i4aryl, and 5-14 membered heteroaryl, or two Rbbgroups 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 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1-2o alkyl, C1-2o perhaloalkyl, C1-2o alkenyl, C1-20 alkynyl, heteroC1-2o alkyl, heteroC1-2o alkenyl, heteroC1-2o alkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce i4aryl, and 5-14 membered heteroaryl, or two Rccgroups 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 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -0N(Rff)2, -N(Rff)2, -N(Rff)3+X“, -N(0Ree)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1-10alkyl, C1-10perhaloalkyl, C1-10alkenyl, C1-10alkynyl, heteroC1-10alkyl, heteroC1-10alkenyl, heteroC1-10alkynyl, C3-io carbocyclyl, 3-10 membered heterocyclyl, Ce-io 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 Rgggroups, or two geminal Rddsubstituents are joined to form =0 or =S; wherein X" is a counterion; each instance of Reeis, independently, selected from C1-10alkyl, C1-10perhaloalkyl, C1-10alkenyl, C1-10alkynyl, hetero C1-10alkyl, heteroC1-10alkenyl, heteroC1-10alkynyl, C3-io carbocyclyl, Ce-io 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 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-10alkyl, C1-10perhaloalkyl, C1-10alkenyl, C1-10alkynyl, heteroC1-10alkyl, heteroC1-10alkenyl, heteroC1-10alkynyl, C3-io carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, or two Rffgroups 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 Rgggroups; each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6alkyl, -ON(C1-6alkyl)2, -N(C1-6alkyl)2, -N(C1-6alkyl)3+X“, -NH(C1-6alkyl)2+X“, -NH2(C1-6alkyl)+X~, -NH3+X“, -NlOC1-6alkyl)(C1-6alkyl), -N(OH)(C1-6alkyl), -NH(OH), -SH, -SC1-6alkyl, -SSlC1-6alkyl), -C(=O)(C1-6alkyl), -CO2H, -CO2(C1-6alkyl), -OC(=O)(C1-6alkyl), -OCO2(C,6alkyl), -C(=O)NH2, -C(=O)N(C1-6alkyl)2, -OC(=O)NH(C1-6alkyl), -NHC(=O)( Cwalkyl), -N(C1-6alkyl)C(=O)( Cwalkyl), -NHCO4C,Galkyl), -NHC(=O)N(C1-6alkyl)2, -NHC(=O)NH(C1-6alkyl), -NHC(=O)NH2, -C(=NH)O(C1-6alkyl), -OC(=NH)(C1-6alkyl), — OC(=NH)OC1-6alkyl, -C(=NH)N(C1-6alkyl)2, -C(=NH)NH(C1-6alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6alkyl)2, -OC(NH)NH(C1-6alkyl), -OC(NH)NH2, -NHC(NH)N(CI_6 alkyl)2, -NHC(=NH)NH2, — NHSO2(C1-6alkyl), -SO2N(CIGalkyl)2, -SO2NH(CI_6 alkyl), -SO2NH2, -SO2C1-6alkyl, -SO2OC1-6alkyl, -OSO2C1-6alkyl, -SOC1-6alkyl, -Si(Ci_6 alkyl)3, -OSi(C1-6alkyl)3-C(=S)N(C1-6alkyl)2, C(=S)NH(C1-6alkyl), C(=S)NH2, -C(=O)S(aCc6 6lkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, -P(=O)(OC1-6alkyl)2, -P(=O)(Ci_6 alkyl)2, -OP(=O)(C1-6alkyl)2, -OP(=O)(OC1-6alkyl)2, C1-10alkyl, C1-10perhaloalkyl, C1-10alkenyl, C1-10alkynyl, heteroC1-10alkyl, heteroC1-10alkenyl, heteroC1-10 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; and each X" is a counterion.

[0049]

[0042] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, - NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2, wherein Raais 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 Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 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 C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)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 C1-10 alkyl, -ORaa, -SR311, -N(Rbb)2, -CN, -SCN, or - NO2, wherein Raais 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 Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0050]

[0043] In certain embodiments, the molecular weight of a carbon atom substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0051]

[0044] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0045] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxy,” 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 -ORaa, -ON(Rbb)2, -OC(=O)SRaa, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OSiCR^s, -OP(RCC)2, -OP(RCC)3+X-, -OP(ORCC)2, -OP(ORCC)3+X-, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, and -OP(=O)(N(Rbb))2, wherein X“, Raa, Rbb, and Rccare as defined herein.

[0052]

[0046] The term “alkoxy” as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

[0053]

[0047] 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 -SR311, - S=SRCC, -SC(=S)SRaa, -SC(=S)ORaa, -SC(=S) N(Rbb)2, -SC(=O)SRaa, -SC(=O)ORaa, -SC(=O)N(Rbb)2, and -SC(=O)Raa, wherein Raaand Rccare as defined herein.

[0054]

[0048] 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.

[0055]

[0049] 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(Rbb), -NHC(=O)Raa, -NHCCTKT -NHC(=O)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, -NHSO2Raa, -NHP(=O)(ORCC)2, and -NHP(=O)(N(Rbb)2)2, wherein Raa. Rbband Rccare as defined herein, and wherein Rbbof the group -NH(Rbb) is not hydrogen.

[0056]

[0050] 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(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -NRbbSO2Raa, -NRbbP(=O)(ORcc)2, and -NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0057]

[0051] 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(Rbb)3and -N(Rbb)3+X“, wherein Rbband X“ are as defined herein.

[0058]

[0052] The term “sulfonyl” refers to a group selected from -SO2N(Rbb)2, -SO2Pa''. and -SO2ORaa, wherein Raaand Rbbare as defined herein.

[0059]

[0053] The term “sulfinyl” refers to the group -S(=O)Raa, wherein K1'1is as defined herein.

[0060]

[0054] The term “acyl” refers to a group having the general formula -C(=O)RX1, -C(=O)ORX1, -C(=O)-O-C(=O)RX1, -C(=O)SRX1, -C(=O)N(RX1)2, -C(=S)RX1, -C(=S)N(RX1)2, and -C(=S)S(RX1), -C(=NRX1)RX1, -C(=NRX1)ORX1, -C(=NRX1)SRX1, and -C(=NRX1)N(RX1)2, wherein RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or diheteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0061]

[0055] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (-C(=O)Raa), carboxylic acids (-CO2H), aldehydes (-CHO), esters (-CC>2Raa, -C(=O)SRaa, - C(=S)SRaa), amides (-C(=O)N(Rbb)2, -C(=O)NRbbSO2Raa, -C(=S)N(Rbb)2), and imines (-C(=NRbb)Raa, - C(=NRbb)ORaa), -C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0062]

[0056] The term “silyl” refers to the group -Si(Raa)3, wherein Raais as defined herein.

[0063]

[0057] The term “boronyl” refers to boranes, boronic acids, boronic esters, borinic acids, and borinic esters, e.g., boronyl groups of the formula -B(Raa)2, -B(ORCC)2, and -BRaa(ORcc), wherein Raaand Rccare as defined herein.

[0064]

[0058] The term “phosphino” refers to the group -P(RCC)2, wherein Rccis as defined herein.

[0065]

[0059] The term “phosphono” refers to the group - (P=O)(ORCC)2, wherein Raaand Rccare as defined herein.

[0066]

[0060] The term “phosphoramido” refers to the group -O(P=O)(N(Rbb)2)2, wherein each Rbbis as defined herein.

[0067]

[0061] The term “oxo” refers to the group =0, and the term “thiooxo” refers to the group =S.

[0062] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOBA -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(ORCC)2, -P(=O)(Raa)2, -P(=O)(N(RCC)2)2, Ci20alkyl, Ci20perhaloalkyl, C1-2o alkenyl, C1-20 alkynyl, hetero C1-20 alkyl, hetero C1-2o alkenyl, hetero C1-2o alkynyl, C3 10 carbocyclyl, 3-14 membered heterocyclyl, Ce -14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom 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 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0068]

[0063] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CO^, -C(=O)N(Rbb)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 C1-10 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 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 C1-6 alkyl or a nitrogen protecting group.

[0069]

[0064] 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, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, C1-10 alkyl (e.g., aralkyl, heteroaralkyl), C1-20 alkenyl, C1-2o alkynyl, hetero C1-20 alkyl, hetero C1-2o alkenyl, hetero C1-2o alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce -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 Rddgroups, and wherein Raa, Rbb, Rccand Rddare 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, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0070]

[0065] 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)Raa) 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-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’ -dithiobenzyloxy acylamino) 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, A-acetyhnethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0071]

[0066] 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)ORaa) 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-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl- [9-( 10,10-dioxo-l 0,10,10,10- tetrahydrothioxanthyl)] methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2- trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, 1,1-dimethyl- 2,2-dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1- methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), 1 -(3 ,5-di-t-butylphenyl)-l -methylethyl carbamate (t- Bumeoc), 2-(2z- and 4'-py ridy l)cthy 1 carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-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-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2- methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2- phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1 -dime thyl-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-(A,A-dimethylcarboxamido)benzyl carbamate, l,l-dimethyl-3-(A,A- 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, l-methyl-l-(3,5- dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1- phenylethyl carbamate, 1 -methyl- l-(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.

[0067] 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)2Raa) 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- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4z,8z- dimethoxynaphthylmethyl)benzenesulfonamide (DNMB S) , benzylsulfonamide , trifluoromethylsulfonamide, and phenacylsulfonamide.

[0072]

[0068] 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, A’-p-tohienesulfonylaminoacyl derivatives, N’- phenylaminothioacyl derivatives, A-bcnzoylphcnylalanyl derivatives, A-acctylmcthioninc derivatives,

[0073] 4.5-diphenyl-3-oxazolin-2-one, A-phthalimidc, A-dithiasuccinimidc (Dts), A-2,3-diphcnylmalcimidc, N-

[0074] 2.5-dimethylpyrrole, N-l ,1 ,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3- dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1- substituted 3,5-dinitro-4-pyridone, A-methylamine, A-allylamine, A-[2- (trimethylsilyl)ethoxy]methylamine (SEM), A-3-acetoxypropylamine, N-(l -isopropyl-4-nitro-2-oxo-3- pyroolin-3-yl)amine, quaternary ammonium salts, A-benzylamine, A-di(4-methoxyphenyl)methylamine, A-5-dibenzosuberylamine, A-triphenylmethylamine (Tr), A-[(4-methoxyphenyl)diphenylmethyl ]amine (MMTr), A-9-phenylfluorenylamine (PhF), A-2,7-dichloro-9-fluorenylmethyleneamine, N- ferrocenylmethylamino (Fem), A-2-picolylamino N ’-oxide, N- 1 , 1 -dimethylthiomethyleneamine, N- benzylideneamine, A-p-methoxybenzylideneamine, A-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, A-(A’,A’-dimethylaminomethylene)amine, A-p-nitrobenzylideneamine, A-salicylideneamine, A-5-chlorosalicylideneamine, A-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, A-cyclohexylideneamine, A-(5,5-dimethyl-3-oxo-l- cyclohexenyl) amine, A-borane derivatives, A-diphenylborinic acid derivatives, A- [phenyl(pentaacylchromium- or tungsten)acyl] amine, A-copper chelate, A-zinc chelate, A-nitroamine, A- nitrosoamine, amine A-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphor amidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3 -nitropyridinesulf enamide (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 A,A’-isopropylidenediamine.

[0069] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0075]

[0070] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, -C(=O)Raa, -CC>2Raa, -C(=O)N(Rbb)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 C1-6 alkyl, -C(=O)Raa, -CChR^, -C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io 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 C1-6 alkyl or an oxygen protecting group.

[0076]

[0071] 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 -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X“, -P(ORCC)2, -P(ORCC)3+X’, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb) 2)2, wherein X“, Raa, Rbb, and Rccare 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, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0077]

[0072] 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 methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4- methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl .S'..S'-dioxidc, l-[(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- ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 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 A-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, 4,4'-dimethoxytrityl (4,4'-dimethoxytriphenylmethyl or DMT), a- 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) Jtrityl Ether (IDTr-OR), 4,4’- Dimethoxy-3"‘-[N-(imidazolylethyl)carbamoyl]trityl Ether (lETr-OR), l,l-bis(4-methoxyphenyl)-T- pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,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, methoxy acetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxy acetate, 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-l-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-(l , 1 ,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(l , 1- dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2- butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl Mphcnylcarbamatc, borate, dimethylphosphinothioyl, alkyl 2,4- dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0078]

[0073] 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]

[0074] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)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 C1-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io 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 C1-6 alkyl or a sulfur protecting group.

[0075] 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 -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -S^R^s, -P(RCC)2, -P(RCC)3+X-, -P(ORCC)2, -P(ORCC)3+X-, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare 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, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0080]

[0076] 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.

[0081]

[0077] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be 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", CP, Br , I"), NO3, CIO4 , OH , H2PO4 . HCOf, 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~, PEp, PFe", AsFe", SbFe", B[3,5-(CF3)2CeH3]4]4 B(C6F5)4~, BPtu , A1(OC(CF3)3)4", and carborane anions (e.g., CBnHi2" or (HCBi iMesBre) ). Exemplary counterions which may be multivalent include CO32-, HPOr2-, POr3-, B4O?2-, SOr2-, 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.

[0082]

[0078] A “leaving group” (EG) is an art-understood term referring to an atomic or molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See e.g., Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., fluoro, chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SRaa, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, - OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Paa. -OP(RCC)2, -OP(RCC)3, - OP(=O)2Raa, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -OP(=O)2N(Rbb)2, and -OP(=O)(NRbb)2, wherein B'1'1. Rbb, and Rccare as defined herein). Additional examples of suitable leaving groups include, but are not limited to, halogen alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, A,O-dimethylhydroxylamino, pixyl, and haloformates. In some embodiments, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), - OS(=O)2(CF2)3CF3(nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some embodiments, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some embodiments, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. In some embodiments, the leaving group is a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0083]

[0079] 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]

[0080] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0085]

[0081] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The present disclosure is not limited in any manner by the above exemplary listing of substituents.

[0086]

[0082] As used herein, 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 the present 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 NACi 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.

[0087]

[0083] 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 the present 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+(C1-4 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.

[0088]

[0084] 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. The compounds described herein may be prepared, e.g., in crystalline form, and may be 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.

[0089]

[0085] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H2O, wherein R is the compound, and x is a number greater than 0. A given compound 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)).

[0086] 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]

[0087] 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”.

[0088] 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. An enantiomer can be 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”.

[0089] The terms “composition” and “formulation” are used interchangeably.

[0091]

[0090] 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. The non-human animal may be a male or female at any stage of development. The non- human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0092]

[0091] 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.

[0093]

[0092] The term “target 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, which is the object to which a compound, particle, and / or composition of the present disclosure is delivered. A target tissue may be an abnormal or unhealthy tissue, which may need to be treated. A target 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. In certain embodiments, the target tissue is the liver. In certain embodiments, the target tissue is the lung. A “non-target tissue” is 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, which is not a target tissue.

[0094]

[0093] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject. Administering a compound described herein encompasses administering the compound, a pharmaceutically acceptable salt thereof, a drug delivery system comprising the compound (e.g., a liposome or lipid nanoparticle (LNP) comprising the compound), or a monovalent form of the compound (e.g., a radical of the compound), which monovalent form may be bonded to a chemical moiety that is cleavable by solvolysis or under physiological conditions (thereby providing a prodrug of the compound), or may be bonded to another agent (e.g., a targeting moiety) via a linker (e.g., a bond or a divalent chemical moiety that is bonded to (z.e., that connects) two separate monovalent chemical moieties). Accordingly, administering a compound described herein encompasses administering the compound, a pharmaceutically acceptable salt thereof, a prodrug, a degrader (e.g., PROTAC), an antibody-drug conjugate (ADC), a liposome or other drug delivery system comprising the compound, and the like. Also contemplated by the disclosure are prodrugs, degraders (e.g., PROTACs), antibodydrug conjugates (ADC), and drug delivery systems comprising a compound provided herein.

[0095]

[0094] 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 may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be 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.

[0096]

[0095] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0097]

[0096] 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).

[0098]

[0097] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0098] In certain embodiments, the compounds of the present disclosure are administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0099]

[0099] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0100]

[0100] 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 modulating protein synthesis (e.g., decreasing protein synthesis). In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a proliferative disease (e.g., cancer (e.g., prostate cancer, pancreatic cancer, lung cancer, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, bladder cancer, biliary cancer, hematopoietic cancer, neuroblastoma)), neurological disease (e.g., cerebellar ataxia, neurodegenerative disease (e.g., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathy (including frontotemporal dementia), Huntington’s disease, Friedreich's ataxia)), or immune disorder (e.g., psoriasis, lupus, rheumatoid arthritis). In certain embodiments, a therapeutically effective amount is an amount sufficient for modulating protein synthesis (e.g., decreasing protein synthesis) and a proliferative disease (e.g., cancer (e.g., prostate cancer, pancreatic cancer, lung cancer, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, bladder cancer, biliary cancer, hematopoietic cancer, neuroblastoma)), neurological disease (e.g., cerebellar ataxia, neurodegenerative disease (e.g., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathy (including frontotemporal dementia), Huntington’s disease, Friedreich's ataxia)), or immune disorder (e.g., psoriasis, lupus, rheumatoid arthritis).

[0101]

[0101] 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 modulating protein synthesis (e.g., decreasing protein synthesis). In certain embodiments, a prophylactically effective amount is an amount sufficient for treating a proliferative disease (e.g., cancer (e.g., prostate cancer, pancreatic cancer, lung cancer, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, bladder cancer, biliary cancer, hematopoietic cancer, neuroblastoma)), neurological disease (e.g., cerebellar ataxia, neurodegenerative disease (e.g., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathy (including frontotemporal dementia), Huntington’s disease, Friedreich's ataxia)), or immune disorder (e.g., psoriasis, lupus, rheumatoid arthritis). In certain embodiments, a prophylactically effective amount is an amount sufficient for modulating protein synthesis (e.g., decreasing protein synthesis) and a proliferative disease (e.g., cancer (e.g., prostate cancer, pancreatic cancer, lung cancer, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, bladder cancer, biliary cancer, hematopoietic cancer, neuroblastoma)), neurological disease (e.g., cerebellar ataxia, neurodegenerative disease (e.g., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathy (including frontotemporal dementia), Huntington’s disease, Friedreich's ataxia)), or immune disorder (e.g., psoriasis, lupus, rheumatoid arthritis).

[0102]

[0102] 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.

[0103]

[0103] The term “about X,” where X is a number or percentage, refers to a number or percentage that is between 99.5% and 100.5%, between 99% and 101%, between 98% and 102%, between 97% and 103%, between 96% and 104%, between 95% and 105%, between 92% and 108%, or between 90% and 110%, inclusive, of X.

[0104]

[0104] 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.

[0105]

[0105] 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.

[0106]

[0106] 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, but are not limited to, 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.

[0107]

[0107] 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.

[0108] Exemplary cancers include, but are not limited to, 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, triple-negative breast cancer (TNBC)); 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., Waldenstrom’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 andenocarcinoma, 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).

[0109]

[0108] The terms “inflammatory disease” and “inflammatory condition” are used interchangeably herein, and refer to a disease or condition caused by, resulting from, or resulting in inflammation. Inflammatory diseases and conditions include those diseases, disorders or conditions that are characterized by signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and / or loss of function (functio laesa, which can be partial or complete, temporary or permanent. Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative 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, without limitation, 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, inflammatory dermatoses, 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, 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, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[0110]

[0109] Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu’s arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter’s arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, Type II diabetes mellitus), a skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, sarcoidosis, spondyloarthopathies, Sjogren’s syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo and Wegener’s granulomatosis. In certain embodiments, the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatitis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease). The compounds may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia. The compounds disclosed herein may also be useful in treating inflammation associated with cancer.

[0111]

[0110] 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, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, , psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic poly angiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[0112]

[0111] 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, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), Huntington’s disease, and Friedreich's ataxia. Examples of neurological diseases include, but are not limited to, 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, but are not limited to, 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; Arnold- 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; bbrain 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; cerebellar ataxia; 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; HTEV-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;

[0113] 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; multiinfarct 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.

[0114]

[0112] Immune disorders, such as auto-immune disorders, include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren’s syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet’s disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amylosis, acute painful shoulder, psoriatic, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), enuresis, eosinophilic disease, gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), and disorders ameliorated by a gastroprokinetic agent (e.g., ileus, postoperative ileus and ileus during sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD); eosinophilic esophagitis, gastroparesis such as diabetic gastroparesis; food intolerances and food allergies and other functional bowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costo-chondritis)).

[0115]

[0113] A “kinase” is a type of enzyme that transfers phosphate groups from high energy donor molecules, such as ATP, to specific substrates, referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases. One of the largest groups of kinases are protein kinases, which act on and modify the activity of specific proteins. Kinases are used extensively to transmit signals and control complex processes in cells. Various other kinases act on small molecules such as lipids, carbohydrates, amino acids, and nucleotides, either for signaling or to prime them for metabolic pathways. Kinases are often named after their substrates. More than 500 different protein kinases have been identified in humans. These exemplary human protein kinases include, but are not limited to, AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1, AKT2, AKT3, ALK, ALK1, ALK2, ALK4, ALK7, AMPKal, AMPKa2, ANKRD3, ANPa, ANPb, ARAF, ARAFps, ARG, AurA, AurApsl, AurAps2, AurB, AurBpsl, AurC, AXL, BARK1, BARK2, BIKE, BLK, BMPR1A, BMPRlApsl, BMPRlAps2, BMPR1B, BMPR2, BMX, BRAF, BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMKla, CaMKlb, CaMKld, CaMKlg, CaMK2a, CaMK2b, CaMK2d, CaMK2g, CaMK4, CaMKKl, CaMKK2, caMLCK, CASK, CCK4, CCRK, CDC2, CDC7, CDK10, CDK11, CDK2, CDK3, CDK4, CDK4ps, CDK5, CDK5ps, CDK6, CDK7, CDK7ps, CDK8, CDK8ps, CDK9, CDKL1, CDKL2, CDKL3, CDKL4, CDKL5, CGDps, CHED, CHK1, CHK2, CHK2psl, CHK2ps2, CKla, CKla2, CKlapsl, CKlaps2, CKlaps3, CKld, CKle, CKlgl, CKlg2, CKlg2ps, CKlg3, CK2al, CK2al-rs, CK2a2, CLIK1, CLIK1L, CLK1, CLK2, CLK2ps, CLK3, CLK3ps, CLK4, COT, CRIK, CRK7, CSK, CTK, CYGD, CYGF, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK1, DMPK2, DRAK1, DRAK2, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, EGFR, EphAl, EphAlO, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphBl, EphB2, EphB3, EphB4, EphB6, Erkl, Erk2, Erk3, Erk3psl, Erk3ps2, Erk3ps3, Erk3ps4, Erk4, Erk5, Erk7, FAK, FER, FERps, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1, FLTlps, FLT3, FLT4, FMS, FRK, Fused, FYN, GAK, GCK, GCN2, GCN22, GPRK4, GPRK5, GPRK6, GPRK6ps, GPRK7, GSK3A, GSK3B, Haspin, HCK, HER2 / ErbB2, HER3 / ErbB3, HER4 / ErbB4, HH498, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HRI, HRIps, HSER, HUNK, ICK, IGF1R, IKKa, IKKb, IKKe, ILK, INSR, IRAKI, IRAK2, IRAK3, IRAK4, IRE1, IRE2, IRR, ITK, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR, KHS1, KHS2, KIS, KIT, KSGCps, KSR1, KSR2, LATS1, LATS2, LCK, LIMK1, LIMK2, LIMK2ps, LKB1, LMR1, LMR2, LMR3, LOK, LRRK1, LRRK2, LTK, LYN, LZK, MAK, MAP2K1, MAP2Klps, MAP2K2, MAP2K2ps, MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7, MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K8, MAPKAPK2, MAPKAPK3, MAPKAPK5, MAPKAPKpsl, MARK1, MARK2, MARK3, MARK4, MARKpsOl, MARKpsO2, MARKps03, MARKpsO4, MARKps05, MARKpsO7, MARKps08, MARKpsO9, MARKpslO, MARKpsll, MARKpsl2, MARKpsl3, MARKpsl5, MARKpsl6, MARKpsl7, MARKpsl8, MARKpsl9, MARKps20, MARKps21, MARKps22, MARKps23, MARKps24, MARKps25, MARKps26, MARKps27, MARKps28, MARKps29, MARKps30, MAST1, MAST2, MAST3, MAST4, MASTL, MELK, MER, MET, MISR2, MLK1, MLK2, MLK3, MLK4, MLKL, MNK1, MNKlps, MNK2, MOK, MOS, MPSK1, MPSKlps, MRCKa, MRCKb, MRCKps, MSK1, MSK12, MSK2, MSK22, MSSK1, MST1, MST2, MST3, MST3ps, MST4, MUSK, MYO3A, MYO3B, MYT1, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK2psl, NEK2ps2, NEK2ps3, NEK3, NEK4, NEK4ps, NEK5, NEK6, NEK7, NEK8, NEK9, NIK, NIM1, NLK, NRBP1, NRBP2, NuaKl, NuaK2, Obscn, Obscn2, 0SR1, p38a, p38b, p38d, p38g, p70S6K, p70S6Kb, p70S6Kpsl, p70S6Kps2, PAK1, PAK2, PAK2ps, PAK3, PAK4, PAK5, PAK6, PASK, PBK, PCTAIRE1, PCTAIRE2, PCTAIRE3, PDGFRa, PDGFRb, PDK1, PEK, PFTAIRE1, PFTAIRE2, PHKgl, PHKglpsl, PHKglps2, PHKglps3, PHKg2, PIK3R4, PIM1, PIM2, PIM3, PINK1, PITSLRE, PKACa, PKACb, PKACg, PKCa, PKCb, PKCd, PKCe, PKCg, PKCh, PKCi, PKCips, PKCt, PKCz, PKD1, PKD2, PKD3, PKG1, PKG2, PKN1, PKN2, PKN3, PKR, PLK1, PLKlpsl, PLKlps2, PLK2, PLK3, PLK4, PRKX, PRKXps, PRKY, PRP4, PRP4ps, PRPK, PSKH1, PSKHlps, PSKH2, PYK2, QIK, QSK, RAFI, RAFlps, RET, RHOK, RIPK1, RIPK2, RIPK3, RNAseL, ROCK1, ROCK2, RON, ROR1, ROR2, ROS, RSK1, RSK12, RSK2, RSK22, RSK3, RSK32, RSK4, RSK42, RSKL1, RSKL2, RYK, RYKps, SAKps, SBK, SCYL1, SCYL2, SCYL2ps, SCYL3, SGK, SgK050ps, SgK069, SgK071, SgK085, SgKllO, SgK196, SGK2, SgK223, SgK269, SgK288, SGK3, SgK307, SgK384ps, SgK396, SgK424, SgK493, SgK494, SgK495, SgK496, SIK(e.g., SIK1, SIK2), skMLCK, SLK, Slob, smMLCK, SNRK, SPEG, SPEG2, SRC, SRM, SRPK1, SRPK2, SRPK2ps, SSTK, STK33, STK33ps, STLK3, STLK5, STLK6, STLK6psl, STLK6-rs, SuRTK106, SYK, TAK1, TAO1, TAO2, TAO3, TBCK, TBK1, TEC, TESK1, TESK2, TGFbRl, TGFbR2, TIE1, TIE2, TLK1, TLKlps, TLK2, TLK2psl, TLK2ps2, TNK1, Trad, Trbl, Trb2, Trb3, Trio, TRKA, TRKB, TRKC, TSSK1, TSSK2, TSSK3, TSSK4, TSSKpsl, TSSKps2, TTBK1, TTBK2, TTK, TTN, TXK, TYK2, TYK22, TYR03, TYRO3ps, ULK1, ULK2, ULK3, ULK4, VACAMKL, VRK1, VRK2, VRK3, VRK3ps, Weel, WeelB, WeelBps, Weelpsl, Weelps2, Wnkl, Wnk2, Wnk3, Wnk4, YANK1, YANK2, YANK3, YES, YESps, YSK1, ZAK, ZAP70, ZC1 / HGK, ZC2 / TNIK, ZC3 / MINK, and ZC4 / NRK.

[0116]

[0114] A “protein,” “peptide,” or “polypeptide” comprises a polymer of amino acid residues linked together by peptide bonds. The term refers to proteins, polypeptides, and peptides of any size, structure, or function. Typically, a protein will be at least three amino acids long. A protein may refer to an individual protein or a collection of proteins. Proteins preferably contain only natural amino acids, although non-natural amino acids (z.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain) and / or amino acid analogs as are known in the art may alternatively be employed. Also, one or more of the amino acids in a protein may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation or functionalization, or other modification. A protein may also be a single molecule or may be a multi- molecular complex. A protein may be a fragment of a naturally occurring protein or peptide. A protein may be naturally occurring, recombinant, synthetic, or any combination of these.

[0117]

[0115] The term “mRNA” or “mRNA molecule” refers to messenger RNA, or the RNA that serves as a template for protein synthesis in a cell. The sequence of a strand of mRNA is based on the sequence of a complementary strand of DNA comprising a sequence coding for the protein to be synthesized.

[0118]

[0116] The term “inhibition,” “inhibiting,” “inhibit,” or “inhibitor” refer to the ability of a compound to reduce, slow, halt or prevent activity of a particular biological process (e.g., protein activity, protein synthesis) in a cell relative to vehicle.

[0119] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0120]

[0117] The counterbalancing aspect of protein homeostasis relates to modulating the rate of protein synthesis. In this manner, one means to address specific protein targets is to block their synthesis by inhibition of the translation machinery of the cell. Protein synthesis takes place in the ribosome, where a molecule of mRNA encoding for the protein of interest is translated into the protein through a sequence of steps including initiation, elongation, and termination. Small molecules can bind either to elongation or initiation accessory factors to disable proper assembly and operation of the translation machinery or bind directly inside the ribosome to impede translation. In this way, cellular levels of a given protein can be downregulated to ameliorate diseases arising from an overabundance of pathologic proteins. This has broad applications in all therapeutic areas, including, but not limited to oncology, immunology and inflammation, neurodegeneration, cardiovascular and metabolic diseases, rare genetic diseases, and infectious diseases.

[0121]

[0118] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, and as such can, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.

[0122] Compounds

[0123]

[0119] In one aspect, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0124] R1is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -ORla, or -N(Rla)2; each instance of Rlais independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two instances of Rlaare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;

[0125] R3is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0126] R4is hydrogen or optionally substituted alkyl;

[0127] R5aand R5bare each hydrogen, or R5aand R5bare joined together with their intervening atom to form optionally substituted carbocyclyl; each instance of Y is independently -C(RY)2-, -O-, or -N(Rla)-, or two instances of Y are taken together to form -C(RY)=C(RY)- or -C=C-; each instance of RYis independently hydrogen or halogen, or two instances of RYare taken together to form =0; and n is 0, 1, 2, 3, 4, or 5; provided that: if n is 0, then R1is not optionally substituted aryl, optionally substituted heteroaryl, -ORla, or - N(Rla)2; if n is 1, 2, 3, 4, or 5, the Y attached to the oxygen atom of the moiety and if R1is -ORlaor -N(Rla)2, then the Y attached to R1is -C(RY)2-

[0128]

[0120] In some embodiments, if n is 0, then R1is not optionally substituted aryl. In some embodiments, if n is 0, then R1is not optionally substituted heteroaryl. In some embodiments, if n is 0, then R1is not optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, if n is 0, then R1is not -ORla. In some embodiments, if n is 0, then R1is not -N(Rla)2-

[0129]

[0121] In some embodiments, n is 1, and the Y attached to the oxygen atom of the moie - C(RY)2- . In some embodiments, n is 2, and the Y attached to the oxygen atom of the moiety — . In some embodiments, n is 3, and the Y attached to the oxygen atom of the ( ) In some embodiments, n is 4, and the Y attached to the oxygen atom of the moiety )2- . In some embodiments, n is 5, and the Y attached to the oxygen atom of the moiety

[0130]

[0122] In some embodiments, if R1is -ORla, then the Y attached to R1is -C(RY)2- In some embodiments, if R1is -N(Rla)2, then the Y attached to R1is -C(RY)2-

[0131] R1, Rla, Y, RY, and n

[0132]

[0123] As generally described herein, R1is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -ORla, or -N(Rla)2; provided that if R1is -ORlaor -N(Rla)2, then the Y attached to R1is -C(RY)2-

[0133]

[0124] In some embodiments, R1is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -ORla, or -N(Rla)2. In some embodiments, R1is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, -ORla, or -N(Rla)2. In some embodiments, R1is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or -N(Rla)2. In some embodiments, R1is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, -ORla, or -N(Rla)2. In some embodiments, R1is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or -N(Rla)2.

[0134]

[0125] In some embodiments, R1is not optionally substituted aryl. In some embodiments, R1is not optionally substituted heteroaryl. In some embodiments, R1is not -ORla. In some embodiments, R1is not -N(Rla)2. In some embodiments, R1is not optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R1is not optionally substituted aryl, optionally substituted heteroaryl, -ORla, or -N(Rla)2.

[0135]

[0126] In some embodiments, R1is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl. In some embodiments, R1is hydrogen, C1 3 alkyl, C2-3 alkenyl, or C2-3 alkynyl, wherein the alkyl, alkenyl, or alkynyl is substituted with 0, 1 , 2, or 3 instances of halogen. In some embodiments, R1is hydrogen, Cm alkyl, C2-3 alkenyl, or C2-3 alkynyl, wherein the alkyl, alkenyl, or alkynyl is substituted with 0, 1, 2, or 3 instances of -F. In some embodiments, R1is: hydrogen,

[0136]

[0127] In some embodiments, R1is hydrogen.

[0137]

[0128] In some embodiments, R1is halogen.

[0138]

[0129] In some embodiments, R1is optionally substituted alkyl. In some embodiments, R1is optionally substituted C1-6 alkyl. In some embodiments, R1is substituted C1-6 alkyl. In some embodiments, R1is unsubstituted C1-6 alkyl. In some embodiments, R1is optionally substituted Cm alkyl. In some embodiments, R1is substituted Cm alkyl. In some embodiments, R1is unsubstituted Cm alkyl. In some embodiments, R1is -CH3 or -CH2CH3.

[0139]

[0130] In some embodiments, R1is Cm alkyl substituted with 0, 1, 2, or 3 instances of halogen. In some embodiments, R1is Cm alkyl substituted with 1, 2, or 3 instances of halogen. In some embodiments, R1is C1-3 alkyl substituted with 1 instance of halogen. In some embodiments, R1is Cm alkyl substituted with 2 instances of halogen. In some embodiments, R1is Cm alkyl substituted with 3 instances of halogen.

[0140]

[0131] In some embodiments, R1is Cm alkyl substituted with 0, 1, 2, or 3 instances of -F. In some embodiments, R1is Cm alkyl substituted with 1, 2, or 3 instances of -F. In some embodiments, R1is Cm alkyl substituted with 1 instance of -F. In some embodiments, R1is Cm alkyl substituted with 2 instances of -F. In some embodiments, R1is Cm alkyl substituted with 3 instances of -F. In some embodiments,

[0141]

[0132] In some embodiments, R1is optionally substituted alkenyl. In some embodiments, R1is optionally substituted C2-6 alkenyl. In some embodiments, R1is substituted C2-6 alkenyl. In some embodiments, R1is unsubstituted C2-6 alkenyl. In some embodiments, R1is optionally substituted C2-3 alkenyl. In some embodiments, R1is substituted C2-3 alkenyl. In some embodiments, R1is unsubstituted C2-3 alkenyl.

[0142]

[0133] In some embodiments, R1is C2-3 alkenyl substituted with 0, 1, 2, or 3 instances of halogen. In some embodiments, R1is C2-3 alkenyl substituted with 1, 2, or 3 instances of halogen. In some embodiments, R1is C2-3 alkenyl substituted with 1 instance of halogen. In some embodiments, R1is C2-3 alkenyl substituted with 2 instances of halogen. In some embodiments, R1is C2-3 alkenyl substituted with 3 instances of halogen.

[0143]

[0134] In some embodiments, R1is C2-3 alkenyl substituted with 0, 1, 2, or 3 instances of -F. In some embodiments, R1is C2-3 alkenyl substituted with 1, 2, or 3 instances of -F. In some embodiments, R1is C2-3 alkenyl substituted with 1 instance of -F. In some embodiments, R1is C2i alkenyl substituted with 2 instances of -F. In some embodiments, R1is C2i alkenyl substituted with 3 instances of -F. In some embodiments,

[0144]

[0135] In some embodiments, R1is optionally substituted alkynyl. In some embodiments, R1is optionally substituted C2-6 alkynyl. In some embodiments, R1is substituted C2-6 alkynyl. In some embodiments, R1is unsubstituted C2-6 alkynyl. In some embodiments, R1is optionally substituted C2-3 alkynyl. In some embodiments, R1is substituted C2-3 alkynyl. In some embodiments, R1is unsubstituted C2-3 alkynyl.

[0145]

[0136] In some embodiments, R1is C2-3 alkynyl substituted with 0, 1, 2, or 3 instances of halogen. In some embodiments, R1is C2-3 alkynyl substituted with 1, 2, or 3 instances of halogen. In some embodiments, R1is C2-3 alkynyl substituted with 1 instance of halogen. In some embodiments, R1is C2-3 alkynyl substituted with 2 instances of halogen. In some embodiments, R1is C2-3 alkynyl substituted with 3 instances of halogen.

[0146]

[0137] In some embodiments, R1is C2-3 alkynyl substituted with 0, 1, 2, or 3 instances of -F. In some embodiments, R1is C2-3 alkynyl substituted with 1, 2, or 3 instances of -F. In some embodiments, R1is C2-3 alkynyl substituted with 1 instance of -F. In some embodiments, R1is C2-3 alkynyl substituted with 2 instances of -F. In some embodiments, R1is C2-3 alkynyl substituted with 3 instances of -F. In some embodiments,

[0147]

[0138] In some embodiments, R1is optionally substituted C3-10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted Ce-io aryl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R1is optionally substituted C3-10 carbocyclyl or optionally substituted 3-10 membered heterocyclyl.

[0148]

[0139] In some embodiments, R1is C3-6 carbocyclyl, 4-6 membered heterocyclyl containing 1 ring N atom or 1 ring O atom, 8-10 membered heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, phenyl, 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms, or 8-10 membered heteroaryl containing 1, 2, or 3 ring N atoms; wherein the carbocyclyl, heterocyclyl, phenyl, or heteroaryl is substituted with 0, 1, or 2 instances of Rlb, as valency permits; wherein each instance of Rlbis independently halogen, optionally substituted CM alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -N(Rlc)2, -CN, -NO2, -C(=O)Rlc, -C(=O)ORlc, -C(=O)N(Rlc)2, -C(=NRlc)N(Rlc)2, or -NRlcC(=O)Rlc, or two instances of Rlbare taken together to form =0, as valency permits, or two instances of Rlbare joined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring; and each instance of Rlcis independently hydrogen, optionally substituted C1-3 alkyl, or optionally substituted 5-6 membered heteroaryl.

[0149]

[0140] In some embodiments, R1is optionally substituted carbocyclyl. In some embodiments, R1is optionally substituted C3-10 carbocyclyl. In some embodiments, R1is optionally substituted C3-6 carbocyclyl.

[0141] In some embodiments, R1is C3-6 carbocyclyl substituted with 0, 1, or 2 instances of Rlb, as valency permits; wherein each instance of Rlbis independently halogen, optionally substituted CM alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -N(Rlc)2, -CN, -NO2, -C(=O)Rlc, - C(=O)OR1C, -C(=O)N(R1C)2, -C(=NR1C)N(R1C)2, or -NRlcC(=O)Rlc, or two instances of Rlbare taken together to form =0, as valency permits, or two instances of Rlbare joined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring; and each instance of Rlcis independently hydrogen, optionally substituted C1-3 alkyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R1is C3-6 carbocyclyl substituted with 0 instances of Rlb. In some embodiments, R1is C3-6 carbocyclyl substituted with 1 instance of Rlb, wherein Rlbis optionally substituted C1-3 alkyl or -NRlcC(=O)Rlc, and each instance of Rlcis independently hydrogen or optionally substituted C1-3 alkyl. In some embodiments, R1is C3-6 carbocyclyl substituted with 2 instances of Rlbjoined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring. In some embodiments, R is , ,

[0150]

[0142] In some embodiments, R1is optionally substituted heterocyclyl. In some embodiments, R1is optionally substituted 3-10 membered heterocyclyl. In some embodiments, R1is optionally substituted 4- 6 membered heterocyclyl. In some embodiments, R1is substituted 4-6 membered heterocyclyl. In some embodiments, R1is unsubstituted 4-6 membered heterocyclyl. In some embodiments, R1is optionally substituted 4-6 membered heterocyclyl containing 1 ring N atom. In some embodiments, R1is substituted 4-6 membered heterocyclyl containing 1 ring N atom. In some embodiments, R1is unsubstituted 4-6 membered heterocyclyl containing 1 ring N atom.

[0151]

[0143] In some embodiments, R1is 4-6 membered heterocyclyl containing 1 ring N atom, 1 ring O atom, or 1 S atom or 8-10 membered heterocyclyl containing 1 or 2 ring heteroatoms selected from O, N, and S, wherein the heterocyclyl is substituted with 0, 1, or 2 instances of Rlb, as valency permits; wherein each instance of Rlbis independently halogen, optionally substituted CM alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -N(Rlc)2, -CN, -NO2, -C(=O)Rlc, -C(=O)ORlc, -C(=O)N(Rlc)2, - C(=NR1C)N(R1C)2, or -NRlcC(=O)Rlc, or two instances of Rlbare taken together to form =0, as valency permits, or two instances of Rlbare joined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring; and each instance of Rlcis independently hydrogen, optionally substituted C1-3 alkyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R1is 4-6 membered heterocyclyl containing 1 ring N atom, 1 ring O atom, or 1 S atom, wherein the heterocyclyl is substituted with 0 instances of Rlb. In some embodiments, R1is 4-6 membered heterocyclyl containing 1 ring N atom, 1 ring O atom, or 1 S atom, wherein the heterocyclyl is substituted with 1 instance of Rlb. In some embodiments, R1is 4-6 membered heterocyclyl containing 1 ring N atom, 1 ring O atom, or 1 S atom, wherein the heterocyclyl is substituted with 2 instances of Rlb. In some embodiments, R1is 8-10 membered heterocyclyl containing 1 or 2 ring heteroatoms selected from O, N, and S, wherein the heterocyclyl is substituted with 0 instances of Rlb. In some embodiments, R1is 8-10 membered heterocyclyl containing 1 or 2 ring heteroatoms selected from O, N, and S, wherein the heterocyclyl is substituted with 1 instance of Rlb. In some embodiments, R1is:

[0152]

[0144] In some embodiments, R1is optionally substituted aryl. In some embodiments, R1is optionally substituted Ce-io aryl. In some embodiments, R1is optionally substituted phenyl. In some embodiments, R1is substituted phenyl. In some embodiments, R1is unsubstituted phenyl.

[0153]

[0145] In some embodiments, R1is phenyl substituted with 0, 1, or 2 instances of Rlb, as valency permits; wherein each instance of Rlbis independently halogen, optionally substituted CM alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -N(Rlc)2, -CN, -NO2, -C(=O)Rlc, -C(=O)ORlc, -C(=O)N(R1C)2, -C(=NR1C)N(R1C)2, or -NRlcC(=O)Rlc, or two instances of Rlbare joined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring; and each instance of Rlcis independently hydrogen, optionally substituted C1-3 alkyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R1is phenyl substituted with 1 instance of Rlb. In some embodiments, R1is phenyl substituted with 1 instance of Rlb, wherein Rlbis halogen, optionally substituted 4-6 membered heterocyclyl, or -ORlc. In some embodiments, R1is phenyl substituted with 1 instance of Rlb, wherein Rlbis halogen, optionally substituted 4-6 membered heterocyclyl containing 1 ring N atom, -ORlc, wherein Rlcis unsubstituted C1-3 alkyl or C1-3 haloalkyl, -NO2, or -C(=NR1C)N(R1C)2- In some embodiments, R1is phenyl substituted with 2 instances of Rlb. In some embodiments, R1is phenyl substituted with 2 instances of Rlbjoined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring. In some embodiments, R1is phenyl substituted with 2 instances of Rlbjoined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring containing 1 ring N atom.

[0146] In some embodiments, R1is:

[0154]

[0147] In some embodiments, R1is optionally substituted heteroaryl. In some embodiments, R1is optionally substituted 5-10 membered heteroaryl. In some embodiments, R1is substituted 5-10 membered heteroaryl. In some embodiments, R1is unsubstituted 5-10 membered heteroaryl. In some embodiments, R1is optionally substituted 5-6 membered heteroaryl. In some embodiments, R1is substituted 5-6 membered heteroaryl. In some embodiments, R1is unsubstituted 5-6 membered heteroaryl. In some embodiments, R1is optionally substituted 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms. In some embodiments, R1is substituted 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms. In some embodiments, R1is unsubstituted 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms. In some embodiments, R1is optionally substituted 8-10 membered heteroaryl. In some embodiments, R1is substituted 8-10 membered heteroaryl. In some embodiments, R1is unsubstituted 8- 10 membered heteroaryl. In some embodiments, R1is optionally substituted 8-10 membered heteroaryl containing 1, 2, or 3 ring N atoms. In some embodiments, R1is substituted 8-10 membered heteroaryl containing 1, 2, or 3 ring N atoms. In some embodiments, R1is unsubstituted 8-10 membered heteroaryl containing 1, 2, or 3 ring N atoms.

[0155]

[0148] In some embodiments, R1is 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms or 8-10 membered heteroaryl containing 1, 2, or 3 ring N atoms, wherein the heteroaryl is substituted with 0, 1, or 2 instances of Rlb, as valency permits; wherein each instance of Rlbis independently halogen, optionally substituted CM alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -N(Rlc)2, -CN, -C(=O)Rlc, -C(=O)ORlc, -C(=O)N(R1C)2, or -NRlcC(=O)Rlc, or two instances of Rlbare joined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring; and each instance of Rlcis independently hydrogen, optionally substituted Cm alkyl, or optionally substituted 5-6 membered heteroaryl.

[0156]

[0149] In some embodiments, R1is 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms, wherein the heteroaryl is substituted with 1 instance of Rlb, as valency permits. In some embodiments, R1is 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms, wherein the heteroaryl is substituted with 1 instance of Rlb, as valency permits, wherein Rlbis halogen, optionally substituted C1-4 alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -N(Rlc)2, -CN, -NO2, -C(=O)Rlc, -C(=O)ORlc, -C(=O)N(R1C)2, -C(=NR1C)N(R1C)2, or -NRlcC(=O)Rlc. In some embodiments, R1is 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms, wherein the heteroaryl is substituted with 1 instance of Rlb, as valency permits, wherein Rlbis optionally substituted C1-4 alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -N(Rlc)2, -CN, -C(=O)ORlc, or -C(=O)N(Rlc)2, wherein each instance of Rlcis independently hydrogen, optionally substituted Cm alkyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R1is 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms, wherein the heteroaryl is substituted with 1 instance of Rlb, as valency permits, wherein Rlbis optionally substituted C1-4 alkyl, optionally substituted 4-6 membered heterocyclyl containing 1 ring N atom, -ORlc, -N(R1C)2, -CN, -C(=O)OR1C, or -C(=O)N(Rlc)2, wherein each instance of Rlcis independently hydrogen, optionally substituted Cm alkyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R1is 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms, wherein the heteroaryl is substituted with 2 instances of Rlb, as valency permits. In some embodiments, R1is 8-10 membered heteroaryl containing 1, 2, or 3 ring N atoms, wherein the heteroaryl is substituted with 0 instances of Rlb.

[0157]

[0150] In some embodiments, R1is:

[0158]

[0159]

[0152] In some embodiments, R1is -ORlaor -N(Rla)2, wherein each instance of Rlais independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted Ce-io aryl, or optionally substituted 5-10 membered heteroaryl.

[0160]

[0153] In some embodiments, R1is -ORlaor -N(Rla)2, wherein each instance of Rlais independently hydrogen, C1-3 alkyl, C1-3 heteroalkyl, C4-6 carbocyclyl, 4-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein each alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1 , 2, or 3 instances of halogen.

[0161]

[0154] In some embodiments, R1is -ORlaor -N(Rla)2, wherein each instance of Rlais independently hydrogen, C1-3 alkyl, C1-3 heteroalkyl, C4-6 carbocyclyl, 4-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein each alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1 , 2, or 3 instances of -F.

[0162]

[0155] In some embodiments, R1is -ORla. In some embodiments, R1is -ORla, wherein each instance of Rlais independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted Ce 10 aryl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R1is -ORla, wherein each instance of Rlais independently hydrogen, C1-3 alkyl, C1-3 heteroalkyl, C4-6 carbocyclyl, 4-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein each alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1 , 2, or 3 instances of halogen. In some embodiments, R1is -ORla, wherein each instance of Rlais independently hydrogen, C1-

[0163] 3 alkyl, C1-3 heteroalkyl, C4-6 carbocyclyl, 4-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein each alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1 , 2, or 3 instances of -F.

[0164]

[0156] In some embodiments, R1is -N(Rla)2- In some embodiments, R1is -NH2.

[0165]

[0159] As generally described herein, each instance of Rlais independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two instances of Rlaare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.

[0166]

[0160] In some embodiments, at least one instance of Rlais hydrogen.

[0167]

[0161] In some embodiments, at least one instance of Rlais optionally substituted alkyl. In some embodiments, at least one instance of Rlais optionally substituted C1-6 alkyl. In some embodiments, at least one instance of Rlais unsubstituted C1-6 alkyl. In some embodiments, at least one instance of Rlais substituted C1-6 alkyl. In some embodiments, at least one instance of Rlais optionally substituted Cm alkyl. In some embodiments, at least one instance of Rlais unsubstituted Cm alkyl. In some embodiments, at least one instance of Rlais substituted Cm alkyl. In some embodiments, at least one instance

[0168]

[0162] In some embodiments, at least one instance of Rlais optionally substituted alkenyl. In some embodiments, at least one instance of Rlais optionally substituted C2-6 alkenyl. In some embodiments, at least one instance of Rlais optionally substituted C2-3 alkenyl.

[0169]

[0163] In some embodiments, at least one instance of Rlais optionally substituted alkynyl. In some embodiments, at least one instance of Rlais optionally substituted C2-6 alkynyl. In some embodiments, at least one instance of Rlais optionally substituted C2-3 alkynyl.

[0170]

[0164] In some embodiments, at least one instance of Rlais optionally substituted carbocyclyl. In some embodiments, at least one instance of Rlais optionally substituted C3-14 carbocyclyl. In some embodiments, at least one instance of Rlais optionally substituted C3-6 carbocyclyl.

[0171]

[0165] In some embodiments, at least one instance of Rlais optionally substituted membered heterocyclyl. In some embodiments, at least one instance of Rlais optionally substituted 3-10 membered heterocyclyl. In some embodiments, at least one instance of Rlais optionally substituted 4-6 membered heterocyclyl.

[0172]

[0166] In some embodiments, at least one instance of Rlais optionally substituted aryl. In some embodiments, at least one instance of Rlais optionally substituted 6-10 membered aryl. In some embodiments, at least one instance of Rlais optionally substituted phenyl. In some embodiments, at least one instance

[0173]

[0167] In some embodiments, at least one instance of Rlais optionally substituted membered heteroaryl. In some embodiments, at least one instance of Rlais optionally substituted 5-6 membered heteroaryl.

[0168] In some embodiments, at least one instance of Rlais a nitrogen protecting group when attached to a nitrogen atom.

[0174]

[0169] In some embodiments, at least one instance of Rlais an oxygen protecting group when attached to an oxygen atom.

[0175]

[0170] In some embodiments, at least two instances of Rlaare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring. In some embodiments, at least two instances of Rlaare joined together with their intervening atom to form an optionally substituted 5-10 membered heterocyclic ring. In some embodiments, at least two instances of Rlaare joined together with their intervening atom to form an optionally substituted 5-14 membered heteroaryl ring.

[0176]

[0171] As generally described herein, each instance of Rlbis independently halogen, optionally substituted C1-4 alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -N(Rlc)2, — CN, -NO2, -C(=O)Rlc, -C(=O)ORlc, -C(=O)N(R1C)2, -C(=NR1C)N(R1C)2, or -NRlcC(=O)Rlc, or two instances of Rlbare taken together to form =0, as valency permits, or two instances of Rlbare joined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring. In some embodiments, each instance of Rlbis independently halogen, optionally substituted C1-3 alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -C(=O)Rlc, -C(=O)ORlc, or -NRlcC(=O)Rlc, or two instances of Rlbare joined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring.

[0177]

[0172] In some embodiments, each instance of Rlbis independently halogen, optionally substituted C1-4 alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -N(Rlc)2, — CN, -C(=O)Rlc, - C(=O)ORlc, -C(=O)N(R1C)2, or -NRlcC(=O)Rlc, or two instances of Rlbare joined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring. In some embodiments, each instance of Rlbis independently halogen, optionally substituted C1-3 alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -C(=O)Rlc, -C(=O)ORlc, or -NRlcC(=O)Rlc, or two instances of Rlbare joined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring.

[0178]

[0173] In some embodiments, at least one instance of Rlbis halogen. In some embodiments, at least one instance of Rlbis -F.

[0179]

[0174] In some embodiments, at least one instance of Rlbis optionally substituted CM alkyl. In some embodiments, at least one instance of Rlbis -CH3, -CH2CH3, -CH2CH(CH3)2, -CH2OCF3, -CH2CN,

[0180]

[0175] In some embodiments, at least one instance of Rlbis optionally substituted 4-6 membered heterocyclyl. In some embodiments, at least one instance of Rlbis

[0176] In some embodiments, at least one instance of Rlbis -ORlc. In some embodiments, at least one instance

[0181]

[0177] In some embodiments, at least one instance of Rlbis -N(Rlc)2- In some embodiments, at least one instance of Rlbis -NHCH3.

[0182]

[0178] In some embodiments, at least one instance of Rlbis -CN.

[0183]

[0179] In some embodiments, at least one instance of Rlbis -NO2.

[0184]

[0180] In some embodiments, at least one instance of Rlbis -C(=O)Rlc. In some embodiments, at least one instance of Rlbis -C(=O)CH3.

[0185]

[0181] In some embodiments, at least one instance of Rlbis -C(=O)ORlc. In some embodiments, at least one instance of Rlbis -C(=O)OCH2CH3.

[0186]

[0182] In some embodiments, at least one instance of Rlbis -C(=O)N(Rlc)2- In some embodiments, at least one instance of Rlbis -C(=O)NH2.

[0187]

[0183] In some embodiments, at least one instance of Rlbis -C(=NRlc)N(Rlc)2- In some embodiments, at least one instance of Rlbis -C(=NH)NH2.

[0188]

[0184] In some embodiments, at least one instance of Rlbis -NRlcC(=O)Rlc. In some embodiments, at least one instance of Rlbis -NHC(=O)CH3.

[0189]

[0185] In some embodiments, two instances of Rlbare taken together to form =0, as valency permits.

[0190]

[0186] In some embodiments, two instances of Rlbare joined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring. In some embodiments, two instances of

[0191] Rlbare joined together with their intervening atoms to form .

[0192]

[0187] As generally described herein, each instance of Rlcis independently hydrogen, optionally substituted C1-3 alkyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, each instance of Rlcis independently hydrogen or optionally substituted C1-3 alkyl.

[0193]

[0188] In some embodiments, at least one instance of Rlcis hydrogen. In some embodiments, at least one instance of Rlcis optionally substituted C1-3 alkyl. In some embodiments, at least one instance of Rlcis substituted C1-3 alkyl. In some embodiments, at least one instance of Rlcis unsubstituted C1-3 alkyl. In some embodiments, at least one instance of Rlcis -CH3, -CH2CH3, or -CF3. In some embodiments, at least one instance of Rlcis optionally substituted 5-6 membered heteroaryl. In some embodiments, at least one instance

[0194]

[0189] As generally described herein, each instance of Y is independently -C(RY)2-, -O-, or -N(Rla)-, or two instances of Y are taken together to form -C(RY)=C(RY)- or -C=C-

[0195]

[0190] In some embodiments, at least one instance of Y is -C(RY)2- or -O-, or two instances of Y are taken together to form -C(RY)=C(RY)- or -C=C- In some embodiments, at least one instance of Y is - C(RY)2- or — O— . In some embodiments, at least one instance of Y is -C(RY)2-, or two instances of Y are taken together to form -C(RY)=C(RY)- or -C=C- In some embodiments, at least one instance of Y is - O- , or two instances of Y are taken together to form -C(RY)=C(RY)- or -C=C- In some embodiments, two instances of Y are taken together to form -C(RY)=C(RY)- or -C=C-

[0196]

[0191] In some embodiments, at least one instance of Y is -C(RY)2- In some embodiments, at least one instance of Y is -CH2-, -CF2-, or -C(=O)-. In some embodiments, at least one instance of Y is

[0197] -CH 2- or -CF2-.

[0198]

[0192] In some embodiments, at least one instance of Y is -O-. In some embodiments, at least one instance of Y is -N(Rla)-. In some embodiments, two instances of Y are taken together to form -C(RY)=C(RY)-. In some embodiments, two instances of Y are taken together to form -C=C-

[0199]

[0193] As generally described herein, each instance of RYis independently hydrogen or halogen, or two instances of RYare taken together to form =0.

[0200]

[0194] In some embodiments, at least one instance of RYis hydrogen. In some embodiments, at least one instance of RYis halogen. In some embodiments, at least one instance of RYis -F. In some embodiments, two instances of RYare taken together to form =0.

[0201]

[0195] As generally described herein, n is 0, 1, 2, 3, 4, or 5, provided that: if n is 0, then R1is not optionally substituted aryl, optionally substituted heteroaryl, -ORla, or -N(Rla)2; and if n is 1, 2, 3, 4, or

[0202] 5, the Y attached to the oxygen atom of the moietyR\vY) '^n°'7 ' is -C(RY)2-

[0203]

[0196] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 0, and R1is not optionally substituted aryl. In some embodiments, n is 0, and R1is not optionally substituted heteroaryl. In some embodiments, n is 0, and R1is not optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, n is

[0204] 0, and R1is not -ORla. In some embodiments, n is 0, and R1is not -N(Rla)2- In some embodiments, n is 0, and R1is not optionally substituted aryl, optionally substituted heteroaryl, -ORla, or -N(Rla)2- In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. is of formula: -

[0205] CH3or -CH2CH3. In some embodiments, is of formula: or F F . in some embodiments, is of formula: R3, R3a, RA, and x

[0206]

[0206] As generally described herein, R3is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0207]

[0207] In some embodiments, R3is optionally substituted C3-10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted Ce-io aryl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R3is optionally substituted C3-6 carbocyclyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted Ce aryl, or optionally substituted 5-6 membered heteroaryl.

[0208]

[0208] In some embodiments, R3is optionally substituted aryl. In some embodiments, R3is optionally substituted Ce 10 aryl. In some embodiments, R3is optionally substituted phenyl. In some embodiments, R3is substituted aryl. In some embodiments, R3is substituted Ce 10 aryl. In some embodiments, R3is substituted phenyl. In some embodiments, R3is unsubstituted aryl. In some embodiments, R3is unsubstituted Ce 10 aryl. In some embodiments, R3is phenyl.

[0209]

[0209] In some embodiments, R3is of formula: (A-l), wherein: each instance of R3ais 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, -ORA, each instance of RAis independently hydrogen, optionally substituted acyl, 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 RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and m is 0, 1, 2, 3, 4, or 5.

[0210]

[0210] In some embodiments, R3is of formula (A-l), wherein at least one instance of R3ais halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -CN, -NO2, - ORla, -N(Rla)2, -NRlaC(=O)Rla, -C(=O)Rla, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R3is of formula (A-l), wherein at least one instance of R3ais halogen, optionally substituted C1-3 alkyl, optionally substituted C2-3 alkynyl, -CN, -NO2, -ORla, -N(Rla)2, -NRlaC(=O)Rla, -C(=O)Rla, optionally substituted C3-4 carbocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S, or optionally substituted 8-10 membered heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, R3is of formula (A-l), wherein at least one instance of R3ais -ORla, wherein Rlais unsubstituted C1-3 alkyl; -C(=O)Rla, wherein Rlais unsubstituted 4-6 membered heterocyclyl containing 1 or 2 ring N atoms; optionally substituted phenyl; optionally substituted 5-6 membered heteroaryl containing 1 ring N atom and 1 ring O atom, 1 ring N atom and 1 ring S atom, or 3 ring N atoms; or optionally substituted 8-10 membered heteroaryl containing 2 ring N atoms and 1 ring S atom.

[0211]

[0211] In some embodiments, R3of formula (A-l) is of formula:

[0212]

[0212] In some embodiments, R3of formula (A-l) is of formula (A-la), (A-lc), or (A- Id). In some embodiments, R3of formula (A-l) is of formula (A-lc) or (A- Id). In some embodiments, R3of formula

[0213] (A-l) is of formula (A-la). In some embodiments, R3of formula (A-l) is of formula (A-lb). In some embodiments, R3of formula (A-l) is of formula (A-lc). In some embodiments, R3of formula (A-l) is of formula (A- Id). In some embodiments, R3of formula (A-l) is of formula (A-le). In some embodiments, R3of formula (A-l) is of formula (A- If). In some embodiments, R3of formula (A-l) is of formula (A- 1g). In some embodiments, R3of formula (A-l) is of formula (A-lh). In some embodiments, R3of formula (A-l) is of formula (A-li). In some embodiments, R3of formula (A-l) is of formula (A-lj).

[0213] In some embodiments, R3of formula (A-l) is of formula (A-lc), wherein R3ais optionally substituted heteroaryl. In some embodiments, R3of formula (A-l) is of formula (A-lc), wherein R3ais optionally substituted 5-6 membered heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, R3of formula (A-l) is of formula (A-lc), wherein R3ais optionally substituted 5-6 membered heteroaryl containing 2 ring N atoms, 1 ring N atom and 1 ring O atom, 1 ring N atom and 1 ring S atom, or 3 ring N atoms.

[0214]

[0214] In some embodiments, R3of formula (A-l) is of formula (A-ld), wherein R3ais halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -CN, -NO2,

[0215] -ORla, -N(Rla)2, -NRlaC(=O)Rla, -C(=O)Rla, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R3of formula (A-l) is of formula (A-ld), wherein R3ais halogen, optionally substituted C1-3alkyl, optionally substituted C2.3alkynyl, -CN, -NO2, -ORla, -N(Rla)2, -NRlaC(=O)Rla, -C(=O)Rla, optionally substituted C3-4 carbocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S, or optionally substituted 8-10 membered heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, R3of formula (A-l) is of formula (A-ld), wherein R3ais -O-(optionally substituted C1-3alkyl); -C(=O)-(optionally substituted 3-4 membered heterocyclyl); optionally substituted phenyl; optionally substituted 5-6 membered heteroaryl containing 2 ring N atoms, 1 ring N atom and 1 ring O atom, 1 ring N atom and 1 ring S atom, or 3 ring N atoms; or optionally substituted 8-10 membered heteroaryl containing 2 ring N atoms and 1 ring S atom.

[0216]

[0215] In some embodiments, R3is of formula (A-l), wherein at least one instance of R3ais:

[0217] -F, -Cl, -Br, -I, -CH3, -CHF2, -CF3, -CF2CH3, -C=CH, -CN, -N02, -OH, -OCH3, -OCH2CH3,

[0216] In some embodiments, R3is of formula (A-l), wherein at least one instance of R3ais:

[0218]

[0217] In s wherein: each instance of R3bis independently halogen, optionally substituted alkyl, optionally substituted heterocyclyl, -CN, -N(RN)2, or -SFs, or two instances of R3bare joined together with their intervening atoms to form an optionally substituted carbocyclic ring or optionally substituted heterocyclic ring; each instance of RNis independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two instances of RNare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring; and p is 0, 1, 2, 3, 4, or 5, as valency permits.

[0219]

[0218] In some embodiments, R3is of formula (A- 2). In some embodiments, R3is of formula (A-3). In some embodiments, R3is of formula (A-4). In some embodiments, R3is of formula (A-5). In some embodiments, R3is of formula (A-6). In some embodiments, R3is of formula (A-7). In some embodiments, R3is of formula (A-8). In some embodiments, R3is of formula (A-9). In some embodiments, R3is of formula (A-10). In some embodiments, R3is of formula (A-ll). In some embodiments, R3is of formula (A-12). In some embodiments, R3is of formula (A-13). In some embodiments, R3is of formula (A-14). In some embodiments, R3is of formula (A-15). In some embodiments, R3is of formula (A-16). In some embodiments, R3is of formula (A-17). In some embodiments, R3is of formula (A-18). In some embodiments, R3is of formula (A-19). In some embodiments, R3is of formula (A-20). In some embodiments, R3is of formula (A-21). In some embodiments, R3is of formula (A-22). In some embodiments, R3is of formula (A-23). In some embodiments, R3is of formula (A-24). In some embodiments, R3is of formula (A-25). In some embodiments, R3is of formula (A-2) to (A-25). In some embodiments, R3is of formula (A- 26). In some embodiments, R3is of formula (A-27). In some embodiments, R3is of formula (A-28). In some embodiments, R3is of formula (A-29). In some embodiments, R3is of formula (A-30). In some embodiments, R3is of formula (A-31). In some embodiments, R3is of formula (A-32). In some embodiments, R3is of formula (A-33). In some embodiments, R3is of formula (A-34). In some embodiments, R3is of formula (A-35). In some embodiments, R3is of formula (A-36). In some embodiments, R3is of formula (A-37). In some embodiments, R3is of formula (A-38).

[0220]

[0219] In some embodiments, R3is of formula (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (A-9), (A- 10), (A-ll), (A-12), (A-13), (A-14), (A-15), (A-16), (A-17), (A-18), (A-19), (A-20), (A-21), (A-22), (A- 23), (A-24), (A-25), (A-26), (A-27), (A-28), (A-29), (A-30), (A-31), (A-32), (A-33), (A-34), (A-35), (A- 36), (A-37), or (A-38), and p is 0. In some embodiments, R3is of formula (A-2), (A-3), (A-4), (A-5), (A- 6), (A-7), (A-8), (A-9), (A-10), (A-ll), (A-12), (A-13), (A-14), (A-15), (A- 16), (A-17), (A-18), (A-20),

[0221] (A-21), (A-22), (A-23), (A-24), (A-25), (A-26), (A-27), (A-28), (A-29), (A-30), (A-31), (A-32), (A-33), (A-34), (A-35), (A-36), (A-37), or (A-38), and p is 1. In some embodiments, R3is of formula (A-2), (A- 3), (A-4), (A-5), (A-6), (A-7), (A-8), (A-9), (A-10), (A-ll), (A-12), (A-13), (A-15), (A-20), (A-21), (A-

[0222] 22), (A-23), (A-24), (A-25), (A-26), (A-27), (A-28), (A-29), (A-30), (A-31), (A-32), (A-33), (A-34), (A- 35), (A-36), (A-37), or (A-38), and p is 2. In some embodiments, R3is of formula (A-2), (A-3), (A-6), (A-20), (A-22), (A-23), (A-24), (A-26), (A-27), (A-28), (A-29), (A-30), (A-31), (A-32), (A-33), (A-34), (A-35), (A-36), (A-37), or (A-38), and p is 3. In some embodiments, R3is of formula (A-2), (A-22), (A-

[0223] 23), (A-28), (A-29), (A-33), (A-34), (A-35), (A-36), or (A-37), and p is 4. In some embodiments, R3is of formula (A-2), (A-22), (A-34), (A-35), or (A-36), and p is 5.

[0224]

[0220] In some embodiments, R3of formula (A-2) is of formula:

[0225] [22 formula (A-2) is of formula (A-2b). In some embodiments, R3of formula (A-2) is of formula (A-2c). In some embodiments, R3of formula (A-2) is of formula (A-2d). In some embodiments, R3of formula (A- 2) is of formula (A-2e).

[0226]

[0222] In some embodiments, R3of formula (A-7) is of formula:

[0227]

[0223] In some embodiments, R3of formula (A-7) is of formula (A-7a). In some embodiments, R3of formula (A-7) is of formula (A-7b). In some embodiments, R3of formula (A-7) is of formula (A-7c).

[0228]

[0224] In some embodiments, R3of formula (A-10) is of formula:

[0225] In some embodiments, R3of formula (A-10) is of formula (A-lOa). In some embodiments, R3of formula (A-10) is of formula (A-lOb). In some embodiments, R3of formula (A-10) is of formula (A-

[0229] 10c).

[0230]

[0226] In some embodiments, R3of formula (A- 13) is of formula:

[0231]

[0227] In some embodiments, R3of formula (A- 13) is of formula (A-13a). In some embodiments, R3of formula (A- 13) is of formula (A-13b). In some embodiments, R3of formula (A- 13) is of formula (A- 13c).

[0232]

[0228] In some embodiments, R3of formula (A- 14) is of formula:

[0233]

[0229] In some embodiments, R3of formula (A- 14) is of formula (A-14a). In some embodiments, R3of formula (A- 14) is of formula (A-14b).

[0234]

[0230] In some embodiments, R3of formula (A- 16) is of formula:

[0235]

[0231] In some embodiments, R3of formula (A- 16) is of formula (A-16a). In some embodiments, R3of formula (A- 16) is of formula (A-16b).

[0236]

[0232] In some embodiments, R3of formula (A-20) is of formula:

[0233] In some embodiments, R3of formula (A-20) is of formula (A-20a). In some embodiments, R3of formula (A-20) is of formula (A-20b). In some embodiments, R3of formula (A-20) is of formula (A- 20c). In some embodiments, R3of formula (A-20) is of formula (A-20d).

[0237]

[0234] In some embodiments, R3of formula (A-25) is of formula:

[0238]

[0235] In some embodiments, R3of formula (A-25) is of formula (A-25a). In some embodiments, R3of formula (A-25) is of formula (A-25b). In some embodiments, R3of formula (A-25) is of formula (A-

[0239] 25c).

[0240]

[0236] In some embodiments, R3of formula (A-26) is of formula:

[0241]

[0237] In some embodiments, R3of formula (A-26) is of formula (A-26a). In some embodiments, R3of formula (A-26) is of formula (A-26b). In some embodiments, R3of formula (A-26) is of formula (A- 26c). In some embodiments, R3of formula (A-26) is of formula (A-26d).

[0242]

[0238] In some embodiments, R3of formula (A-27) is of formula:

[0243]

[0239] In some embodiments, R3of formula (A-27) is of formula (A-27a). In some embodiments, R3of formula (A-27) is of formula (A-27b). In some embodiments, R3of formula (A-27) is of formula (A- 27c). In some embodiments, R3of formula (A-27) is of formula (A-27d).

[0240] In some embodiments, R3of formula (A-28) is of formula:

[0244]

[0241] In some embodiments, R3of formula (A-28) is of formula (A-28a). In some embodiments, R3of formula (A-28) is of formula (A-28b). In some embodiments, R3of formula (A-28) is of formula (A- 28c). In some embodiments, R3of formula (A-28) is of formula (A-28d). In some embodiments, R3of formula (A- 28) is of formula (A-28e).

[0245]

[0242] In some embodiments, R3of formula (A-29) is of formula:

[0246]

[0243] In some embodiments, R3of formula (A-29) is of formula (A-29a). In some embodiments, R3of formula (A-29) is of formula (A-29b). In some embodiments, R3of formula (A-29) is of formula (A- 29c). In some embodiments, R3of formula (A-29) is of formula (A-29d). In some embodiments, R3of formula (A-29) is of formula (A-29e).

[0244] In some embodiments, R3of formula (A-30) is of formula:

[0247]

[0245] In some embodiments, R3of formula (A-30) is of formula (A-30a). In some embodiments, R3of formula (A-30) is of formula (A-30b). In some embodiments, R3of formula (A-30) is of formula (A- 30c). In some embodiments, R3of formula (A-30) is of formula (A-30d).

[0248]

[0246] In some embodiments, R3of formula (A-31) is of formula:

[0249]

[0247] In some embodiments, R3of formula (A-31) is of formula (A-31a). In some embodiments, R3of formula (A-31) is of formula (A-31b). In some embodiments, R3of formula (A-31) is of formula (A- 31c). In some embodiments, R3of formula (A-31) is of formula (A-31d).

[0250]

[0248] In some embodiments, R3of formula (A-32) is of formula:

[0251] [24 formula (A-32) is of formula (A-32b). In some embodiments, R3of formula (A-32) is of formula (A- 32c). In some embodiments, R3of formula (A-32) is of formula (A-32d).

[0250] In some embodiments, R3of formula (A-33) is of formula:

[0252]

[0251] In some embodiments, R3of formula (A-33) is of formula (A-33a). In some embodiments, R3of formula (A- 33) is of formula (A-33b). In some embodiments, R3of formula (A-33) is of formula (A-

[0253] 33c). In some embodiments, R3of formula (A-33) is of formula (A-33d).

[0254]

[0252] In some embodiments, R3of formula (A-34) is of formula:

[0255]

[0253] In some embodiments, R3of formula (A-34) is of formula (A-34a). In some embodiments, R3of formula (A-34) is of formula (A-34b). In some embodiments, R3of formula (A-34) is of formula (A- 34c). In some embodiments, R3of formula (A-34) is of formula (A-34d). In some embodiments, R3of formula (A-34) is of formula (A-34e). In some embodiments, R3of formula (A-34) is of formula (A-34f).

[0256]

[0254] In some embodiments, R3of formula (A-35) is of formula:

[0257]

[0255] In some embodiments, R3of formula (A-35) is of formula (A-35a). In some embodiments, R3of formula (A- 35) is of formula (A-35b). In some embodiments, R3of formula (A-35) is of formula (A-

[0258] 35c). In some embodiments, R3of formula (A-35) is of formula (A-35d). In some embodiments, R3of formula (A-35) is of formula (A-35e). In some embodiments, R3of formula (A-35) is of formula (A-35f).

[0259]

[0256] In some embodiments, R3of formula (A-36) is of formula:

[0260]

[0257] In some embodiments, R3of formula (A-36) is of formula (A-36a). In some embodiments, R3of formula (A-36) is of formula (A-36b). In some embodiments, R3of formula (A-36) is of formula (A- 36c). In some embodiments, R3of formula (A-36) is of formula (A-36d). In some embodiments, R3of formula (A-36) is of formula (A-36e). In some embodiments, R3of formula (A-36) is of formula (A-36f).

[0261]

[0258] In some embodiments, R3of formula (A-37) is of formula:

[0262]

[0259] In some embodiments, R3of formula (A-37) is of formula (A-37a). In some embodiments, R3of formula (A-37) is of formula (A-37b). In some embodiments, R3of formula (A-37) is of formula (A- 37c). In some embodiments, R3of formula (A-37) is of formula (A-37d). In some embodiments, R3of formula (A-37) is of formula (A-37e).

[0263]

[0260] In some embodiments, R3is of formula (A- 2b), (A-2c), (A-2d), (A-7b), (A-7c), (A-lOa), (A-lOb),

[0264] (A-lOc), (A-13a), (A- 13b), (A- 13c), (A- 14b), (A-16b), (A-20b), (A-20c), (A-20d), (A-25b), or (A-25c), wherein R3bis halogen, unsubstituted Cm alkyl, Cm haloalkyl, optionally substituted 4-6 membered heterocyclyl containing 1 or 2 N atoms, -CN, -N(RN)2, or -SF5. In some embodiments, R3is of formula (A-2b), (A-2c), (A-2d), (A-7b), (A-7c), (A-lOa), (A- 10b), (A-lOc), (A-13a), (A-13b), (A-13c), (A-14b), (A-16b), (A-20b), (A-20c), (A-20d), (A-25b), or (A-25c), wherein R3bis -F, -Cl, -CN,

[0265]

[0261] In some embodiments, R3is of formula (A-2e), wherein two instances of R3bare joined together with their intervening atoms to form an optionally substituted C5-6 carbocyclic ring or optionally substituted 5-6 membered heterocyclic ring. In some embodiments, R3is of formula (A-2e), wherein two instances of R3bare joined together with their intervening atoms to form

[0266]

[0262] In some embodiments, R3is of formula (A-7a), (A-7b), (A-7c), (A- 16a), (A-16b), (A-26a), (A-

[0267] 28a), (A-29a), (A-31a), or (A-32a), wherein RNis optionally substituted alkyl. In some embodiments, R3is of formula (A-7a), (A-7b), (A-7c), (A-16a), (A-16b), (A-26a), (A-28a), (A-29a), (A-31a), or (A-32a), wherein RNis Cm alkyl or Cm haloalkyl. In some embodiments, R3is of formula (A-7a), (A-7b), (A-7c), (A-16a), (A-16b), (A-26a), (A-28a), (A-29a), (A-31a), or (A-32a), wherein RNis -CH3or -CHF2.

[0268]

[0263] In some embodiments, R3is of formula:

[0269]

[0270]

[0264] In some embodiments, R3is of formula:

[0271]

[0265] In some embodiments, R3is of formula:

[0272]

[0273]

[0266] In some embodiments, R3is optionally substituted carbocyclyl. In some embodiments, R3is optionally substituted C3-10 carbocyclyl. In some embodiments, R3is optionally substituted C3-6 carbocyclyl.

[0274]

[0267] In some embodiments, R3is of formula: wherein: each instance of R3ais 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, -ORA, each instance of RAis independently hydrogen, optionally substituted acyl, 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 RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and m is 0, 1, 2, 3, 4, or 5.

[0275]

[0268] In some embodiments, R3is of formula (B-l), wherein at least one instance of R3ais optionally substituted heteroaryl. In some embodiments, R3is of formula (B-l), wherein at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, R3is of formula (B-l), wherein at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 1 ring N atom and 1 ring O atom, 1 ring N atom and 1 ring S atom, or 3 ring N atoms.

[0276]

[0269] In some embodiments, R3of formula (B-l) is of formula:

[0277] 5 5 5

[0278] R3a(B-la), R3a(B-lb), or R3a(B-lc).

[0279]

[0270] In some embodiments, R3of formula (B-l) is of formula (B-la). In some embodiments, R3of formula (B-l) is of formula (B-lb). In some embodiments, R3of formula (B-l) is of formula (B-lc).

[0280]

[0271] In some embodiments,

[0281]

[0272] In some embodiments, R3is optionally substituted heterocyclyl. In some embodiments, R3is optionally substituted 3-10 membered heterocyclyl. In some embodiments, R3is optionally substituted 4- 6 membered heterocyclyl. In some embodiments, R3is optionally substituted 4-6 membered heterocyclyl containing 1 ring N atom.

[0282]

[0273] In some embodiments, R3is of formula: wherein: each instance of R3ais 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, -ORA, each instance of RAis independently hydrogen, optionally substituted acyl, 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 RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;

[0283] RNis hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; and m is 0, 1, 2, 3, 4, or 5.

[0284]

[0274] In some embodiments, R3is of formula (C-l) or (C-2), wherein at least one instance of R3ais optionally substituted heteroaryl. In some embodiments, R3is of formula (C-l) or (C-2), wherein at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, R3is of formula (C-l) or (C-2), wherein at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 1 ring N atom and 1 ring O atom, 1 ring N atom and 1 ring S atom, or 3 ring N atoms.

[0285]

[0275] In some embodiments, R3of formula (C-l) is of formula: -lc).

[0286]

[0276] In some embodiments, R3of formula (C-l) is of formula (C-la). In some embodiments, R3of formula (C-l) is of formula (C-lb). In some embodiments, R3of formula (C-l) is of formula (C-lc).

[0277] In some embodiments, R3of formula (C-2) is of formula: ,

[0287]

[0279] In some embodiments, R3is optionally substituted heteroaryl. In some embodiments, R3is optionally substituted 5-10 membered heteroaryl. In some embodiments, R3is optionally substituted 5-6 membered heteroaryl. In some embodiments, R3is optionally substituted 8-10 membered heteroaryl. each instance of R3ais 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, -ORA, each instance of RAis independently hydrogen, optionally substituted acyl, 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 RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;

[0288] RNis hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; and m is 0, 1, 2, 3, or 4, as valency permits.

[0289]

[0281] In some embodiments, R3is of formula (D-l). In some embodiments, R3is of formula (D-2). In some embodiments, R3is of formula (D-3). In some embodiments, R3is of formula (D-4). In some embodiments, R3is of formula (D-5). In some embodiments, R3is of formula (D-6). In some embodiments, R3is of formula (D-7). In some embodiments, R3is of formula (D-8).

[0290]

[0282] In some embodiments, R3is of formula (D-l) to (D-6), wherein at least one instance of R3ais optionally substituted heteroaryl. In some embodiments, R3is of formula (D-l) to (D-6), wherein at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, R3is of formula (D-l) to (D-6), wherein at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 1 ring N atom and 1 ring O atom, 1 ring N atom and 1 ring S atom, or 3 ring N atoms.

[0291]

[0283] In some embodiments, R3is of formula (D-7) or (D-8), wherein RNis optionally substituted heteroaryl. In some embodiments, R3is of formula (D-7) or (D-8), wherein RNis optionally substituted 5- 6 membered heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, R3is of formula (D-7) or (D-8), wherein RNis optionally substituted 5-6 membered heteroaryl containing 1 ring N atom and 1 ring O atom, 1 ring N atom and 1 ring S atom, or 3 ring N atoms.

[0284] In some embodiments, R3of formula (D-l) is of formula: -la).

[0292]

[0285] In some embodiments, R3of formula (D-2) is of formula:

[0293]

[0286] In some embodiments, R3of formula (D-3) is of formula:

[0294]

[0287] In some embodiments, R3of formula (D-3) is of formula (D-3a). In some embodiments, R3of formula (D-3) is of formula (D-3b).

[0295]

[0288] In some embodiments, R3of formula (D-4) is of formula:

[0296]

[0289] In some embodiments, R3of formula (D-5) is of formula:

[0297]

[0290] In some embodiments, R3of formula (D-6) is of formula:

[0298]

[0291] In some embodiments, R3of formula (D-6) is of formula (D-6a). In some embodiments, R3of formula (D-6) is of formula (D-6b).

[0299]

[0292] In some embodiments, R3of formula (D-7) is of formula:

[0300] R3a(D-7a).

[0293] In some embodiments, R3of formula (D-8) is of formula:

[0301]

[0295] As generally described herein, each instance of R3ais 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, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA,

[0302] -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2.

[0303]

[0296] In some embodiments, at least one instance of R3ais halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -CN, -NO2, -ORla, -N(Rla)2, -NRlaC(=O)Rla, -C(=O)Rla, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R3ais halogen, optionally substituted C1-3 alkyl, optionally substituted C2.3alkynyl, -CN, -NO2, -ORla, -N(Rla)2, -NRlaC(=O)Rla, -C(=O)Rla, optionally substituted C3-4 carbocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S, or optionally substituted 8-10 membered heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, at least one instance of R3ais -ORla, wherein Rlais unsubstituted C1-3 alkyl; -C(=O)Rla, wherein Rlais unsubstituted 4-6 membered heterocyclyl containing 1 or 2 ring N atoms; optionally substituted phenyl; optionally substituted 5-6 membered heteroaryl containing 2 ring N atoms, 1 ring N atom and 1 ring O atom, 1 ring N atom and 1 ring S atom, or 3 ring N atoms; or optionally substituted 8-10 membered heteroaryl containing 2 ring N atoms and 1 ring S atom.

[0304]

[0297] In some embodiments, at least one instance of R3ais halogen. In some embodiments, at least one instance of R3ais -F, -Cl, -Br, or -I. In some embodiments, at least one instance of R3ais -Cl or -Br.

[0305]

[0298] In some embodiments, at least one instance of R3ais optionally substituted alkyl. In some embodiments, at least one instance of R3ais optionally substituted C1-6 alkyl. In some embodiments, at least one instance of R3ais optionally substituted C1-3 alkyl. In some embodiments, at least one instance of R3ais -CH3, -CHF2, -CF3, or -CF2CH3.

[0306]

[0299] In some embodiments, at least one instance of R3ais optionally substituted alkynyl. In some embodiments, at least one instance of R3ais optionally substituted C2-6 alkynyl. In some embodiments, at least one instance of R3ais optionally substituted C2.3alkynyl. In some embodiments, at least one instance of R3ais -C=CH.

[0307]

[0300] In some embodiments, at least one instance of R3ais -CN.

[0308]

[0301] In some embodiments, at least one instance of R3ais -NO2.

[0309]

[0302] In some embodiments, at least one instance of R3ais -ORla. In some embodiments, at least one instance of R3ais -ORla, wherein Rlais hydrogen, optionally substituted C1-6 alkyl, optionally substituted

[0310] C3-10 carbocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, at least one instance of R3ais -ORla, wherein Rlais hydrogen, optionally substituted C1-3 alkyl, optionally substituted C3-6 carbocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, at least one instance of R3ais -ORla, wherein Rlais hydrogen, unsubstituted C1-3 alkyl, C1-3 haloalkyl, unsubstituted C3-6 carbocyclyl, or unsubstituted 5-6 membered heteroaryl. In some embodiments, at least one instance . in some embodiments, at least one instance of R3ais unsubstituted C1-3 alkyl. In some embodiments, at least one instance of R3ais -OCH3.

[0311]

[0303] In some embodiments, at least one instance of R3ais -N(RA)2. In some embodiments, at least one instance of R3ais -N(RA)2, wherein each instance of RAis independently hydrogen or optionally substituted C1-3 alkyl. In some embodiments, at least one instance of R3ais -N(CH3)2.

[0312]

[0304] In some embodiments, at least one instance of R3ais -NRAC(=O)RA. In some embodiments, at least one instance of R3ais -NRAC(=O)RA, wherein each instance of RAis independently hydrogen or optionally substituted C1-3 alkyl. In some embodiments, at least one instance of R3ais -NHC(=O)CH3.

[0313]

[0305] In some embodiments, at least one instance of R3ais -C(=O)Rla. In some embodiments, at least one instance of R3ais -C(=O)Rla, wherein Rlais optionally substituted 4-6 membered heterocyclyl. In some embodiments, at least one instance of R3ais -C(=O)Rla, wherein Rlais unsubstituted 4-6 membered heterocyclyl containing 1 or 2 ring N atoms. In some embodiments, at least one instance of R3ais

[0314]

[0306] In some embodiments, at least one instance of R3ais optionally substituted carbocyclyl. In some embodiments, at least one instance of R3ais optionally substituted C3-6 carbocyclyl. In some embodiments, at least one instance of R3ais unsubstituted C3-6 carbocyclyl. In some embodiments, at least one instance

[0315]

[0307] In some embodiments, at least one instance of R3ais optionally substituted heterocyclyl. In some embodiments, at least one instance of R3ais optionally substituted 4-6 membered heterocyclyl. In some embodiments, at least one instance of R3ais 4-6 membered heterocyclyl containing 1 or 2 ring N atoms, wherein the heterocyclyl is substituted with 0, 1, or 2 -F. In some embodiments, at least one instance of

[0316]

[0308] In some embodiments, at least one instance of R3ais optionally substituted aryl. In some embodiments, at least one instance of R3ais optionally substituted phenyl. In some embodiments, at least one instance of R3ais unsubstituted phenyl. In some embodiments, at least one instance of R3ais substituted phenyl. In some embodiments, at least one instance some embodiments, at least one instance of R3a

[0317]

[0309] In some embodiments, at least one instance of R3ais optionally substituted heteroaryl. In some embodiments, at least one instance of R3ais optionally substituted 5-6 membered heteroaryl. In some embodiments, at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 1 ring S atom; 2 ring N atoms; 1 ring N atom and 1 ring O atom; 1 ring N atom and 1 ring S atom; 2 ring N atoms and 1 ring S atom; 3 ring N atoms; or 4 ring N atoms. In some embodiments, at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 2 ring N atoms, 1 ring N atom and 1 ring O atom, 1 ring N atom and 1 ring S atom, or 3 ring N atoms.

[0318]

[0310] In some embodiments, at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 1 ring S atom. In some embodiments, at least substituted thiophenyl. In some embodiments, at least one instance

[0319]

[0311] In some embodiments, at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 2 ring N atoms. In some embodiments, at least one instance of R3ais optionally substituted pyrazolyl or optionally substituted imidazolyl. In some embodiments, at least one instance of some embodiments, at least one instance some embodiments, at least one instance

[0312] In some embodiments, at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 1 ring N atom and 1 ring O atom. In some embodiments, at least one instance of R3ais optionally substituted oxazolyl or optionally substituted isoxazolyl. In some embodiments, at least

[0320]

[0313] In some embodiments, at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 1 ring N atom and 1 ring S atom. In some embodiments, at least one instance of R3ais optionally substituted thiazolyl, optionally substituted isothiazolyl, or optionally substituted thiazolonyl. In some embodiments, at least one instance

[0321]

[0314] In some embodiments, at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 2 ring N atoms and 1 ring S atom. In some embodiments, at least one instance of R3ais optionally substituted thiadiazolyl. In some embodiments, at least one instance of R3ais

[0322]

[0315] In some embodiments, at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 3 ring N atoms. In some embodiments, at l substituted triazolyl. In some embodiments, at least one instance

[0323]

[0324]

[0316] In some embodiments, at least one instance of R3ais optionally substituted 5-6 membered heteroaryl containing 4 ring N atoms. In some embodiments, at least one instance of R3ais optionally substituted tetrazolyl. In some embodiments, at least one instance of R3ais .

[0325]

[0317] In some embodiments, at least one instance of R3ais optionally substituted 8-10 membered heteroaryl. In some embodiments, at least one instance of R3ais optionally substituted 8-10 membered heteroaryl containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S. In some embodiments, at least one instance of R3ais optionally substituted 8-10 membered heteroaryl containing 2 ring N atoms; 1 ring N atom and 1 ring S atom; 2 ring N atoms and 1 ring S atom; 2 ring N atoms and 1 ring O atom; or 3 ring N atoms and 1 ring S atom. In some embodiments, at least one instance of R3ais optionally substituted 8-10 membered heteroaryl containing 2 ring N atoms and 1 ring S atom. In some

[0326]

[0319] In some embodiments, at least one instance of R3ais:

[0327]

[0320] As generally described herein, each instance of RAis independently hydrogen, optionally substituted acyl, 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 RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.

[0328]

[0321] In some embodiments, at least one instance of RAis hydrogen. In some embodiments, at least one instance of RAis optionally substituted acyl. In some embodiments, at least one instance of RAis optionally substituted Cm alkyl. In some embodiments, at least one instance of RAis optionally substituted C1-6 alkyl. In some embodiments, at least one instance of RAis unsubstituted C1-6 alkyl. In some embodiments, at least one instance of RAis substituted C1-6 alkyl. In some embodiments, at least one instance of RAis optionally substituted C2-12 alkenyl. In some embodiments, at least one instance of RAis optionally substituted C2-6 alkenyl. In some embodiments, at least one instance of RAis optionally substituted C2-12 alkynyl. In some embodiments, at least one instance of RAis optionally substituted C2-6 alkynyl. In some embodiments, at least one instance of RAis optionally substituted heteroC1-12 alkyl. In some embodiments, at least one instance of RAis optionally substituted heteroC1-6alkyl. In some embodiments, at least one instance of RAis optionally substituted heteroC1-12 alkenyl. In some embodiments, at least one instance of RAis optionally substituted heteroC1-6alkenyl. In some embodiments, at least one instance of RAis optionally substituted heteroC1-12 alkynyl. In some embodiments, at least one instance of RAis optionally substituted heteroC1-6alkynyl. In some embodiments, at least one instance of RAis optionally substituted C3-14 cycloalkyl. In some embodiments, at least one instance of RAis optionally substituted 5-10 membered heterocyclyl. In some embodiments, at least one instance of RAis optionally substituted 6-14 membered aryl. In some embodiments, at least one instance of RAis optionally substituted 5-14 membered heteroaryl. In some embodiments, at least one instance of RAis a nitrogen protecting group when attached to a nitrogen atom. In some embodiments, at least one instance of RAis an oxygen protecting group when attached to an oxygen atom. In some embodiments, at least one instance of RAis a sulfur protecting group when attached to a sulfur atom. In some embodiments, at least two instances of RAare joined together with their intervening atom to form an optionally substituted 5-10 membered heterocyclic ring. In some embodiments, at least two instances of RAare joined together with their intervening atom to form an optionally substituted 5-14 membered heteroaryl ring.

[0329]

[0322] As generally described herein, m is 0, 1, 2, 3, 4, or 5, as valency permits.

[0330]

[0323] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0331]

[0324] As generally described herein, each instance of R3bis independently halogen, optionally substituted alkyl, optionally substituted heterocyclyl, -CN, -N(RN)2, or -SF5, or two instances of R3bare joined together with their intervening atoms to form an optionally substituted carbocyclic ring or optionally substituted heterocyclic ring.

[0332]

[0325] In some embodiments, at least one instance of R3bis halogen. In some embodiments, at least one instance of R3bis -F or -Cl.

[0333]

[0326] In some embodiments, at least one instance of R3bis optionally substituted alkyl. In some embodiments, at least one instance of R3bis unsubstituted Cm alkyl. In some embodiments, at least one instance of R3bis Cm haloalkyl. In some embodiments, at least one instance of R3bis -CH3, -CHF2, or -CF3.

[0334]

[0327] In some embodiments, at least one instance of R3bis optionally substituted heterocyclyl. In some embodiments, at least one instance of R3bis optionally substituted 4-6 membered heterocyclyl containing

[0335] 1 or 2 N atoms. In some embodiments, at least one instance

[0328] In some embodiments, at least one instance of R3bis -CN.

[0336]

[0329] In some embodiments, at least one instance of R3bis -N(RN)2- In some embodiments, at least one instance

[0337]

[0330] In some embodiments, at least one instance of R3bis -SF5.

[0338]

[0331] In some embodiments, two instances of R3bare joined together with their intervening atoms to form an optionally substituted carbocyclic ring or optionally substituted heterocyclic ring. In some embodiments, two instances of R3bare joined together with their intervening atoms to form an optionally substituted C5-6 carbocyclic ring or optionally substituted 5-6 membered heterocyclic ring. In some embodiments, two instances of R3bare joined together with their intervening atoms to form F or

[0339]

[0332] In some embodiments, at least one instance of R3bis -F, -Cl, -CN, -CH3, -CHF2, -CF3, -NH2, - two instances of R3bare joined together with their intervening atoms to form

[0340]

[0333] As generally described herein, each instance of RNis independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two instances of RNare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring.

[0341]

[0334] In some embodiments, at least one instance of RNis hydrogen.

[0342]

[0335] In some embodiments, at least one instance of RNis optionally substituted alkyl. In some embodiments, at least one instance of RNis optionally substituted Cm alkyl. In some embodiments, at least one instance of RNis -CH3, . In some embodiments, at least one instance of RNis Cm haloalkyl. In some embodiments, at least one instance of RNis -CHF2.

[0343]

[0336] In some embodiments, at least one instance of RNis optionally substituted carbocyclyl. In some embodiments, at least one instance of RNis optionally substituted C3-6 heterocyclyl. In some embodiments, at least one instance of RNis cyclopropyl.

[0344]

[0337] In some embodiments, at least one instance of RNis optionally substituted heterocyclyl. In some embodiments, at least one instance of RNis optionally substituted 4-6 membered heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N. In some embodiments, at least one instance of RNis

[0345]

[0338] In some embodiments, at least one instance of RNis optionally substituted aryl. In some embodiments, at least one instance of RNis optionally substituted phenyl. In some embodiments, at least

[0346]

[0339] In some embodiments, at least one instance of RNis optionally substituted heteroaryl. In some embodiments, at least one instance of RNis optionally substituted 5-10 membered heteroaryl containing 1 or 2 ring heteroatoms selected from O, N, and S. In some embodiments, at least one instance of RNis

[0347]

[0340] In some embodiments, at least one instance of RNis a nitrogen protecting group.

[0348]

[0341] In some embodiments, two instances of RNare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring. In some embodiments, two instances of RNare joined together with their intervening nitrogen atom to form an optionally substituted 4-6 membered heterocyclyl containing 1 or 2 N atoms. In some embodiments, two instances of RNare joined together with their intervening nitrogen atom to form

[0349]

[0342] In some embodiments, at least one instance of RNis hydrogen, -CH3, -CHF2, nitrogen atom to form

[0350]

[0343] As generally described herein, p is 0, 1, 2, 3, 4, or 5, as valency permits.

[0351]

[0344] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0352] R4, R5a, and R"

[0353]

[0345] As generally described herein, R4is hydrogen or optionally substituted alkyl.

[0354]

[0346] In some embodiments, R4is hydrogen.

[0355]

[0347] In some embodiments, R4is optionally substituted alkyl. In some embodiments, R4is optionally substituted C1-6 alkyl. In some embodiments, R4is substituted C1-6 alkyl. In some embodiments, R4is substituted methyl, substituted ethyl, substituted n-propyl, substituted isopropyl, substituted n-butyl, substituted tert-butyl, substituted sec-butyl, substituted isobutyl, substituted n-pentyl, substituted 3- pentanyl, substituted amyl, substituted neopentyl, substituted 3-methyl-2-butanyl, substituted tert-amyl, or substituted / z-hcxyl. In some embodiments, R4is unsubstituted C1-6 alkyl. In some embodiments, R4is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl, or / z-hcxyl.

[0356]

[0348] In some embodiments, R4is optionally substituted Cm alkyl. In some embodiments, R4is substituted Cm alkyl. In some embodiments, R4is substituted methyl, substituted ethyl, substituted n- propyl, or substituted isopropyl. In some embodiments, R4is unsubstituted Cm alkyl. In some embodiments, R4is methyl, ethyl, n-propyl, or isopropyl.

[0357]

[0349] In some embodiments, R4is optionally substituted methyl. In some embodiments, R4is substituted methyl. In some embodiments, R4is methyl.

[0358]

[0350] In some embodiments, R4is hydrogen or optionally substituted C1-6 alkyl. In some embodiments, R4is hydrogen or unsubstituted C1-6 alkyl. In some embodiments, R4is hydrogen or optionally substituted Cm alkyl. In some embodiments, R4is hydrogen or unsubstituted Cm alkyl. In some embodiments, R4is hydrogen or optionally substituted methyl. In some embodiments, R4is hydrogen or methyl.

[0359]

[0351] As generally described herein, R5aand R5bare each hydrogen, or R5aand R5bare joined together with their intervening atom to form optionally substituted carbocyclyl.

[0360]

[0352] In some embodiments, R5aand R5bare each hydrogen.

[0361]

[0353] In some embodiments, R5aand R5bare joined together with their intervening atom to form optionally substituted carbocyclyl. In some embodiments, R5aand R5bare joined together with their intervening atom to form optionally substituted C3-10 carbocyclyl. In some embodiments, R5aand R5bare joined together with their intervening atom to form optionally substituted C3-6 carbocyclyl. In some embodiments, R5aand R5bare joined together with their intervening atom to form substituted C3-6 carbocyclyl. In some embodiments, R5aand R5bare joined together with their intervening atom to form unsubstituted C3-6 carbocyclyl. In some embodiments, R5aand R5bare joined together with their intervening atom to form optionally substituted cyclopropyl. In some embodiments, R5aand R5bare joined together with their intervening atom to form substituted cyclopropyl. In some embodiments, R5aand R5bare joined together with their intervening atom to form unsubstituted cyclopropyl.

[0362]

[0354] In some embodiments, R5aand R5bare each hydrogen, or R5aand R5bare joined together with their intervening atom to form optionally substituted cyclopropyl. In some embodiments, R5aand R5bare each hydrogen, or R5aand R5bare joined together with their intervening atom to form substituted cyclopropyl. In some embodiments, R5aand R5bare each hydrogen, or R5aand R5bare joined together with their intervening atom to form unsubstituted cyclopropyl.

[0363]

[0355] In some embodiments, R4is hydrogen, and R5aand R5bare each hydrogen.

[0364] Additional Subgeneric Embodiments

[0365]

[0356] In some embodiments, the compound of Formula (I) is of Formula (I-a), (I-b), or (I-c): or a pharmaceutically acceptable salt thereof.

[0366]

[0357] In some embodiments, the compound of Formula (I) is of Formula (I-a), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (I-b), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (I-c), or a pharmaceutically acceptable salt thereof.

[0367]

[0358] In some embodiments, the compound of Formula (I) is of Formula (I-a), (I-b), or (I-c), or a pharmaceutically acceptable salt thereof, wherein R3is of formula (A-2), (A-3), (A-4), (A-5), (A-6), (A- 7), (A-8), (A-9), (A-10), (A-ll), (A-12), (A-13), (A-14), (A-15), (A-16), (A-17), (A-18), (A-19), (A-20), (A-21), (A-22), (A-23), (A-24), (A-25), (A-26), (A-27), (A-28), (A-29), (A-30), (A-31), (A-32), (A-33), (A-34), (A-35), (A-36), (A-37), or (A-38). In some embodiments, the compound of Formula (I) is of Formula (I-a), (I-b), or (I-c), or a pharmaceutically acceptable salt thereof, wherein R3is of formula (A- 2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (A-9), (A-10), (A-ll), (A-12), (A-13), (A-14), (A-15), (A- 16), (A-17), (A-18), (A-19), (A-20), (A-21), (A-22), (A-23), (A-24), or (A-25).

[0368]

[0359] In some embodiments, the compound of Formula (I) is of Formula (I-a), (I-b), or (I-c), or a pharmaceutically acceptable salt thereof, wherein R3is of formula (A-2), (A-7), (A-10), (A-13), (A-14), (A-16), (A-20), (A-25), (A-26), (A-28), (A-29), (A-31), or (A-32). In some embodiments, the compound of Formula (I) is of Formula (I-a), (I-b), or (I-c), or a pharmaceutically acceptable salt thereof, wherein R3is of formula (A-2), (A-7), (A-10), (A-13), (A-14), (A-16), (A-20), or (A-25). In some embodiments, the compound of Formula (I) is of Formula (I-a), (I-b), or (I-c), or a pharmaceutically acceptable salt thereof, wherein R3is of formula (A-2b), (A-2c), (A-2d), (A-7a), (A-7b), (A-7c), (A-lOa), (A- 10b), (A- 10c), (A- 13a), (A-13b), (A-13c), (A-14b), (A-16b), (A-20b), (A-20c), (A-20d), (A-25b), (A-25c), (A- 26a), (A-28a), (A- 29a), (A-31a), or (A-32a). In some embodiments, the compound of Formula (I) is of Formula (I-a), (I-b), or (I-c), or a pharmaceutically acceptable salt thereof, wherein R3is of formula (A- 2b), (A-2c), (A-2d), (A-7a), (A-7b), (A-7c), (A-lOa), (A-lOb), (A- 10c), (A- 13a), (A- 13b), (A-13c), (A- 14b), (A-16b), (A-20b), (A-20c), (A-20d), (A-25b), or (A-25c).

[0369]

[0360] In some embodiments, the compound of Formula (I) is of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: each instance of R3ais 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, -ORA, each instance of RAis independently hydrogen, optionally substituted acyl, 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 RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and m is 0, 1, 2, 3, 4, or 5.

[0361] In some embodiments, the compound of Formula (II) is of Formula (Il-a), (II-b), or (II-c): or a pharmaceutically acceptable salt thereof.

[0370]

[0362] In some embodiments, the compound of Formula (II) is of Formula (Il-a), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) is of Formula (Il-b), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) is of Formula (II-c), or a pharmaceutically acceptable salt thereof.

[0371]

[0363] In some embodiments, the compound of Formula (II) is of Formula (II-d-1), (II-d-2), or (II-d-3): or a pharmaceutically acceptable salt thereof.

[0372]

[0364] In some embodiments, the compound of Formula (Il-d) is of Formula (II-d-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Il-d) is of Formula (II-d-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Il-d) is of Formula (II-d-3), or a pharmaceutically acceptable salt thereof.

[0373]

[0365] In some embodiments, the compound of Formula (II) is of Formula (II-e-1), (II-e-2), or (II-e-3): or a pharmaceutically acceptable salt thereof.

[0374]

[0366] In some embodiments, the compound of Formula (Il-e) is of Formula (II-e-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Il-e) is of Formula (II-e-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Il-e) is of Formula (II-e-3), or a pharmaceutically acceptable salt thereof.

[0375]

[0367] In some embodiments of Formula (II), or a subgenus thereof (e.g., Formula (Il-a), (II-b), (II-c), (II-d-1), (II-d-2), (II-d-3), (II-e-1), (II-e-2), or (II-e-3)), or a pharmaceutically acceptable salt thereof, R1is C3-6 carbocyclyl, 4-6 membered heterocyclyl containing 1 ring N atom or 1 ring O atom, 8-10 membered heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, phenyl, 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms, or 8-10 membered heteroaryl containing 1, 2, or 3 ring N atoms; wherein the carbocyclyl, heterocyclyl, phenyl, or heteroaryl is substituted with 0, 1, or 2 instances of Rlb, as valency permits; wherein each instance of Rlbis independently halogen, optionally substituted C1-4 alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -N(Rlc)2, — CN, -NO2, -C(=O)Rlc, -C(=O)ORlc, -C(=O)N(R1C)2, -C(=NR1C)N(R1C)2, or -NRlcC(=O)Rlc, or two instances of Rlbare taken together to form =0, as valency permits, or two instances of Rlbare joined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring; and each instance of Rlcis independently hydrogen, optionally substituted Cm alkyl, or optionally substituted 5-6 membered heteroaryl; and each instance of Rlcis independently hydrogen, optionally substituted Cm alkyl, or optionally substituted 5-6 membered heteroaryl.

[0376]

[0368] In some embodiments of Formula (II), or a subgenus thereof, or a pharmaceutically acceptable salt thereof, R1is unsubstituted Cm alkyl or Cm haloalkyl, and n is 0. In some embodiments of Formula (II), or a subgenus thereof, or a pharmaceutically acceptable salt thereof, R1is unsubstituted Cm alkyl. In some embodiments of Formula (II), or a subgenus thereof, or a pharmaceutically acceptable salt thereof, R1is Cm haloalkyl, and n is 0.

[0377]

[0369] In some embodiments of Formula (II), or a subgenus thereof, or a pharmaceutically acceptable salt

[0378]

[0379] 10601.7 #14415592vl

[0380] or a pharmaceutically acceptable salt thereof, wherein: each instance of R3bis independently halogen, optionally substituted alkyl, optionally substituted heterocyclyl, -CN, -N(RN)2, or -SF5, or two instances of R3bare joined together with their intervening atoms to form an optionally substituted carbocyclic ring or optionally substituted heterocyclic ring; each instance of RNis independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two instances of RNare joined together with their intervening nitrogen atom to form an optionally substituted heterocyclic ring; and p is 0, 1, 2, 3, 4, or 5, as valency permits.

[0381]

[0371] In some embodiments, the compound of Formula (I) is of Formula (Ill-a), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-b), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (III-c), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-d), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-e), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-f), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-g), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-h), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-i), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-j), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-k), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (III-l), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-m), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-n), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (III-o), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (III-p), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-q), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-r), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (III-s), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (Ill-t), or a pharmaceutically acceptable salt thereof.

[0382]

[0372] In some embodiments of Formula (Ill-a) to (III- 1) , or a pharmaceutically acceptable salt thereof, R1is C3-6 carbocyclyl, 4-6 membered heterocyclyl containing 1 ring N atom or 1 ring O atom, 8-10 membered heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, phenyl, 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms, or 8-10 membered heteroaryl containing 1, 2, or 3 ring N atoms; wherein the carbocyclyl, heterocyclyl, phenyl, or heteroaryl is substituted with 0, 1, or 2 instances of Rlb, as valency permits; wherein each instance of Rlbis independently halogen, optionally substituted C1-4 alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -N(Rlc)2, — CN, -NO2, -C(=O)Rlc, -C(=O)ORlc, -C(=O)N(R1C)2, -C(=NR1C)N(R1C)2, or -NRlcC(=O)Rlc, or two instances of Rlbare taken together to form =0, as valency permits, or two instances of Rlbare joined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring; and each instance of Rlcis independently hydrogen, optionally substituted Cm alkyl, or optionally substituted 5-6 membered heteroaryl; and each instance of Rlcis independently hydrogen, optionally substituted Cm alkyl, or optionally substituted 5-6 membered heteroaryl.

[0383]

[0373] In some embodiments of Formula (Ill-a) to (Ill-t), or a pharmaceutically acceptable salt thereof, R1is unsubstituted Cm alkyl or Cm haloalkyl, and n is 0. In some embodiments of Formula (Ill-a) to (in-t), or a pharmaceutically acceptable salt thereof, R1is unsubstituted C1-3 alkyl, and n is 0. In some embodiments of Formula (Ill-a) to (Ill-t), or a pharmaceutically acceptable salt thereof, R1is Cm haloalkyl, and n is 0. In some embodiments of Formula (Ill-e), (Ill-h), (Ill-i), (Ill-k), (III-l), (IILm), (Ill-n), or (in-o), or a pharmaceutically acceptable salt thereof, RNis hydrogen, unsubstituted C1-3 alkyl, or Cm haloalkyl. In some embodiments of Formula (Ill-e), (Ill-h), (IILi), (Ill-k), (III-l), (Ill-m), (III- n), or (III-o), or a pharmaceutically acceptable salt thereof, RNis hydrogen. In some embodiments of Formula (Ill-e), (Ill-h), (IILi), (Ill-k), (III-l), (Ill-m), (Ill-n), or (III-o), or a pharmaceutically acceptable salt thereof, RNis unsubstituted Cm alkyl. In some embodiments of Formula (Ill-e), (Ill-h), (IILi), (Ill-k), (III-l), (Ill-m), (Ill-n), or (III-o), or a pharmaceutically acceptable salt thereof, RNis Cm haloalkyl.

[0384]

[0374] In some embodiments of Formula (Ill-e), (Ill-h), (IILi), (Ill-k), (III-l), (Ill-m), (Ill-n), or (III- o), or a pharmaceutically acceptable salt thereof, R1is unsubstituted Cm alkyl or Cm haloalkyl; n is 0; and RNis hydrogen, unsubstituted Cm alkyl, or Cm haloalkyl. In some embodiments of Formula (Ill-e), (Ill-h), (IILi), (Ill-k), (III-l), (Ill-m), (Ill-n), or (III-o), or a pharmaceutically acceptable salt thereof, R1is unsubstituted Cm alkyl; n is 0; and RNis hydrogen, unsubstituted Cm alkyl, or Cm haloalkyl. In some embodiments of Formula (Ill-e), (Ill-h), (IILi), (Ill-k), (III-l), (IILm), (Ill-n), or (III-o), or a pharmaceutically acceptable salt thereof, R1is Cm haloalkyl; n is 0; and RNis hydrogen, unsubstituted Cm alkyl, or Cm haloalkyl. In some embodiments of Formula (Ill-e), (Ill-h), (IILi), (Ill-k), (III-l), (HI -m), (Ill-n), or (III-o), or a pharmaceutically acceptable salt thereof, R1is unsubstituted Cm alkyl or Cm haloalkyl; n is 0; and RNis hydrogen. In some embodiments of Formula (Ill-e), (Ill-h), (IILi), (III- k), (III-l), (Ill-m), (Ill-n) , or (III-o), or a pharmaceutically acceptable salt thereof, R1is unsubstituted Cm alkyl or Cm haloalkyl; n is 0; and RNis unsubstituted Cm alkyl. In some embodiments of Formula (Ill-e), (Ill-h), (IILi), (IILk), (IILI), (IILm), (Ill-n), or (IILo), or a pharmaceutically acceptable salt thereof, R1is unsubstituted Cm alkyl or Cm haloalkyl; n is 0; and RNis Cm haloalkyl.

[0385]

[0375] In some embodiments of Formula (Ill-a) to (Ill-t), or a pharmaceutically acceptable salt thereof,

[0386] In some embodiments of Formula (Ill-a) to (Ill-t), is of formula: -CH2CH3 or F F

[0387]

[0376] In some embodiments, the compound of Formula (I) is of Formula (IV): or a pharmaceutically acceptable salt thereof, wherein: each instance of R3ais 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, -ORA, each instance of RAis independently hydrogen, optionally substituted acyl, 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 RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;

[0388] RNis hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; and m is 0, 1, 2, 3, 4, or 5, as valency permits.

[0389]

[0377] In some embodiments of Formula (IV), or a pharmaceutically acceptable salt thereof, Ring Q is of formula (B-l). In some embodiments of Formula (IV), or a pharmaceutically acceptable salt thereof, Ring Q is of formula (C-l). In some embodiments of Formula (IV), or a pharmaceutically acceptable salt thereof, Ring Q is of formula (C-2). In some embodiments of Formula (IV), or a pharmaceutically acceptable salt thereof, Ring Q is of formula (D-l). In some embodiments of Formula (IV), or a pharmaceutically acceptable salt thereof, Ring Q is of formula (D-2). In some embodiments of Formula (IV), or a pharmaceutically acceptable salt thereof, Ring Q is of formula (D-3). In some embodiments of Formula (IV), or a pharmaceutically acceptable salt thereof, Ring Q is of formula (D-4). In some embodiments of Formula (IV), or a pharmaceutically acceptable salt thereof, Ring Q is of formula (D-5). In some embodiments of Formula (IV), or a pharmaceutically acceptable salt thereof, Ring Q is of formula (D-6). In some embodiments of Formula (IV), or a pharmaceutically acceptable salt thereof, Ring Q is of formula (D-7). In some embodiments of Formula (IV), or a pharmaceutically acceptable salt thereof, Ring Q is of formula (D-8).

[0378] In some embodiments, the compound of Formula (I) is of Formula (V): or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.

[0390]

[0379] In some embodiments of Formula (V), or a pharmaceutically acceptable salt thereof, R1is optionally substituted alkyl. In some embodiments of Formula (V), or a pharmaceutically acceptable salt thereof, R1is optionally substituted C1-6 alkyl. In some embodiments of Formula (V), or a pharmaceutically acceptable salt thereof, R1is Cm alkyl substituted with 0, 1, 2, or 3 instances of halogen. In some embodiments of Formula (V), or a pharmaceutically acceptable salt thereof, R1is Cm alkyl substituted with 0, 1, 2, or 3 instances of -F. In some embodiments of Formula (V), or a pharmaceutically acceptable salt thereof, R1is -CH3, -CH2CH3, -CF3,FF , or F

[0391]

[0380] In some embodiments, the compound of Formula (V) is of Formula (V-a) to (V-e): or a pharmaceutically acceptable salt thereof.

[0392]

[0381] In some embodiments of Formula (V), or a subgenus thereof (e.g., Formula (V-a), (V-b), (V-c), (V-d), or (V-e)), or a pharmaceutically acceptable salt thereof, R3is of formula (A-2), (A-7), (A-10), (A- 13), (A-14), (A- 16), (A-20), (A-25), (A- 26), (A-28), (A-29), (A-31), or (A-32). In some embodiments of Formula (V), or a subgenus thereof, or a pharmaceutically acceptable salt thereof, R3is of formula (A-2), (A-7), (A-10), (A-13), (A-14), (A-16), (A-20), or (A-25). In some embodiments of Formula (V), or a subgenus thereof, or a pharmaceutically acceptable salt thereof, R3is of formula (A-2b), (A-2c), (A-2d), (A-7a), (A-7b), (A-7c), (A-lOa), (A-lOb), (A-lOc), (A-13a), (A-13b), (A-13c), (A-14b), (A-16b), (A- 20b), (A- 20c), (A-20d), (A-25b), (A-25c), (A-26a), (A-28a), (A-29a), (A-31a), or (A-32a). In some embodiments of Formula (V), or a subgenus thereof, or a pharmaceutically acceptable salt thereof, R3is of formula (A-2b), (A-2c), (A-2d), (A-7a), (A-7b), (A-7c), (A-lOa), (A-lOb), (A-lOc), (A-13a), (A-13b), (A-13c), (A-14b), (A-16b), (A-20b), (A-20c), (A-20d), (A-25b), or (A-25c).

[0393]

[0382] In some embodiments of Formula (V), or a subgenus thereof, or a pharmaceutically acceptable salt thereof, R3is of formula (A-7a), (A- 10a), (A-13a), (A-26a), (A-28a), (A- 29a), (A-31a), or (A-32a). In some embodiments of Formula (V), or a subgenus thereof, or a pharmaceutically acceptable salt thereof, R3is of formula (A-2b), (A-2c), (A-2d), (A-7a), (A-7b), (A-7c), (A- 10a), (A-lOb), (A-lOc), (A-13a), (A- 13b), (A- 13c), (A- 14b), (A- 16b), (A-20b), (A-20c), (A-20d), (A-25b), or (A-25c). In some embodiments of Formula (V), or a subgenus thereof, R3is of formula (A-7a), (A-7b), (A-7c), (A-16a), (A-16b), (A- 26a), (A-28a), (A- 29a), (A-31a), or (A-32a), wherein RNis hydrogen or optionally substituted alkyl. In some embodiments of Formula (V), or a subgenus thereof, R3is of formula (A-7a), (A-7b), (A-7c), (A- 16a), (A-16b), (A-26a), (A- 28a), (A-29a), (A-31a), or (A-32a), wherein RNis hydrogen, Cm alkyl, or C1-3 haloalkyl. In some embodiments of Formula (V), or a subgenus thereof, R3is of formula (A-7a), (A- 7b), (A-7c), (A-16a), (A-16b), (A-26a), (A-28a), (A-29a), (A-31a), or (A-32a), wherein RNis hydrogen, -CH3, or -CHF2.

[0394]

[0383] In some embodiments, the compound of Formula (I) is selected from those in Tables 1-2, and pharmaceutically acceptable salts thereof. In some embodiments, the compound of Formula (I) is selected from pharmaceutically acceptable salts of those in Tables 1-2. In some embodiments, the compound of Formula (I) is selected from those in Tables 1-2.

[0395]

[0384] In some embodiments, the compound of Formula (I) is selected from those in Table 1, and pharmaceutically acceptable salts thereof. In some embodiments, the compound of Formula (I) is selected from pharmaceutically acceptable salts of those in Table 1. In some embodiments, the compound of Formula (I) is selected from those in Table 1.

[0396]

[0385] In some embodiments, the compound of Formula (I) is selected from those in Table 2, and pharmaceutically acceptable salts thereof. In some embodiments, the compound of Formula (I) is selected from pharmaceutically acceptable salts of those in Table 2. In some embodiments, the compound of Formula (I) is selected from those in Table 2.

[0397]

[0398]

[0399]

[0400]

[0401]

[0386] In another aspect, the present disclosure provides a compound selected from those in Tables 1-2, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof. In another aspect, the present disclosure provides a compound selected from those in Tables 1-2, and pharmaceutically acceptable salts and stereoisomers thereof. In another aspect, the present disclosure provides a compound selected from those in Tables 1-2, and pharmaceutically acceptable salts and tautomers thereof. In another aspect, the present disclosure provides a stereoisomer of a compound selected from those in Tables 1-2, and pharmaceutically acceptable salts thereof. In another aspect, the present disclosure provides a tautomer of a compound selected from those in Tables 1-2, and pharmaceutically acceptable salts thereof.

[0402] Pharmaceutical Compositions, Kits, and Administration

[0403]

[0387] The present disclosure provides pharmaceutical compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition described herein comprises a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, a compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0404]

[0388] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (z.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.

[0405]

[0389] Pharmaceutical compositions can be 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.

[0406]

[0390] Relative amounts of the active ingredient, the pharmaceutically acceptable carrier or 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 composition is to be administered.

[0407]

[0391] Pharmaceutically acceptable carriers / excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0408]

[0392] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, 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).

[0409]

[0393] 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 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.

[0410]

[0394] 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 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.

[0411]

[0395] 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. An effective amount may be 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.

[0412]

[0396] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be 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), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. 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.

[0413]

[0397] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise 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 may 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 a single unit dosage form. Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating and / or preventing a disease, disorder, or condition in a subject in need thereof.

[0414]

[0398] In certain embodiments, a kit described 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 provide instructions for treating a disease (e.g., cancer) in a subject in need thereof. In certain embodiments, the kits provide instructions for preventing a disease in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[0415] Methods of Modulating Protein Synthesis

[0416]

[0399] In another aspect, the present disclosure provides a method of modulating protein synthesis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a provided compound (e.g., a compound of the present disclosure, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof. In another aspect, the present disclosure provides a method of modulating protein synthesis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I), or a pharmaceutical composition thereof.

[0417]

[0400] In some embodiments, the present disclosure provides a method of modulating protein synthesis in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a provided compound, or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides a method of modulating protein synthesis in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound, or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides a provided compound, or a pharmaceutical composition thereof, for use in modulating protein synthesis in a subject in need thereof. In some embodiments, the present disclosure provides a provided compound, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for modulating protein synthesis in a subject in need thereof.

[0418]

[0401] In some embodiments modulating protein synthesis comprises modulating synthesis of a target protein. In some embodiments, modulating protein synthesis comprises decreasing protein synthesis. In some embodiments, the protein synthesis is decreased 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 some embodiments, protein synthesis is decreased by not more than about 10%, not more than about 20%, not more than about 30%, not more than about 40%, not more than about 50%, not more than about 60%, not more than about 70%, not more than about 80%, not more than about 90%, not more than about 95%, or not more than about 98%. In some embodiments, protein synthesis is decreased by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0419]

[0402] In another aspect, the present disclosure provides a method of decreasing protein synthesis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a provided compound (e.g., a compound of the present disclosure, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides a method of decreasing protein synthesis in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a provided compound, or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides a method of decreasing protein synthesis in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound, or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides a provided compound, or a pharmaceutical composition thereof, for use in decreasing protein synthesis in a subject in need thereof. In some embodiments, the present disclosure provides a provided compound, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for decreasing protein synthesis in a subject in need thereof.

[0420]

[0403] In some embodiments, decreasing protein synthesis comprises decreasing synthesis of a target protein. In some embodiments, the protein synthesis is decreased 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 some embodiments, protein synthesis is decreased by not more than about 10%, not more than about 20%, not more than about 30%, not more than about 40%, not more than about 50%, not more than about 60%, not more than about 70%, not more than about 80%, not more than about 90%, not more than about 95%, or not more than about 98%. In some embodiments, protein synthesis is decreased by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0421]

[0404] In some embodiments, the method is selective for decreasing synthesis of a first protein compared to synthesis of a second protein. In some embodiments, the ratio of the decrease in synthesis of the first protein to the decrease in synthesis of the second protein is about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.5:1, about 3:1, about 3.5:1, about 4:1, about 4.5:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 15:1, about 20:1, about 25:1, about 50:1, about 75:1, about 100:1, about 200:1, about 300:1, about 400:1, about 500:1, about 1,000:1, about 10,000:1, or about 100,000:1. In some embodiments, the ratio of the decrease in synthesis of the first protein to the decrease in synthesis of the second protein is between a ratio described in this paragraph and another ratio described in this paragraph, inclusive.

[0422]

[0405] In some embodiments, the method further comprises decreasing an amount of mRNA, wherein the mRNA is associated with synthesis of the target protein. In some embodiments, the amount of mRNA is decreased 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 some embodiments, the amount of mRNA is decreased 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 some embodiments, the amount of mRNA is decreased by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0423]

[0406] In some embodiments, the method is in vitro. In some embodiments, the method is in vivo.

[0424]

[0407] In some embodiments, the target protein is B-cell lymphoma 2 (BCL-2), MYC proto-oncogene bHLH transcription factor (MYC), cyclin DI (CCND1), myeloid cell leukemia 1 (MCL-1), anaplastic lymphoma kinase (ALK), or GTPase KRas G12D mutant (KRAS-G12D). In some embodiments, the target protein is BCL-2. In some embodiments, the target protein is MYC. In some embodiments, the target protein is CCND1. In some embodiments, the target protein is MCL-1. In some embodiments, the target protein is ALK. In some embodiments, the target protein is KRAS-G12D. The target proteins KRAS-G12D. BCL-2, MYC, CCND1, MCL-1, ALK, and KRAS-G12D are exemplary target proteins, and the methods disclosed herein are not limited to these target proteins.

[0425]

[0408] In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a HEK 293T, HPAF-II, KLE, LS411N, MCF7, NCI-H1915, HCC38, HEPG2, KATO-III, MS751, or T47D cell. In some embodiments, the cell is a HEK 293T cell. In some embodiments, the cell is a HPAF-II cell. In some embodiments, the cell is a KLE cell. In some embodiments, the cell is a LS41 IN cell. In some embodiments, the cell is a MCF7 cell. In some embodiments, the cell is a NCI-H1915 cell. In some embodiments, the cell is a HCC38 cell. In some embodiments, the cell is a HEPG2 cell. In some embodiments, the cell is a KATO-III cell. In some embodiments, the cell is a MS751 cell. In some embodiments, the cell is a T47D cell.

[0426] Methods of Treatment and Prevention

[0427]

[0409] In another aspect, the present disclosure provides a method comprising administering to a subject a provided compound (e.g., a compound of the present disclosure, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof. In another aspect, the present disclosure provides a method comprising administering to a subject a compound of Formula (I), or a pharmaceutical composition thereof.

[0428]

[0410] In another aspect, the present disclosure provides a method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a provided compound (e.g., a compound of the present disclosure, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides a method of treating a disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a provided compound, or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides a method of preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof a prophylactically effective amount of a provided compound, or a pharmaceutical composition thereof. In another aspect, the present disclosure provides a method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of Formula (I), or a pharmaceutical composition thereof. In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutical composition thereof. In another aspect, the present disclosure provides a method of preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof a prophylactically effective amount of a compound of Formula (I), or a pharmaceutical composition thereof.

[0429]

[0411] In some embodiments, the present disclosure provides a provided compound, or a pharmaceutical composition thereof, for use in treating or preventing a disease in a subject in need thereof. In some embodiments, the present disclosure provides a provided compound, or a pharmaceutical composition thereof, for use in treating a disease in a subject in need thereof. In some embodiments, the present disclosure provides a provided compound, or a pharmaceutical composition thereof, for use in preventing a disease in a subject in need thereof.

[0430]

[0412] In some embodiments, the present disclosure provides a provided compound, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease in a subject in need thereof. In some embodiments, the present disclosure provides a provided compound, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating a disease in a subject in need thereof. In some embodiments, the present disclosure provides a provided compound, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for preventing a disease in a subject in need thereof.

[0431]

[0413] In some embodiments, the disease is a proliferative disease (e.g., cancer (e.g., prostate cancer, pancreatic cancer, lung cancer, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, bladder cancer, biliary cancer, hematopoietic cancer, neuroblastoma)), neurological disease (e.g., cerebellar ataxia, neurodegenerative disease (e.g., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathy (including frontotemporal dementia), Huntington’s disease, Friedreich's ataxia)), or immune disorder (e.g., psoriasis, lupus, rheumatoid arthritis).

[0432]

[0414] In some embodiments, the disease is a proliferative disease (e.g., cancer (e.g., prostate cancer, pancreatic cancer, lung cancer, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, bladder cancer, biliary cancer, hematopoietic cancer, neuroblastoma)). In some embodiments, the proliferative disease is cancer (e.g., prostate cancer, pancreatic cancer, lung cancer, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, bladder cancer, biliary cancer, hematopoietic cancer, neuroblastoma). In some embodiments, the cancer is prostate cancer (e.g., prostate adenocarcinoma), pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast, triple-negative breast cancer (TNBC)), colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), cervical cancer (e.g., cervical adenocarcinoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma), bladder cancer, biliary cancer (e.g., cholangiocarcinoma), hematopoietic cancer (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., Waldenstrom’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 panniculitislike T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), or neuroblastoma.

[0433]

[0415] In some embodiments, the cancer is prostate cancer (e.g., prostate adenocarcinoma). In some embodiments, the cancer is prostate adenocarcinoma. In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors). In some embodiments, the cancer is pancreatic andenocarcinoma. In some embodiments, the cancer is intraductal papillary mucinous neoplasm (IPMN). In some embodiments, the cancer is Islet cell tumors. In some embodiments, the cancer is lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung). In some embodiments, the cancer is bronchogenic carcinoma. In some embodiments, the cancer is small cell lung cancer (SCLC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is adenocarcinoma of the lung. In some embodiments, the cancer is breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast, triple-negative breast cancer (TNBC)). In some embodiments, the cancer is adenocarcinoma of the breast. In some embodiments, the cancer is papillary carcinoma of the breast. In some embodiments, the cancer is mammary cancer. In some embodiments, the cancer is medullary carcinoma of the breast. In some embodiments, the cancer is triple-negative breast cancer (TNBC). In some embodiments, the cancer is colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma). In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is colorectal adenocarcinoma. In some embodiments, the cancer is endometrial cancer (e.g., uterine cancer, uterine sarcoma). In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is uterine sarcoma. In some embodiments, the cancer is ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma). In some embodiments, the cancer is cystadenocarcinoma. In some embodiments, the cancer is ovarian embryonal carcinoma. In some embodiments, the cancer is ovarian adenocarcinoma. In some embodiments, the cancer is cervical cancer (e.g., cervical adenocarcinoma). In some embodiments, the cancer is cervical adenocarcinoma. In some embodiments, the cancer is esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma). In some embodiments, the cancer is adenocarcinoma of the esophagus. In some embodiments, the cancer is Barrett’s adenocarcinoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is biliary cancer (e.g., cholangiocarcinoma). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is hematopoietic cancer (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 (z.e., Waldenstrom’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 panniculitislike T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)). In some embodiments, the cancer is leukemia (e.g., 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), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)). In some embodiments, the cancer is acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL). In some embodiments, the cancer is B-cell ALL. In some embodiments, the cancer is T-cell ALL. In some embodiments, the cancer is acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML). In some embodiments, the cancer is B-cell AML. In some embodiments, the cancer is T-cell AML. In some embodiments, the cancer is chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML). In some embodiments, the cancer is B-cell CML. In some embodiments, the cancer is T-cell CML. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL). In some embodiments, the cancer is B-cell CLL. In some embodiments, the cancer is T-cell CLL.In some embodiments, the cancer is lymphoma (e.g., Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL); nonHodgkin 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 (z.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma); T-cell NHL (e.g., 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)). In some embodiments, the cancer is Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL). In some embodiments, the cancer is B-cell HL. In some embodiments, the cancer is T-cell HL. In some embodiments, the cancer is 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 (z.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL), immunobias tic large cell lymphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma). In some embodiments, the cancer is diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma). In some embodiments, the cancer is diffuse large B-cell lymphoma. In some embodiments, the cancer is follicular lymphoma. In some embodiments, the cancer is chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL). In some embodiments, the cancer is mantle cell lymphoma (MCL). In some embodiments, the cancer is 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). In some embodiments, the cancer is mucosa- associated lymphoid tissue (MALT) lymphomas. In some embodiments, the cancer is nodal marginal zone B-cell lymphoma. In some embodiments, the cancer is splenic marginal zone B-cell lymphoma. In some embodiments, the cancer is primary mediastinal B-cell lymphoma. In some embodiments, the cancer is Burkitt lymphoma. In some embodiments, the cancer is lymphoplasmacytic lymphoma (z.e., Waldenstrom’s macroglobulinemia). In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is hairy cell leukemia (HCL). In some embodiments, the cancer is immunoblastic large cell lymphoma. In some embodiments, the cancer is precursor B -lymphoblastic lymphoma. In some embodiments, the cancer is primary central nervous system (CNS) lymphoma. In some embodiments, the cancer is T-cell NHL (e.g., 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 panniculitislike T-cell lymphoma, and anaplastic large cell lymphoma)). In some embodiments, the cancer is precursor T-lymphoblastic lymphoma / leukemia. In some embodiments, the cancer is 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, anaplastic large cell lymphoma). In some embodiments, the cancer is cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome). In some embodiments, the cancer is mycosis fungoides. In some embodiments, the cancer is Sezary syndrome. In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma. In some embodiments, the cancer is extranodal natural killer T-cell lymphoma. In some embodiments, the cancer is enteropathy type T-cell lymphoma. In some embodiments, the cancer is subcutaneous panniculitis-like T-cell lymphoma. In some embodiments, the cancer is anaplastic large cell lymphoma. In some embodiments, the cancer is a mixture of one or more leukemia / lymphoma as described above. In some embodiments, the cancer is multiple myeloma (MM). In some embodiments, the cancer is neuroblastoma.

[0416] In some embodiments, the disease is a neurological disease (e.g., cerebellar ataxia, neurodegenerative disease (e.g., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathy (including frontotemporal dementia), Huntington’s disease, Friedreich's ataxia)). In some embodiments, the neurological disease is cerebellar ataxia. In some embodiments, the neurological disease is a neurodegenerative disease e.g., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathy (including frontotemporal dementia), Huntington’s disease, Friedreich's ataxia). In some embodiments, the neurodegenerative disease is Alzheimer’s disease. In some embodiments, the neurodegenerative disease is Parkinson’s disease. In some embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis. In some embodiments, the neurodegenerative disease is tauopathy (e.g., frontotemporal dementia). In some embodiments, the neurodegenerative disease is frontotemporal dementia. In some embodiments, the neurodegenerative disease is Huntington’s disease. In some embodiments, the neurodegenerative disease is Friedreich's ataxia.

[0434]

[0417] In some embodiments, the disease is an immune disorder (e.g., psoriasis, lupus, rheumatoid arthritis). In some embodiments, the immune disorder is psoriasis. In some embodiments, the immune disorder is lupus. In some embodiments, the immune disorder is rheumatoid arthritis.

[0435]

[0418] In some embodiments, the disease is associated with BCL-2, MYC, CCND1, MCL-1, ALK, or KRAS-G12D. In some embodiments, the disease is associated with MYC, ALK, or KRAS-G12D. In some embodiments, the disease associated with BCL-2, MYC, CCND1, MCL-1, ALK, or KRAS-G12D is a proliferative disease (e.g., cancer (e.g., prostate cancer, pancreatic cancer, lung cancer, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, bladder cancer, biliary cancer, hematopoietic cancer, neuroblastoma)), neurological disease (e.g., cerebellar ataxia, neurodegenerative disease (e.g., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathy (including frontotemporal dementia), Huntington’s disease, Friedreich's ataxia)), or immune disorder (e.g., psoriasis, lupus, rheumatoid arthritis).

[0436]

[0419] In certain embodiments, the disease or disorder is cancer. In some embodiments, the cancer is breast cancer, lung cancer, prostate cancer, bladder cancer, liver cancer, colorectal cancer, endometrial cancer, ovarian cancer, pancreatic cancer, esophagus cancer, gastric cancer, esophageal cancer, uterine cancer, skin cancer, leukemia, or lymphoma.

[0437]

[0420] In some embodiments, the disease or disorder is Breast cancer, NSCLC, Prostate cancer, Bladder cancer, Colorectal cancer, Endometrial cancer, Melanoma, Ovarian cancer, Pancreatic cancer, Hepatocellular cancer, Esophagus cancer, Gastric cancer, Diffuse Large B-cell lymphoma, Uterine sarcoma, or Acute myeloid leukemia.

[0438]

[0421] In certain embodiments, the disease or disorder is Acral Lentiginous Melanoma, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adenocarcinoma of the Gastroesophageal Junction, AL Amyloidosis, ALK-Positive Anaplastic Large Cell Lymphoma, ALK-Positive Large B-Cell Lymphoma, Anal Carcinoma, Anaplastic Large Cell Lymphoma, Astrocytoma, B-Cell Acute Lymphoblastic Leukemia, B-Cell Lymphoma , B-Cell Non-Hodgkin Lymphoma, Biliary Tract Carcinoma, Bladder Carcinoma, Bladder Papillary Urothelial Neoplasm, Brain Glioblastoma, Breast Angiosarcoma, Breast Carcinoma, Bronchogenic Carcinoma, Burkitt Lymphoma, Carcinoma, Central Nervous System Neoplasm, Cholangiocarcinoma, Chondrosarcoma, Chronic Lymphocytic Leukemia, Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma, Chronic Myeloid Leukemia, Colon Carcinoma, Colorectal Adenocarcinoma, Colorectal Carcinoma, Dedifferentiated Chondrosarcoma, Desmoid-Type Fibromatosis, Desmoplastic / Nodular Medulloblastoma, Diffuse Large B-Cell Lymphoma, Diffuse Large B-Cell Lymphoma Activated B-Cell Type, Double-Hit Lymphoma, EBV-Positive Diffuse Large B-Cell Lymphoma, Endometrial Serous Adenocarcinoma, Erdheim-Chester Disease, Esophageal Adenocarcinoma, Esophageal Adenosquamous Carcinoma, Esophageal Carcinoma, Esophageal Squamous Cell Carcinoma, Ewing Sarcoma, Follicular Lymphoma, Ganglioneuroblastoma, Gastric Adenocarcinoma, Gastric Adenosquamous Carcinoma, Gastric Carcinoma, Gastric Squamous Cell Carcinoma, Germinal Center B -Cell-Like Diffuse Large B-Cell Lymphoma, Glioblastoma, Hairy Cell Leukemia, Head and Neck Carcinoma, Head and Neck Squamous Cell Carcinoma, Hematopoietic and Lymphoid Malignancy, Hepatocellular Carcinoma, High Grade B-Cell Lymphoma, High Grade B-Cell Lymphoma with MYC and BCL2 and / or BCL6 Rearrangements, High Grade Ovarian Serous Adenocarcinoma, Histiocytic and Dendritic Cell Neoplasm, Hodgkin Lymphoma, Hypopharyngeal Squamous Cell Carcinoma, Inflammatory Myofibroblastic Tumor, Intracranial Primitive Neuroectodermal Neoplasm, Intrahepatic Cholangiocarcinoma, Intraocular Lymphoma, Invasive Breast Carcinoma, Juvenile Myelomonocytic Leukemia, Langerhans Cell Histiocytosis, Large Cell / Anaplastic Medulloblastoma, Laryngeal Squamous Cell Carcinoma, Leukemia, Low Grade Glioma, Lung Adenocarcinoma, Lung Carcinoma, Lymphoma, Lymphoplasmacytic Lymphoma, Malignant Breast Neoplasm, Malignant Central Nervous System Neoplasm, Malignant Colon Neoplasm, Malignant Colorectal Neoplasm, Malignant Endometrial Neoplasm, Malignant Gastric Neoplasm, Malignant Glioma, Malignant Lung Neoplasm, Malignant Ovarian Epithelial Tumor, Malignant Ovarian Neoplasm, Malignant Pancreatic Neoplasm, Malignant Pleural Mesothelioma, Malignant Prostate Neoplasm, Malignant Solid Tumor, Malignant Thyroid Gland Neoplasm, Mantle Cell Lymphoma, Marginal Zone Lymphoma, Mature B-Cell Lymphoma / Leukemia, Mature B-Cell Non-Hodgkin Lymphoma, Mature T- Cell and NK-Cell Lymphoma / Leukemia, Medulloblastoma, Medulloblastoma with Extensive Nodularity, Melanoma, Merkel Cell Carcinoma, Multiple Myeloma, Myelodysplastic / Myeloproliferative Neoplasm, Myeloid Neoplasm, Nasopharyngeal Carcinoma, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Carcinoma, Non-Squamous Non-Small Cell Lung Carcinoma, Oral Cavity Carcinoma, Oropharyngeal Squamous Cell Carcinoma, Osteosarcoma, Ovarian Carcinoma, Pancreatic Adenocarcinoma, Pancreatic Carcinoma, Pancreatic Ductal Adenocarcinoma, Penile Carcinoma, Peripheral T-Cell Lymphoma, Primary Central Nervous System Lymphoma, Primary Cutaneous Anaplastic Large Cell Lymphoma, Primary Malignant Liver Neoplasm, Prostate Carcinoma, Rosai- Dorfman Disease, Sarcoma, Small Cell Lung Carcinoma, Small Intestinal Carcinoma, Small Intestinal Lymphoma, Small Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Soft Tissue Sarcoma, Squamous Cell Lung Carcinoma, Synovial Sarcoma, Systemic Anaplastic Large Cell Lymphoma, Thyroid Gland Follicular Carcinoma, Thyroid Gland Medullary Carcinoma, Thyroid Gland Undifferentiated (Anaplastic) Carcinoma, Transformed Non-Hodgkin Lymphoma, Triple-Hit Lymphoma, Urothelial Carcinoma, Vaginal Carcinoma, or Vulvar Carcinoma.

[0439]

[0422] In some embodiments, the disease or disorder is associated with KRAS-G12D. In some embodiments, the disease or disorder is mediated by KRAS-G12D. In some embodiments, the disease or disorder is Juvenile Myelomonocytic Leukemia, Non-Small Cell Lung Carcinoma, Pancreatic Adenocarcinoma, Malignant Ovarian Neoplasm, Colorectal Carcinoma, Malignant Endometrial Neoplasm, Cholangiocarcinoma, Malignant Solid Tumor, Malignant Ovarian Epithelial Tumor, Esophageal Adenocarcinoma, Biliary Tract Carcinoma, Carcinoma, Colorectal Adenocarcinoma, Malignant Gastric Neoplasm, Malignant Colon Neoplasm, Neuroblastoma, Malignant Colorectal Neoplasm, Pancreatic Carcinoma, Intrahepatic Cholangiocarcinoma, Melanoma, Malignant Lung Neoplasm, Myelodysplastic / Myeloproliferative Neoplasm, Pancreatic Ductal Adenocarcinoma, Thyroid Gland Follicular Carcinoma, Malignant Pancreatic Neoplasm, or Lung Adenocarcinoma.

[0440]

[0423] In some embodiments, the disease or disorder is associated with ALK. In some embodiments, the disease or disorder is mediated by ALK. In certain embodiments, the disease or disorder is Small Intestinal Carcinoma, Non-Small Cell Lung Carcinoma, Colon Carcinoma, Soft Tissue Sarcoma, Small Cell Lung Carcinoma, Astrocytoma, Rosai-Dorfman Disease, Colorectal Carcinoma, Malignant Thyroid Gland Neoplasm, Cholangiocarcinoma, Non-Squamous Non-Small Cell Lung Carcinoma, Glioblastoma, Malignant Solid Tumor, Acute Myeloid Leukemia, Leukemia, Erdheim-Chester Disease, Malignant Glioma, Hepatocellular Carcinoma, ALK-Positive Large B-Cell Lymphoma, B-Cell Non-Hodgkin Lymphoma, Thyroid Gland Medullary Carcinoma, EBV-Positive Diffuse Large B-Cell Lymphoma, Colorectal Adenocarcinoma, Systemic Anaplastic Large Cell Lymphoma, Thyroid Gland Undifferentiated (Anaplastic) Carcinoma, Malignant Colon Neoplasm, Hematopoietic and Lymphoid Malignancy, ALK-Positive Anaplastic Large Cell Lymphoma, Diffuse Large B-Cell Lymphoma, Malignant Pleural Mesothelioma, Squamous Cell Lung Carcinoma, Non-Hodgkin Lymphoma, Neuroblastoma, Ganglioneuroblastoma, Malignant Central Nervous System Neoplasm, Primary Cutaneous Anaplastic Large Cell Lymphoma, Malignant Colorectal Neoplasm, Low Grade Glioma, Gastric Carcinoma, Multiple Myeloma, Inflammatory Myofibroblastic Tumor, Pancreatic Carcinoma, Melanoma, Malignant Breast Neoplasm, Malignant Lung Neoplasm, Anaplastic Large Cell Lymphoma, Histiocytic and Dendritic Cell Neoplasm, Central Nervous System Neoplasm, Mature T-Cell and NK- Cell Lymphoma / Leukemia, Esophageal Carcinoma, Pancreatic Ductal Adenocarcinoma, Adenocarcinoma of the Gastroesophageal Junction, Langerhans Cell Histiocytosis, Lymphoma, Mature B-Cell Lymphoma / Leukemia, or Lung Adenocarcinoma.

[0441]

[0424] In certain embodiments, the disease or disorder is associated with CCND-1. In certain embodiments, the disease or disorder is mediated by CCND-1. In some embodiments, the disease or disorder is Non-Small Cell Lung Carcinoma, Malignant Ovarian Neoplasm, Soft Tissue Sarcoma, Malignant Prostate Neoplasm, Oropharyngeal Squamous Cell Carcinoma, Nasopharyngeal Carcinoma, Mature B-Cell Lymphoma / Leukemia, Lung Carcinoma, Oral Cavity Carcinoma, Primary Central Nervous System Lymphoma, Laryngeal Squamous Cell Carcinoma, Malignant Solid Tumor, Osteosarcoma, Bronchogenic Carcinoma, AL Amyloidosis, Bladder Carcinoma, Malignant Glioma, B- Cell Non-Hodgkin Lymphoma, Hypopharyngeal Squamous Cell Carcinoma, Mantle Cell Lymphoma, Squamous Cell Lung Carcinoma, Non-Hodgkin Lymphoma, Malignant Colorectal Neoplasm, Multiple Myeloma, Melanoma, Malignant Breast Neoplasm, Acral Lentiginous Melanoma, Breast Carcinoma, Dedifferentiated Chondrosarcoma, Anaplastic Large Cell Lymphoma, Head and Neck Squamous Cell Carcinoma, Histiocytic and Dendritic Cell Neoplasm, Bladder Papillary Urothelial Neoplasm, Primary Malignant Liver Neoplasm, Chondrosarcoma, Lymphoma, Malignant Pancreatic Neoplasm, or Urothelial Carcinoma.

[0442]

[0425] In some embodiments, the disease or disorder is associated with CCNEL In some embodiments, the disease or disorder is mediated by CCNEL In certain embodiments, the disease or disorder is Vaginal Carcinoma, High Grade Ovarian Serous Adenocarcinoma, Malignant Ovarian Neoplasm, Soft Tissue Sarcoma, Gastric Adenocarcinoma, Vulvar Carcinoma, Malignant Solid Tumor, Osteosarcoma, Hepatocellular Carcinoma, Penile Carcinoma, Anal Carcinoma, Synovial Sarcoma, Non-Hodgkin Lymphoma, Multiple Myeloma, Malignant Breast Neoplasm, Malignant Lung Neoplasm, Breast Carcinoma, Histiocytic and Dendritic Cell Neoplasm, Malignant Pancreatic Neoplasm, or Malignant Ovarian Epithelial Tumor.

[0443]

[0426] In certain embodiments, the disease or disorder is BCL-2. In some embodiments, the disease or disorder is mediated by BCL-2. In some embodiments, the disease or disorder is Non-Small Cell Lung Carcinoma, Burkitt Lymphoma, Small Cell Lung Carcinoma, Acute Lymphoblastic Leukemia, Follicular Lymphoma, Malignant Endometrial Neoplasm, Invasive Breast Carcinoma, Glioblastoma, Malignant Solid Tumor, Acute Myeloid Leukemia, Chronic Lymphocytic Leukemia, B-Cell Non-Hodgkin Lymphoma, Diffuse Large B-Cell Lymphoma Activated B-Cell Type, EBV-Positive Diffuse Large B- Cell Lymphoma, High Grade B-Cell Lymphoma, High Grade B-Cell Lymphoma with MYC and BCL2 and / or BCL6 Rearrangements, Triple-Hit Lymphoma, Chronic Myeloid Leukemia, Transformed Non- Hodgkin Lymphoma, Double-Hit Lymphoma, B-Cell Acute Lymphoblastic Leukemia, Hematopoietic and Lymphoid Malignancy, Diffuse Large B-Cell Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, B-Cell Lymphoma , Hodgkin Lymphoma, Diffuse Large B-Cell Lymphoma, Breast Carcinoma, Head and Neck Squamous Cell Carcinoma, Germinal Center B-Cell-Like Diffuse Large B- Cell Lymphoma, Lymphoma, or Mature B-Cell Lymphoma / Leukemia.

[0444]

[0427] In some embodiments, the disease or disorder is associated with MCL-1. In some embodiments, the disease or disorder is mediated by MCL-1. In some embodiments, the disease or disorder is Melanoma, Malignant Breast Neoplasm, Lymphoma, Non-Small Cell Lung Carcinoma, Malignant Ovarian Neoplasm, Breast Carcinoma, Acute Lymphoblastic Leukemia, Head and Neck Squamous Cell Carcinoma, Hepatocellular Carcinoma, Malignant Prostate Neoplasm, Malignant Thyroid Gland Neoplasm, Pancreatic Ductal Adenocarcinoma, Malignant Colorectal Neoplasm, Malignant Solid Tumor, or Multiple Myeloma.

[0445]

[0428] In some embodiments, the disease or disorder is associated with MYC. In certain embodiments, the disease or disorder is mediated by MYC. In some embodiments, the disease or disorder is Vaginal Carcinoma, Pancreatic Adenocarcinoma, Soft Tissue Sarcoma, Marginal Zone Lymphoma, Small Cell Lung Carcinoma, Follicular Lymphoma, Medulloblastoma, B-Cell Non-Hodgkin Lymphoma, Ewing Sarcoma, Small Lymphocytic Leukemia, Peripheral T-Cell Lymphoma, Transformed Non-Hodgkin Lymphoma, Double-Hit Lymphoma, Intraocular Lymphoma, Neuroblastoma, Merkel Cell Carcinoma, Head and Neck Squamous Cell Carcinoma, Myeloid Neoplasm, Adenocarcinoma of the Gastroesophageal Junction, Hodgkin Lymphoma, Mature B-Cell Non-Hodgkin Lymphoma, High Grade Ovarian Serous Adenocarcinoma, Gastric Squamous Cell Carcinoma, Acute Lymphoblastic Leukemia, Vulvar Carcinoma, Malignant Prostate Neoplasm, Glioblastoma, Esophageal Adenocarcinoma, Small Intestinal Lymphoma, Breast Angiosarcoma, Esophageal Squamous Cell Carcinoma, Diffuse Large B- Cell Lymphoma Activated B-Cell Type, EBV-Positive Diffuse Large B-Cell Lymphoma, High Grade B- Cell Lymphoma, High Grade B-Cell Lymphoma with MYC and BCL2 and / or BCL6 Rearrangements, Triple-Hit Lymphoma, Diffuse Large B-Cell Lymphoma, Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma, ...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I) :or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -ORla, or -N(Rla)2; each instance of Rlais independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two instances of Rlaare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;R3is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;R4is hydrogen or optionally substituted alkyl;R5aand R5bare each hydrogen, or R5aand R5bare joined together with their intervening atom to form optionally substituted carbocyclyl; each instance of Y is independently -C(RY)2-, -O-, or -N(Rla)-, or two instances of Y are taken together to form -C(RY)=C(RY)- or -C=C-; each instance of RYis independently hydrogen or halogen, or two instances of RYare taken together to form =0; and n is 0, 1, 2, 3, 4, or 5; provided that: if n is 0, then R1is not optionally substituted aryl, optionally substituted heteroaryl, -ORla, or- N(Rla)2; if n is 1, 2, 3, 4, or 5, the Y attached to the oxygen atom of the moietyR' 'n 0" / is -C(RY)2-; and if R1is -ORlaor -N(Rla)2, then the Y attached to R1is -C(RY)2-2. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein the compound isof Formula (I-a) or (I-b):or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein the compound is of Formula (I-c):or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, or pharmaceutically acceptable salt thereof, wherein R3is optionally substituted C3-10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted Ce-io aryl, or optionally substituted 5-10 membered heteroaryl.

5. The compound of any one of claims 1-4, or pharmaceutically acceptable salt thereof, wherein R3is optionally substituted C3-6 carbocyclyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted Ce aryl, or optionally substituted 5-6 membered heteroaryl.

6. The compound of any one of claims 1-5, or pharmaceutically acceptable salt thereof, wherein R3is optionally substituted phenyl.

7. The compound of any one of claims 1-6, or pharmaceutically acceptable salt thereof, wherein R3is of formula:wherein: each instance of R3ais 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, -ORA,each instance of RAis independently hydrogen, optionally substituted acyl, 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 RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and m is 0, 1, 2, 3, 4, or 5.

8. The compound of claim 7, or pharmaceutically acceptable salt thereof, wherein R3is of formula:

9. The compound of claim 7 or 8, or pharmaceutically acceptable salt thereof, wherein R3is of formula (A- Id).

10. The compound of any one of claims 1-7, wherein the compound is of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: each instance of R3ais 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, -ORA,each instance of RAis independently hydrogen, optionally substituted acyl, 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 RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and m is 0, 1, 2, 3, 4, or 5.

11. The compound of claim 10, wherein the compound is of Formula (Il-a) or (II- b):or a pharmaceutically acceptable salt thereof.

12. The compound of claim 10 or 11, wherein the compound is of Formula (II-c):or a pharmaceutically acceptable salt thereof.

13. The compound of claim 10, wherein the compound is of Formula (Il-d):or a pharmaceutically acceptable salt thereof.

14. The compound of any one of claims 10-13, wherein the compound is of Formula (II-e-1), (Il-e-2), or (II-e-3):or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 1-5, wherein the compound is of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein:each instance of R3ais 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, -ORA,each instance of RAis independently hydrogen, optionally substituted acyl, 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 groupwhen attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;RNis hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; and m is 0, 1, 2, 3, 4, or 5, as valency permits.

16. The compound of any one of claims 7-15, or pharmaceutically acceptable salt thereof, wherein at least one instance of R3ais halogen, optionally substituted alkynyl, -CN, -NO2, -ORla, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl.

17. The compound of any one of claims 7-16, or pharmaceutically acceptable salt thereof, wherein at least one instance of R3ais -ORla, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl.

18. The compound of any one of claims 7-16, or pharmaceutically acceptable salt thereof, wherein at least one instance of R3ais:-F, -Cl, -Br, -I, -CH3, -CHF2, -CF3, -CF2CH3, -C=CH, -CN, -NO2, -OH, -OCH3, -OCH2CH3,19. The compound of any one of claims 1-14 or 16-18, or pharmaceutically acceptable salt thereof, wherein R3is of formula:

20. The compound of any one of claims 1-14 or 16-19, or pharmaceutically acceptable salt thereof, wherein R3is of formula:

21. The compound of any one of claims 1-20, or pharmaceutically acceptable salt thereof, wherein R1is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionallysubstituted C2-6 alkynyl.

22. The compound of any one of claims 1-21, or pharmaceutically acceptable salt thereof, wherein R1is hydrogen, Cm alkyl, C2-3 alkenyl, or C2-3 alkynyl, wherein the alkyl, alkenyl, or alkynyl is substituted with 0, 1 , 2, or 3 instances of halogen.

23. The compound of any one of claims 1-22, or pharmaceutically acceptable salt thereof, wherein R1is hydrogen, Cm alkyl, C2-3 alkenyl, or C2-3 alkynyl, wherein the alkyl, alkenyl, or alkynyl is substituted with 0, 1 , 2, or 3 instances of -F.

24. The compound of any one of claims 1-23, or pharmaceutically acceptable salt thereof, whereinR1is: hydrogen,25. The compound of any one of claims 1-20, or pharmaceutically acceptable salt thereof, wherein R1is -ORlaor -N(Rla)2, wherein each instance of Rlais independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted Ce-io aryl, or optionally substituted 5-10 membered heteroaryl.

26. The compound of any one of claims 1-20 or 25, or pharmaceutically acceptable salt thereof, wherein R1is -ORlaor -N(Rla)2, wherein each instance of Rlais independently hydrogen, Cm alkyl, Cm heteroalkyl, C4-6 carbocyclyl, 4-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein each alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1 , 2, or 3 instances of halogen.

27. The compound of any one of claims 1-20, 25, or 26, or pharmaceutically acceptable salt thereof, wherein R1is -ORlaor -N(Rla)2, wherein each instance of Rlais independently hydrogen, Cm alkyl, Cm heteroalkyl, C4-6 carbocyclyl, 4-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl, wherein each alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1 , 2, or 3 instances of -F.

28. The compound of any one of claims 1-20 or 25-27, or pharmaceutically acceptable salt thereof, wherein R1is:

29. The compound of any one of claims 1-20, or pharmaceutically acceptable salt thereof, whereinR1is optionally substituted C3-10 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted Ce-io aryl, or optionally substituted 5-10 membered heteroaryl.

30. The compound of any one of claims 1-20 or 29, or pharmaceutically acceptable salt thereof, wherein R1is C3-6 carbocyclyl, 4-6 membered heterocyclyl containing 1 ring N atom or 1 ring O atom, 8- 10 membered heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, phenyl, 5-6 membered heteroaryl containing 1, 2, or 3 ring N atoms, or 8-10 membered heteroaryl containing 1, 2, or 3 ring N atoms; wherein the carbocyclyl, heterocyclyl, phenyl, or heteroaryl is substituted with 0, 1, or 2 instances of Rlb, as valency permits; wherein each instance of Rlbis independently halogen, optionally substituted C1-4 alkyl, optionally substituted 4-6 membered heterocyclyl, -ORlc, -N(Rlc)2, — CN, -NO2, -C(=O)R1C, -C(=O)OR1C, -C(=O)N(R1C)2, -C(=NR1C)N(R1C)2, or -NRlcC(=O)Rlc, or two instances of Rlbare taken together to form =0, as valency permits, or two instances of Rlbare joined together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring; and each instance of Rlcis independently hydrogen, optionally substituted Cm alkyl, or optionally substituted 5-6 membered heteroaryl; and each instance of Rlcis independently hydrogen, optionally substituted Cm alkyl, or optionally substituted 5-6 membered heteroaryl.

31. The compound of any one of claims 1-20, 29, or 30, or pharmaceutically acceptable salt thereof, wherein R1is:

32. The compound of any one of claims 1-31, or pharmaceutically acceptable salt thereof, wherein at least one instance of Y is -C(RY)2-33. The compound of any one of claims 1-32, or pharmaceutically acceptable salt thereof, wherein at least one instance of Y is -CH2-, -CF2-, or -C(=O)-.

34. The compound of any one of claims 1-33, or pharmaceutically acceptable salt thereof, wherein at least one instance of Y is -O-, or two instances of Y are taken together to form -C(RY)=C(RY)- or -C=C-.

35. The compound of any one of claims 1-34, or pharmaceutically acceptable salt thereof, wherein36. The compound of any one of claims 1-35, or pharmaceutically acceptable salt thereof, wherein37. The compound of any one of claims 1-36, or pharmaceutically acceptable salt thereof, wherein38. The compound of any one of claims 1-37, or pharmaceutically acceptable salt thereof, wherein39. The compound of any one of claims 1-38, or pharmaceutically acceptable salt thereof, whereinf formula: -CH3 or -CH2CH3.

40. The compound of any one of claims 1-38, or pharmaceutically acceptable salt thereof, wherein41. The compound of any one of claims 1-37, or pharmaceutically acceptable salt thereof, wherein42. The compound of any one of claims 1-37, or pharmaceutically acceptable salt thereof, wherein43. The compound of any one of claims 1-35, or pharmaceutically acceptable salt thereof, wherein44. The compound of any one of claims 1-35 or 43, or pharmaceutically acceptable salt thereof,45. The compound of any one of claims 1-35 or 43, or pharmaceutically acceptable salt thereof,46. The compound of any one of claims 1-35, 43, or 45, or pharmaceutically acceptable salt thereof,47. The compound of any one of claims 1-35, 43, or 45, or pharmaceutically acceptable salt thereof,48. The compound of any one of claims 1-35, 43, or 45, or pharmaceutically acceptable salt thereof,49. The compound of any one of claims 1-35, 43, or 45, or pharmaceutically acceptable salt thereof,50. The compound of any one of claims 1-35, 43, 45, or 49, or pharmaceutically acceptable salt51. The compound of any one of claims 1-35, 43, 45, or 49, or pharmaceutically acceptable salt52. The compound of any one of claims 1-35, 43, 45, or 49, or pharmaceutically acceptable salt53. The compound of any one of claims 1-35, 43, or 45, or pharmaceutically acceptable salt thereof,54. The compound of any one of claims 1-35, 43, 45, or 53, or pharmaceutically acceptable salt55. The compound of any one of claims 1-35, 43, 45, or 53, or pharmaceutically acceptable salt56. The compound of any one of claims 1-35, 43, or 45, or pharmaceutically acceptable salt thereof, whereinf formula:

57. The compound of any one of claims 1-56, wherein the compound is selected from those in Tables 1-2, and pharmaceutically acceptable salts thereof.

58. The compound of any one of claims 1-57, wherein the compound is selected from those in Tables 1-2.

59. A composition comprising the compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, and an excipient.

60. A method of modulating protein synthesis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of: a compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof; or the composition of claim 59.

61. The method of claim 60, wherein modulating protein synthesis comprises modulating synthesis of a target protein.

62. The method of claim 61, wherein modulating protein synthesis comprises decreasing protein synthesis.

63. A method of decreasing protein synthesis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of: a compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof; or the composition of claim 59.

64. The method of claim 63, wherein decreasing protein synthesis comprises decreasing synthesis of a target protein.

65. The method of any one of claims 61, 62, or 64, further comprising decreasing an amount of mRNA, wherein the mRNA is associated with synthesis of the target protein.

66. The method of any one of claims 61, 62, 64, or 65 wherein the target protein is B-cell lymphoma 2 (BCL-2), MYC proto-oncogene bHLH transcription factor (MYC), cyclin DI (CCND1), myeloid cell leukemia 1 (MCL-1), anaplastic lymphoma kinase (ALK), or GTPase KRas G12D mutant (KRAS- G12D)67. A method comprising administering to a subject: a compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof; orthe composition of claim 59.

68. A method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of: the compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof; or the composition of claim 59.

69. The method of claim 68, wherein the disease is associated with B-cell lymphoma 2 (BCL-2), MYC proto-oncogene bHLH transcription factor (MYC), cyclin DI (CCND1), myeloid cell leukemia 1 (MCL-1), anaplastic lymphoma kinase (ALK), or GTPase KRas G12D mutant (KRAS-G12D).

70. The method of claim 68 or 69, wherein the disease is a proliferative disease.

71. The method of claim 70, wherein the proliferative disease is cancer.

72. The method of claim 71, wherein the cancer is prostate cancer, pancreatic cancer, lung cancer, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, bladder cancer, biliary cancer, hematopoietic cancer, or neuroblastoma.

73. The method of claim 68 or 69, wherein the disease is a neurological disease.

74. The method of claim 73, wherein the neurological disease is cerebellar ataxia or a neurodegenerative disease.

75. The method of claim 68 or 69, wherein the disease is an immune disorder.

76. The method of claim 75, wherein the immune disorder is psoriasis, lupus, or rheumatoid arthritis.

77. A kit comprising : the compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, or the composition of claim 59; and instructions for use of the compound or composition.